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Bi X, Mao Z, Zhang Y, Ren Z, Yang K, Yu C, Chen L, Zheng R, Guan J, Liu Z, Yu B, Huang Y, Shu X, Zheng Y. Endogenous dual-responsive and self-adaptive silk fibroin-based scaffold with enhancement of immunomodulation for skull regeneration. Biomaterials 2025; 320:123261. [PMID: 40132357 DOI: 10.1016/j.biomaterials.2025.123261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Revised: 02/19/2025] [Accepted: 03/16/2025] [Indexed: 03/27/2025]
Abstract
Despite the current biomaterials (e.g. titanium mesh and polyether ether ketone) have been applied to clinical skull repair, the limitations on mechanical match, shape adaptability, bioactivity and osteointegration have greatly limited their clinical application. In this work, we constructed a water and inflammatory microenvironment dual-responsive self-adaptive silk fibroin-magnesium oxide-based scaffold with the matrix metalloproteinase-2-responsive gelatin-methacryloyl-interleukin-4 (IL-4) coating, which presented good mechanical compliance, quickly shape matching and intraoperative reprocessability. With the capability of responding to an acute inflammation microenvironment followed by a triggered on-demand release of the IL-4, the combination of immunoactive IL-4 and Mg2+ co-ordinately facilitated metabolic reprogramming by suppressing glycolysis, promoting mitochondrial oxidative phosphorylation and modulating adenosine 5'-monophosphate-activated protein kinase (AMPK) signalling pathways in macrophages, resulting in significantly facilitating M2 macrophage activation. During the stage of tissue remodelling, the sustained release of Mg2+ further promoted macrophage M2 polarization and the expression of anti-inflammatory cytokines, significantly reduced immune response and improved ectopic osteogenesis ability. Meanwhile, the cranial defect models of male rats demonstrated that this scaffold could significantly enhance biomineralized deposition and vascularisation, and achieve good bone regeneration of cranial defects. Overall, the bioactive scaffold provides a promising biomaterial and alternative repair strategy for critical-size skull defect repair.
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Affiliation(s)
- Xuewei Bi
- Shenzhen Engineering Laboratory of Orthopaedic Regenerative Technologies, Department of Spine Surgery, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Guangdong province, China; School of Materials Science and Engineering, Peking University, Beijing, 100871, China
| | - Zhinan Mao
- Shenzhen Engineering Laboratory of Orthopaedic Regenerative Technologies, Department of Spine Surgery, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Guangdong province, China; School of Materials Science and Engineering, Peking University, Beijing, 100871, China.
| | - Yilin Zhang
- Key Laboratory of Biomechanics and Mechanobiology (Beihang University), Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing 100083, China
| | - Zeqi Ren
- School of Materials Science and Engineering, Peking University, Beijing, 100871, China
| | - Kang Yang
- School of Materials Science and Engineering, Anhui University of Technology, Maanshan 243002, China
| | - Chunhao Yu
- School of Materials Science and Engineering, Peking University, Beijing, 100871, China; School of Life, Beijing Institute of Technology, No.5, Zhongguancun South Street, Haidian District, Beijing, China
| | - Lei Chen
- Beijing Research Institute of Orthopedics and Traumatology, Beijing Jishuitan Hospital, Capital Medical University, Beijing, 100035, China
| | - Rui Zheng
- Beijing Research Institute of Orthopedics and Traumatology, Beijing Jishuitan Hospital, Capital Medical University, Beijing, 100035, China
| | - Juan Guan
- International Research Center for Advanced Structural and Biomaterials, School of Materials Science & Engineering, Beihang University, Beijing 100191, China
| | - Zhenhai Liu
- Beijing Research Institute of Orthopedics and Traumatology, Beijing Jishuitan Hospital, Capital Medical University, Beijing, 100035, China
| | - Binsheng Yu
- Shenzhen Engineering Laboratory of Orthopaedic Regenerative Technologies, Department of Spine Surgery, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Guangdong province, China
| | - Yongcan Huang
- Shenzhen Engineering Laboratory of Orthopaedic Regenerative Technologies, Department of Spine Surgery, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Guangdong province, China.
| | - Xiong Shu
- Beijing Research Institute of Orthopedics and Traumatology, Beijing Jishuitan Hospital, Capital Medical University, Beijing, 100035, China.
| | - Yufeng Zheng
- School of Materials Science and Engineering, Peking University, Beijing, 100871, China.
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2
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Zhang Q, Li J, Jia J, He S, Mei A, Zhang Z, Cao Y, Zhang X, Zhang Y, Li Z, Luo G. Topology scaffolds-enhanced paracrine of BMSCs through mechanotransduction-related metabolism reprogramming for burn wounds healing. Biomaterials 2025; 324:123518. [PMID: 40561655 DOI: 10.1016/j.biomaterials.2025.123518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2025] [Revised: 05/29/2025] [Accepted: 06/17/2025] [Indexed: 06/28/2025]
Abstract
Paracrine function of mesenchymal stem cells (MSCs) plays the core role in applying for tissue regeneration and repair, which can be enhanced by various strategies. However, the underlying law and mechanism of enhancing paracrine function through topology structures remain deficiency. Herein, a series of topology scaffolds are developed to culture bone marrow mesenchymal stem cells (BMSCs) without additional biochemical stimulators, which can significantly promote paracrine-related cytokines expression through mediating cytoskeleton-related mechanotransduction. Topology scaffolds prove that the paracrine function of BMSCs positively correlates to the limited spreading state of cells, while independent of cell shape or specific topology structures. The enhancement in the paracrine function of BMSCs originates from mechanotransduction-related metabolism reprogramming, dominated by depressing cytoskeleton spreading on topology scaffolds. Up-regulated paracrine-related cytokines can effectively enhance vascularization, inhibit apoptosis, depress inflammatory responses, and promote anti-inflammatory cytokines expression. Topology scaffolds-enhanced paracrine of BMSCs can significantly promote healing rate and quality of deep II-degree burn wounds, based on inhibiting inflammatory levels and enhancing collagen deposition and angiogenesis. The novel strategy may overcome side effects of MSCs therapy and can extend topology scaffolds to more complicated tissue repairing situation.
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Affiliation(s)
- Qingrong Zhang
- Institute of Burn Research, Chongqing Key Laboratory of Wound Repair and Tissue Regeneration, Southwest Hospital & State Key Lab of Trauma and Chemical Poisoning, Army Medical University (Third Military Medical University), Chongqing, 400038, PR China; Department of Burn and Plastic Surgery, Affiliated Hospital of Nantong University, Nantong, 226001, PR China
| | - Jiangfeng Li
- Institute of Burn Research, Chongqing Key Laboratory of Wound Repair and Tissue Regeneration, Southwest Hospital & State Key Lab of Trauma and Chemical Poisoning, Army Medical University (Third Military Medical University), Chongqing, 400038, PR China
| | - Jiezhi Jia
- Institute of Burn Research, Chongqing Key Laboratory of Wound Repair and Tissue Regeneration, Southwest Hospital & State Key Lab of Trauma and Chemical Poisoning, Army Medical University (Third Military Medical University), Chongqing, 400038, PR China
| | - Sicen He
- Institute of Burn Research, Chongqing Key Laboratory of Wound Repair and Tissue Regeneration, Southwest Hospital & State Key Lab of Trauma and Chemical Poisoning, Army Medical University (Third Military Medical University), Chongqing, 400038, PR China
| | - Ailian Mei
- Department of Burn and Plastic Surgery, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, PR China
| | - Zeying Zhang
- Key Laboratory of Green Printing, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences (ICCAS), Beijing Engineering Research Center of Nanomaterials for Green Printing Technology, Beijing National Laboratory for Molecular Sciences (BNLMS), Beijing, 100190, PR China
| | - Yunchang Cao
- Institute of Burn Research, Chongqing Key Laboratory of Wound Repair and Tissue Regeneration, Southwest Hospital & State Key Lab of Trauma and Chemical Poisoning, Army Medical University (Third Military Medical University), Chongqing, 400038, PR China
| | - Xiaorong Zhang
- Institute of Burn Research, Chongqing Key Laboratory of Wound Repair and Tissue Regeneration, Southwest Hospital & State Key Lab of Trauma and Chemical Poisoning, Army Medical University (Third Military Medical University), Chongqing, 400038, PR China
| | - Yi Zhang
- Department of Burn and Plastic Surgery, Affiliated Hospital of Nantong University, Nantong, 226001, PR China.
| | - Zheng Li
- Institute of Burn Research, Chongqing Key Laboratory of Wound Repair and Tissue Regeneration, Southwest Hospital & State Key Lab of Trauma and Chemical Poisoning, Army Medical University (Third Military Medical University), Chongqing, 400038, PR China.
| | - Gaoxing Luo
- Institute of Burn Research, Chongqing Key Laboratory of Wound Repair and Tissue Regeneration, Southwest Hospital & State Key Lab of Trauma and Chemical Poisoning, Army Medical University (Third Military Medical University), Chongqing, 400038, PR China.
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3
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Zhao M, Xiang J, Meng Y, Sun H, Yang W, Li Z, Li K, Zhang Q, Ao Z, Han D. Astragalus Polysaccharide Hydrogels with Drug-Carrying Super Self-Assembly from Natural Herbs Promote Wound Healing. ACS NANO 2025; 19:21571-21588. [PMID: 40459062 DOI: 10.1021/acsnano.5c03744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2025]
Abstract
The regulation of the immune microenvironment is a key component of wound healing, where suitable wound dressings with skin immunoreactivity can favorably affect the immune process and promote the repairing progress. Therefore, we developed an injectable photo-cross-linkable composite hydrogel─oxidized astragalus polysaccharide and carboxymethyl chitosan/sodium methacrylated alginate and magnesium ions hydrogel (OAPS-CMC/SAMA-Mg2+, OCS) loaded with curcumin (Cur)-encapsulated Achyranthes bidentata supramolecular self-assemblies (NX SSA) (NX@Cur)─termed OCS/NX@Cur to synergistically accelerate skin repair. The astragalus polysaccharide-dominated hydrogel matrix provided a superior anti-inflammatory ability. Meanwhile, NX@Cur provided strong angiogenesis and accelerated collagen deposition. In cellular experiments and a rat model of total skin defects, the OCS/NX@Cur exhibited superior anti-inflammatory, antioxidant, and angiogenic capabilities. These properties modulated the inflammatory environment of the wound, thereby promoting the formation of granulation tissue and neovascularization and accelerating collagen deposition and re-epithelialization. In conclusion, OCS/NX@Cur showed excellent wound repair capabilities, providing a potential therapeutic option for the combination of super self-assembly and natural polysaccharide hydrogels for wound repair.
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Affiliation(s)
- Mingyuan Zhao
- CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jiawei Xiang
- CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yuan Meng
- CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Huizhen Sun
- CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Wenxiao Yang
- Hebei Key Lab of Nano-biotechnology, Hebei Key Lab of Applied Chemistry, Yanshan University, Qinhuangdao 066004, China
| | - Zhongxian Li
- CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Kai Li
- Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, College of Basic Medicine, Hubei University of Medicine, Shiyan 442000, China
| | - Qiang Zhang
- Hebei Key Lab of Nano-biotechnology, Hebei Key Lab of Applied Chemistry, Yanshan University, Qinhuangdao 066004, China
| | - Zhuo Ao
- CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China
| | - Dong Han
- CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China
- University of Chinese Academy of Sciences, Beijing 100049, China
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4
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Bülow JM, Rinderknecht H, Becker N, Köhler K, Wagner A, Yang Y, Bundkirchen K, Neunaber C, Relja B. Exploring the Bone-Liver Axis: Impact of Acute Ethanol Intoxication on Post-Traumatic Liver Inflammation and Damage Following Femur Fracture. Int J Mol Sci 2025; 26:4923. [PMID: 40430063 PMCID: PMC12112679 DOI: 10.3390/ijms26104923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2025] [Revised: 05/12/2025] [Accepted: 05/18/2025] [Indexed: 05/29/2025] Open
Abstract
Bone fracture activates the immune system and induces inflammation crucial for fracture healing but may also affect trauma-distant organs like the liver. Acute alcohol intoxication (AAI) dysregulates immune responses and affects organ damage post-trauma. However, the bone-liver axis and alcohol's role in this process remain poorly understood. This study explores liver inflammation and damage following fracture, with and without prior AAI. Twenty-four male C57BL/6J mice were randomly assigned to four groups (n = 6) and received either NaCl (control) or 35% ethanol via gavage. Mice underwent femur osteotomy with external fixation or sham surgery. After 24 h, liver damage was assessed using hematoxylin-eosin and activated caspase-3 staining. Liver inflammation was evaluated through CXCL1 and polymorphonuclear leukocyte (PMNL) immunostaining, cytokine gene and protein expression analyses, and immune cell profiling in the liver via flow cytometry. Western blotting assessed NF-κB and Wnt signaling. Neither fracture alone nor with AAI caused significant liver damage. However, fracture significantly increased PMNL infiltration and altered monocyte populations, effects that were amplified by AAI. The hepatic neutrophil-to-monocyte ratio significantly decreased after fracture and was absent in the fracture AAI group. CXCL1 increased post-fracture, while MCP-1 and IL-10 decreased significantly, with AAI further significantly amplifying these changes. Wnt1 and Wnt3a levels increased significantly after fracture and were further strongly elevated by AAI. AAI completely abolished fracture-induced significant β-catenin reduction and significantly increased its phosphorylation, effects that potentially involve an AAI-induced β-catenin stabilization as well as its increased degradation. NF-κB activation was significantly decreased, while A20 expression significantly increased after fracture and AAI. Fracture influences the inflammatory liver response and signaling pathways, effects which were further modulated by AAI.
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Affiliation(s)
- Jasmin Maria Bülow
- Department of Trauma, Hand, Plastic and Reconstructive Surgery, Translational and Experimental Trauma Research, Ulm University Medical Center, 89081 Ulm, Germany; (J.M.B.); (H.R.); (N.B.); (A.W.); (Y.Y.)
| | - Helen Rinderknecht
- Department of Trauma, Hand, Plastic and Reconstructive Surgery, Translational and Experimental Trauma Research, Ulm University Medical Center, 89081 Ulm, Germany; (J.M.B.); (H.R.); (N.B.); (A.W.); (Y.Y.)
| | - Nils Becker
- Department of Trauma, Hand, Plastic and Reconstructive Surgery, Translational and Experimental Trauma Research, Ulm University Medical Center, 89081 Ulm, Germany; (J.M.B.); (H.R.); (N.B.); (A.W.); (Y.Y.)
| | - Kernt Köhler
- Institute of Veterinary Pathology, Justus Liebig University Giessen, 35390 Giessen, Germany;
| | - Alessa Wagner
- Department of Trauma, Hand, Plastic and Reconstructive Surgery, Translational and Experimental Trauma Research, Ulm University Medical Center, 89081 Ulm, Germany; (J.M.B.); (H.R.); (N.B.); (A.W.); (Y.Y.)
| | - Yuntao Yang
- Department of Trauma, Hand, Plastic and Reconstructive Surgery, Translational and Experimental Trauma Research, Ulm University Medical Center, 89081 Ulm, Germany; (J.M.B.); (H.R.); (N.B.); (A.W.); (Y.Y.)
| | - Katrin Bundkirchen
- Hannover Medical School, Department of Trauma Surgery, 30625 Hannover, Germany; (K.B.); (C.N.)
| | - Claudia Neunaber
- Hannover Medical School, Department of Trauma Surgery, 30625 Hannover, Germany; (K.B.); (C.N.)
| | - Borna Relja
- Department of Trauma, Hand, Plastic and Reconstructive Surgery, Translational and Experimental Trauma Research, Ulm University Medical Center, 89081 Ulm, Germany; (J.M.B.); (H.R.); (N.B.); (A.W.); (Y.Y.)
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5
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Nazari M, Taremi S, Elahi R, Mostanadi P, Esmeilzadeh A. Therapeutic Properties of M2 Macrophages in Chronic Wounds: An Innovative Area of Biomaterial-Assisted M2 Macrophage Targeted Therapy. Stem Cell Rev Rep 2025; 21:390-422. [PMID: 39556244 DOI: 10.1007/s12015-024-10806-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/16/2024] [Indexed: 11/19/2024]
Abstract
Wound healing is a dynamic, multi-stage process essential for restoring skin integrity. Dysregulated wound healing is often linked to impaired macrophage function, particularly in individuals with chronic underlying conditions. Macrophages, as key regulators of wound healing, exhibit significant phenotypic diversity, ranging from the pro-healing M2 phenotype to the pro-inflammatory M1 phenotype. Imbalances in the M1/M2 ratio or hyperactivation of the M1 phenotype can delay the normal healing. Consequently, strategies aimed at suppressing the M1 phenotype or promoting the shift of local skin macrophages toward the M2 phenotype can potentially treat chronic non-healing wounds. This manuscript provides an overview of macrophages' role in normal and pathological wound-healing processes. It examines various therapeutic approaches targeting M2 macrophages, such as ex vivo-activated macrophage therapy, immunopharmacological strategies, and biomaterial-directed macrophage polarization. However, it also highlights that M2 macrophage therapies and immunopharmacological interventions may have drawbacks, including rapid phenotypic changes, adverse effects on other skin cells, biotoxicity, and concerns related to biocompatibility, stability, and drug degradation. Therefore, there is a need for more targeted macrophage-based therapies that ensure optimal biosafety, allowing for effective reprogramming of dysregulated macrophages and improved therapeutic outcomes. Recent advances in nano-biomaterials have demonstrated promising regenerative potential compared to traditional treatments. This review discusses the progress of biomaterial-assisted macrophage targeting in chronic wound repair and addresses the challenges faced in its clinical application. Additionally, it explores novel design concepts for combinational therapies, such as incorporating regenerative particles like exosomes into dressing materials or encapsulating them in microneedling systems to enhance wound healing rates.
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Affiliation(s)
- Mahdis Nazari
- School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Siavash Taremi
- School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Reza Elahi
- School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Parsa Mostanadi
- School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Abdolreza Esmeilzadeh
- Department of Immunology, Zanjan University of Medical Sciences, Zanjan, Iran.
- Cancer Gene Therapy Research Center, Zanjan University of Medical Sciences, Zanjan, Iran.
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6
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Steele LA, Hernaez Estrada B, Spiller KL. Effects of a Bioengineered Allogeneic Cellularized Construct (BACC) on Primary Human Macrophage Phenotype. Adv Healthc Mater 2025; 14:e2303044. [PMID: 38507713 DOI: 10.1002/adhm.202303044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 03/01/2024] [Indexed: 03/22/2024]
Abstract
The mechanisms behind the pro-healing effects of multicellular, bioengineered allogeneic cellularized constructs (BACC) are not known. Macrophages are key regulators of every phase of the wound healing process and the primary cells that mediate the response to biomaterials. It is hypothesized that cells within the BACC modulate macrophage behavior, which may contribute to the mechanism by which BACC promotes healing. To probe the influence of cells within the BACC compared to effects of the underlying collagen substrate, primary human macrophages are cultured in direct or indirect contact with BACC or with the same collagen substrate used in the BACC manufacturing. Macrophage phenotype is characterized over time via multiplex gene expression, protein secretion, multidimensional flow cytometry, and functional assays with fibroblasts and endothelial cells. The BACC causes macrophages to exhibit a predominately reparative phenotype over time compared to relevant collagen substrate controls, with multiple subpopulations expressing both pro-inflammatory and reparative markers. Conditioned media from macrophage-BACC co-cultures causes distinct effects on fibroblast and endothelial cell proliferation, migration, and network formation. Given the critical role of the reparative macrophage phenotype in wound healing, these results suggest that modulation of macrophage phenotype may be a critical part of the mechanisms behind BACC's pro-healing effects.
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Affiliation(s)
- Lindsay A Steele
- School of Biomedical Engineering, Science, and Health Systems, Drexel University, Philadelphia, PA, 19104, USA
| | - Beatriz Hernaez Estrada
- School of Biomedical Engineering, Science, and Health Systems, Drexel University, Philadelphia, PA, 19104, USA
| | - Kara L Spiller
- School of Biomedical Engineering, Science, and Health Systems, Drexel University, Philadelphia, PA, 19104, USA
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7
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Isali I, McClellan P, Wong TR, Hijaz S, Fletcher DR, Liu G, Bonfield TL, Anderson JM, Hijaz A, Akkus O. Differential effects of macrophage subtype-specific cytokines on fibroblast proliferation and endothelial cell function in co-culture system. J Biomed Mater Res A 2025; 113:e37799. [PMID: 39295242 DOI: 10.1002/jbm.a.37799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 08/25/2024] [Accepted: 09/06/2024] [Indexed: 09/21/2024]
Abstract
Macrophages are involved in several critical activities associated with tissue repair and regeneration. Current approaches in regenerative medicine are focusing on leveraging the innate immune response to accelerate tissue regeneration and improve long-term healing outcomes. Of particular interest in this regard are the currently known, four main M2 macrophage subtypes: M2interleukin (IL)-4,IL-13, M2IC, M2IL-10, M2non-selective adenosine receptor agonists (NECA) (M2IL-4,IL-13 → M2NECA). In this study, rat bone marrow-derived macrophages (M0) were polarized to each of the four subtypes M2IL-4,IL-13 → M2NECA and cultured for 72 h in vitro. Luminex assay results highlighted increased production of tissue inhibitor of metalloproteinases-1 (TIMP-1) for M2IL-4,IL-13, higher amounts of transforming growth factor-beta 1 (TGF-β1) for M2IL-10, and elevated vascular endothelial growth factor A (VEGF-A) from M2NECA. Co-culture experiments performed with M2IL-10 macrophages and L929 fibroblasts highlighted the increased production of soluble collagen within the media as well as higher amounts of collagen in the extracellular matrix. Human umbilical vein endothelial cells (HUVECs) were co-cultured with M2NECA macrophages, which demonstrated an increase in intercellular adhesion molecule (ICAM) and platelet endothelial cell adhesion molecule (PECAM), as well as increased formation of endothelial tubes. The findings of this study emphasize a critical demand for further characterization and analyses of distinct M2 subtypes and careful selection of specific macrophage populations for regeneration of specific tissue types. The current, broad classification of "M2" may be sufficient in many general tissue engineering applications, but, as conditions are constantly in flux within the microenvironment in vivo, a higher degree of specificity and control over the initial M2 subtype could result in more consistent long-term outcomes where macrophages are utilized as part of an overall regenerative strategy.
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Affiliation(s)
- Ilaha Isali
- Department of Urology, Weill Cornell Medicine, New York, New York, USA
| | - Phillip McClellan
- Department of Mechanical and Aerospace Engineering, Case Western Reserve University, Cleveland, Ohio, USA
| | - Thomas R Wong
- Department of Urology, Case Western Reserve University, Cleveland, Ohio, USA
| | - Sara Hijaz
- Department of Urology, Case Western Reserve University, Cleveland, Ohio, USA
| | - David R Fletcher
- Case Western Reserve University, Department of Genetics and Genome Sciences, Cleveland, Ohio, USA
| | - Guiming Liu
- Department of Anatomy and Neurobiology, Northeast Ohio Medical University (NEOMED), Rootstown, Ohio, USA
| | - Tracey L Bonfield
- Case Western Reserve University, Department of Genetics and Genome Sciences, Cleveland, Ohio, USA
| | - James M Anderson
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA
| | - Adonis Hijaz
- Department of Urology, Case Western Reserve University, Cleveland, Ohio, USA
| | - Ozan Akkus
- Department of Mechanical and Aerospace Engineering, Case Western Reserve University, Cleveland, Ohio, USA
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, USA
- Department of Orthopedics, Case Western Reserve University, Cleveland, Ohio, USA
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8
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Chen YJN, Shi RC, Xiang YC, Fan L, Tang H, He G, Zhou M, Feng XZ, Tan JD, Huang P, Ye X, Zhao K, Fu WY, Li LL, Bian XT, Chen H, Wang F, Wang T, Zhang CK, Zhou BH, Chen W, Liang TT, Lv JT, Kang X, Shi YX, Kim E, Qin YH, Hettinghouse A, Wang KD, Zhao XL, Yang MY, Tang YZ, Piao HL, Guo L, Liu CJ, Miao HM, Tang KL. Malate initiates a proton-sensing pathway essential for pH regulation of inflammation. Signal Transduct Target Ther 2024; 9:367. [PMID: 39737965 PMCID: PMC11683149 DOI: 10.1038/s41392-024-02076-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 11/14/2024] [Accepted: 11/15/2024] [Indexed: 01/01/2025] Open
Abstract
Metabolites can double as a signaling modality that initiates physiological adaptations. Metabolism, a chemical language encoding biological information, has been recognized as a powerful principle directing inflammatory responses. Cytosolic pH is a regulator of inflammatory response in macrophages. Here, we found that L-malate exerts anti-inflammatory effect via BiP-IRF2BP2 signaling, which is a sensor of cytosolic pH in macrophages. First, L-malate, a TCA intermediate upregulated in pro-inflammatory macrophages, was identified as a potent anti-inflammatory metabolite through initial screening. Subsequent screening with DARTS and MS led to the isolation of L-malate-BiP binding. Further screening through protein‒protein interaction microarrays identified a L-malate-restrained coupling of BiP with IRF2BP2, a known anti-inflammatory protein. Interestingly, pH reduction, which promotes carboxyl protonation of L-malate, facilitates L-malate and carboxylate analogues such as succinate to bind BiP, and disrupt BiP-IRF2BP2 interaction in a carboxyl-dependent manner. Both L-malate and acidification inhibit BiP-IRF2BP2 interaction, and protect IRF2BP2 from BiP-driven degradation in macrophages. Furthermore, both in vitro and in vivo, BiP-IRF2BP2 signal is required for effects of both L-malate and pH on inflammatory responses. These findings reveal a previously unrecognized, proton/carboxylate dual sensing pathway wherein pH and L-malate regulate inflammatory responses, indicating the role of certain carboxylate metabolites as adaptors in the proton biosensing by interactions between macromolecules.
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Affiliation(s)
- Yu-Jia-Nan Chen
- Department of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, 400038, China.
- Department of Pathophysiology, College of High Altitude Military Medicine, Army Medical University, Chongqing, 400038, China.
- Department of Orthopedic Surgery, NYU Grossman School of Medicine, New York, NY, 10003, USA.
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases & Department of Neurology, The First Affiliated Hospital, Chongqing Medical University, 400016, Chongqing, China.
- Department of Biochemistry and Molecular Biology, Army Medical University, Chongqing, 400038, China.
| | - Rong-Chen Shi
- Department of Pathophysiology, College of High Altitude Military Medicine, Army Medical University, Chongqing, 400038, China
- Department of Biochemistry and Molecular Biology, Army Medical University, Chongqing, 400038, China
| | - Yuan-Cai Xiang
- Department of Pathophysiology, College of High Altitude Military Medicine, Army Medical University, Chongqing, 400038, China
- Department of Biochemistry and Molecular Biology, Army Medical University, Chongqing, 400038, China
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Li Fan
- Department of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, 400038, China
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases & Department of Neurology, The First Affiliated Hospital, Chongqing Medical University, 400016, Chongqing, China
| | - Hong Tang
- Department of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, 400038, China
| | - Gang He
- Department of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, 400038, China
| | - Mei Zhou
- Department of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, 400038, China
| | - Xin-Zhe Feng
- Department of Orthopedic Surgery, NYU Grossman School of Medicine, New York, NY, 10003, USA
| | - Jin-Dong Tan
- Department of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, 400038, China
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Pan Huang
- Department of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, 400038, China
| | - Xiao Ye
- Department of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, 400038, China
| | - Kun Zhao
- Department of Pathophysiology, College of High Altitude Military Medicine, Army Medical University, Chongqing, 400038, China
- Department of Biochemistry and Molecular Biology, Army Medical University, Chongqing, 400038, China
| | - Wen-Yu Fu
- Department of Orthopedic Surgery, NYU Grossman School of Medicine, New York, NY, 10003, USA
- Department of Orthopedics and Rehabilitations, Yale University School of Medicine, New Haven, CT, 06519, USA
| | - Liu-Li Li
- Department of Pathophysiology, College of High Altitude Military Medicine, Army Medical University, Chongqing, 400038, China
| | - Xu-Ting Bian
- Department of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, 400038, China
| | - Huan Chen
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China
| | - Feng Wang
- Department of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, 400038, China
| | - Teng Wang
- Department of Pathophysiology, College of High Altitude Military Medicine, Army Medical University, Chongqing, 400038, China
- Department of Biochemistry and Molecular Biology, Army Medical University, Chongqing, 400038, China
| | - Chen-Ke Zhang
- Department of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, 400038, China
| | - Bing-Hua Zhou
- Department of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, 400038, China
| | - Wan Chen
- Department of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, 400038, China
| | - Tao-Tao Liang
- Department of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, 400038, China
| | - Jing-Tong Lv
- Department of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, 400038, China
| | - Xia Kang
- Department of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, 400038, China
- Department of Pathophysiology, College of High Altitude Military Medicine, Army Medical University, Chongqing, 400038, China
- Department of Biochemistry and Molecular Biology, Army Medical University, Chongqing, 400038, China
| | - You-Xing Shi
- Department of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, 400038, China
| | - Ellen Kim
- Department of Orthopedic Surgery, NYU Grossman School of Medicine, New York, NY, 10003, USA
| | - Yin-Hua Qin
- Department of Anatomy, Engineering Research Center for Organ Intelligent Biological Manufacturing of Chongqing, Key Lab for Biomechanics and Tissue Engineering of Chongqing, Army Medical University, Chongqing, 400038, China
| | - Aubryanna Hettinghouse
- Department of Orthopedic Surgery, NYU Grossman School of Medicine, New York, NY, 10003, USA
| | - Kai-di Wang
- Department of Orthopedic Surgery, NYU Grossman School of Medicine, New York, NY, 10003, USA
- Department of Medical Experimental Center, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, 266000, China
| | - Xiang-Li Zhao
- Department of Orthopedic Surgery, NYU Grossman School of Medicine, New York, NY, 10003, USA
- Department of Orthopedics and Rehabilitations, Yale University School of Medicine, New Haven, CT, 06519, USA
| | - Ming-Yu Yang
- Department of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, 400038, China
| | - Yu-Zhen Tang
- Department of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, 400038, China
| | - Hai-Long Piao
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China
| | - Lin Guo
- Department of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, 400038, China.
| | - Chuan-Ju Liu
- Department of Orthopedic Surgery, NYU Grossman School of Medicine, New York, NY, 10003, USA.
- Department of Orthopedics and Rehabilitations, Yale University School of Medicine, New Haven, CT, 06519, USA.
| | - Hong-Ming Miao
- Department of Pathophysiology, College of High Altitude Military Medicine, Army Medical University, Chongqing, 400038, China.
- Jinfeng Laboratory, Chongqing, 401329, China.
| | - Kang-Lai Tang
- Department of Orthopedic Surgery/Sports Medicine Center, Southwest Hospital, Army Medical University, Chongqing, 400038, China.
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9
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Lee IN, Stening JZ, Rose FRAJ, White LJ. Functional interleukin-4 releasing microparticles impact THP-1 differentiated macrophage phenotype. Front Bioeng Biotechnol 2024; 12:1496111. [PMID: 39564101 PMCID: PMC11573512 DOI: 10.3389/fbioe.2024.1496111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Accepted: 10/14/2024] [Indexed: 11/21/2024] Open
Abstract
Introduction Macrophage cell therapies offer potential treatment in inflammatory diseases due to their ability to mobilize and stimulate their environment. However, successful treatment requires a pro-regenerative macrophage phenotype to be retained in vivo. Polymeric microparticles may provide a potential route to direct and sustain macrophage phenotype. Interleukin-4 (IL-4) is the most commonly used cytokine for in vitro modulation towards M2a macrophage phenotype. We designed IL-4 encapsulated microparticles to investigate the impact of drug release kinetics and developed a robust human peripheral blood monocyte cell (THP-1) in vitro assay to assess functional IL-4 release upon macrophage phenotype. Methods IL-4 was encapsulated with human serum albumin (HSA) in microparticles fabricated from a blend of PLGA and a PLGA-PEG-PLGA triblock copolymer. Functional release of IL-4 and HSA over different time periods was measured using ELISAs. THP-1 differentiated macrophages were cultured either in direct contact with microparticles or indirectly through transwells. The immunomodulatory impact of microparticles on THP-1 cells were measured using ELISA and qPCR. Results and Discussion IL-4 release kinetics fit with the first-order release kinetics model, indicating concentration dependent release. IL-4/HSA encapsulated microparticles modulated THP-1 differentiated macrophages towards pro-immunoregulatory subgroups. This strategy provides a novel approach in drug carrier development for in vitro assessments of macrophage phenotype to inform development of targeted therapies for inflammation and immune modulation.
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Affiliation(s)
- I-Ning Lee
- School of Pharmacy, Nottingham Biodiscovery Institute, University of Nottingham, University Park, Nottingham, United Kingdom
| | - Jasmine Z Stening
- School of Pharmacy, Nottingham Biodiscovery Institute, University of Nottingham, University Park, Nottingham, United Kingdom
| | - Felicity R A J Rose
- School of Pharmacy, Nottingham Biodiscovery Institute, University of Nottingham, University Park, Nottingham, United Kingdom
| | - Lisa J White
- School of Pharmacy, Nottingham Biodiscovery Institute, University of Nottingham, University Park, Nottingham, United Kingdom
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10
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Almansour S, Dunster JL, Crofts JJ, Nelson MR. Modelling the continuum of macrophage phenotypes and their role in inflammation. Math Biosci 2024; 377:109289. [PMID: 39243940 DOI: 10.1016/j.mbs.2024.109289] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 07/15/2024] [Accepted: 09/03/2024] [Indexed: 09/09/2024]
Abstract
Macrophages are a type of white blood cell that play a significant role in determining the inflammatory response associated with a wide range of medical conditions. They are highly plastic, having the capacity to adopt numerous polarisation states or 'phenotypes' with disparate pro- or anti-inflammatory roles. Many previous studies divide macrophages into two categorisations: M1 macrophages are largely pro-inflammatory in nature, while M2 macrophages are largely restorative. However, there is a growing body of evidence that the M1 and M2 classifications represent the extremes of a much broader spectrum of phenotypes, and that intermediate phenotypes can play important roles in the progression or treatment of many medical conditions. In this article, we present a model of macrophage dynamics that includes a continuous description of phenotype, and hence incorporates intermediate phenotype configurations. We describe macrophage phenotype switching via nonlinear convective flux terms that scale with background levels of generic pro- and anti-inflammatory mediators. Through numerical simulation and bifurcation analysis, we unravel the model's resulting dynamics, paying close attention to the system's multistability and the extent to which key macrophage-mediator interactions provide bifurcations that act as switches between chronic states and restoration of health. We show that interactions that promote M1-like phenotypes generally result in a greater array of stable chronic states, while interactions that promote M2-like phenotypes can promote restoration of health. Additionally, our model admits oscillatory solutions reminiscent of relapsing-remitting conditions, with macrophages being largely polarised toward anti-inflammatory activity during remission, but with intermediate phenotypes playing a role in inflammatory flare-ups. We conclude by reflecting on our observations in the context of the ongoing pursuance of novel therapeutic interventions.
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Affiliation(s)
- Suliman Almansour
- School of Science & Technology, Nottingham Trent University, Nottingham, NG11 8NS, UK
| | - Joanne L Dunster
- Institute for Cardiovascular and Metabolic Research, University of Reading, Reading, RG6 6AS, UK
| | - Jonathan J Crofts
- School of Science & Technology, Nottingham Trent University, Nottingham, NG11 8NS, UK
| | - Martin R Nelson
- School of Science & Technology, Nottingham Trent University, Nottingham, NG11 8NS, UK.
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11
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He Z, Lv JC, Zheng ZL, Gao CT, Xing JW, Li BL, Liu HH, Liu Y, Xu JZ, Li ZM, Luo E. Hierarchically structured nanofibrous scaffolds spatiotemporally mediate the osteoimmune micro-environment and promote osteogenesis for periodontitis-related alveolar bone regeneration. Acta Biomater 2024; 189:323-336. [PMID: 39395703 DOI: 10.1016/j.actbio.2024.10.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 09/24/2024] [Accepted: 10/06/2024] [Indexed: 10/14/2024]
Abstract
Periodontitis suffer from inflammation-induced destruction of periodontal tissues, resulting in the serious loss of alveolar bone. Controlling inflammation and promoting bone regeneration are two crucial aspects for periodontitis-related alveolar bone defect treatment. Herein, we developed a hierarchically structured nanofibrous scaffold with a nano-embossed sheath and a bone morphogenetic protein 2-loaded core to match the periodontitis-specific features that spatiotemporally modulated the osteoimmune environment and promoted periodontal bone regeneration. We investigated the potential of this unique scaffold to treat periodontitis-related alveolar bone defects in vivo and in vitro. The results demonstrated that the hierarchically structured scaffold effectively reduced the inflammatory levels in macrophages and enhanced the osteogenic potential of bone mesenchymal stem cells in an inflammatory microenvironment. Moreover, in vivo experiments revealed that the hierarchically structured scaffold significantly ameliorated inflammation in the periodontium and inhibited alveolar bone resorption. Notably, the hierarchically structured scaffold also exhibited a prolonged effect on promoting alveolar bone regeneration. These findings highlight the significant therapeutic potential of hierarchically structured nanofibrous scaffolds for the treatment of periodontitis, and their promising role in the field of periodontal tissue regeneration. STATEMENT OF SIGNIFICANCE: We present a novel hierarchically structured nanofibrous scaffold of coupling topological and biomolecular signals for precise spatiotemporal modulation of the osteoimmune micro-environment. Specifically, the scaffold was engineered via coaxial electrospinning of the poly(ε-caprolactone) sheath and a BMP-2/polyvinyl alcohol core, followed by surface-directed epitaxial crystallization to generate cyclic nano-lamellar embossment on the sheath. With this unique hierarchical structure, the cyclic nano-lamellar sheath provided a direct nano-topographical cue to alleviate the osteoimmune environment, and the stepwise release of BMP-2 from the core provided a biological cue for bone regeneration. This research underscores the potential of hierarchically structured nanofibrous scaffolds as a promising therapeutic approach for periodontal tissue regeneration and highlights their role in advancing periodontal tissue engineering.
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Affiliation(s)
- Ze He
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China
| | - Jia-Cheng Lv
- College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu 610065, China
| | - Zi-Li Zheng
- College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu 610065, China
| | - Cui-Ting Gao
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China
| | - Jia-Wei Xing
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China
| | - Bo-Lun Li
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China
| | - Hang-Hang Liu
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China
| | - Yao Liu
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China
| | - Jia-Zhuang Xu
- College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu 610065, China.
| | - Zhong-Ming Li
- College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu 610065, China
| | - En Luo
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China.
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12
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Hernaez-Estrada B, Steele LA, Spiller KL. Effects of a bioengineered allogeneic cellular construct on burn-related macrophage phenotype. Wound Repair Regen 2024; 32:992-1007. [PMID: 39359182 DOI: 10.1111/wrr.13227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 09/05/2024] [Accepted: 09/16/2024] [Indexed: 10/04/2024]
Abstract
Bioengineered allogeneic cellularised constructs (BACC) exert pro-healing effects in burn wounds and skew macrophage phenotype towards a predominately reparative phenotype. However, whether BACC can modulate the phenotype of dysregulated macrophages, like those present in burn wounds, is not known. To better understand the macrophage modulatory characteristics of the BACC, primary human macrophages were polarised to the M2b phenotype, an immunosuppressive phenotype relevant to burn wounds, by simultaneously exposing macrophages to polystyrene plate-coated immunoglobulin G and the endotoxin lipopolysaccharide (LPS). The resulting macrophage phenotype upregulated both inflammatory and reparative genes, and increased secretion of the M2b marker CCL1 compared to five different in vitro macrophage phenotypes. M2b macrophages were cultured with the BACC in the presence or absence of LPS to mimic infection, which is a common occurrence in burn wounds. The BACC caused up-regulation of reparative gene sets and down-regulation of pro-inflammatory gene sets, even when LPS was present in the cell culture media. Co-cultures were maintained for 1, 3, or 5 days in the presence of LPS, and by day 1 both non-activated macrophages and M2b macrophages exhibited signs of endotoxin tolerance, as demonstrated by a reduced secretion of tumour necrosis factor α (TNFα) in response to fresh LPS stimulus. The BACC was not able to prevent endotoxin tolerance, but reparative genes were upregulated in macrophages chronically exposed to LPS. These results suggest that the BACC can promote a reparative phenotype in dysregulated macrophages relevant to the pathophysiology of burns.
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Affiliation(s)
- Beatriz Hernaez-Estrada
- School of Biomedical Engineering, Science, and Health Systems, Drexel University, Philadelphia, Pennsylvania, USA
| | - Lindsay A Steele
- School of Biomedical Engineering, Science, and Health Systems, Drexel University, Philadelphia, Pennsylvania, USA
| | - Kara L Spiller
- School of Biomedical Engineering, Science, and Health Systems, Drexel University, Philadelphia, Pennsylvania, USA
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13
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Ding S, Zhang X, Wang G, Shi J, Zhu J, Yan J, Wang J, Wu J. Promoting diabetic oral mucosa wound healing with a light-responsive hydrogel adaptive to the microenvironment. Heliyon 2024; 10:e38599. [PMID: 39435107 PMCID: PMC11492349 DOI: 10.1016/j.heliyon.2024.e38599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 09/24/2024] [Accepted: 09/26/2024] [Indexed: 10/23/2024] Open
Abstract
In diabetic patients, compromised angiogenesis due to endothelial dysfunction leads to delayed intraoral wound healing. However, the moist and dynamic environment of the oral cavity impedes the use of normal wound dressings. Sulfated chitosan (SCS) is a promising biomaterial that promoting angiogenesis. Here, a light-responsive hydrogel combined with SCS explored intraoral wound healing. We designed a SCS-modified hydrogel combined with alginate Methacryloyl (AlgMA) and acrylamide (AM) and demonstrated efficient wet adhesion and mechanical properties suitable for the wet and dynamic oral environment. In vitro, the SAA hydrogel improved the tube formation of human umbilical vein endothelial cells (HUVECs) under high-glucose conditions. Further investigations revealed that the SAA hydrogel can regulate HUVEC-macrophage interactions, leading to a shift in macrophage polarization from M1 to M2, thereby fostering an environment conducive to angiogenesis under high-glucose condition. The results demonstrated the substantial therapeutic impact of the SAA hydrogel on diabetic oral defect repair by effectively enhancing the local blood supply and angiogenesis.
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Affiliation(s)
- Shuwen Ding
- Department of Prosthodontics, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, PR China
| | - Xiaohui Zhang
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, PR China
- Engineering Research Center for Biomedical Materials of Ministry of Education, East China University of Science and Technology, Shanghai, 200237, PR China
| | - Gaopeng Wang
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, PR China
- Engineering Research Center for Biomedical Materials of Ministry of Education, East China University of Science and Technology, Shanghai, 200237, PR China
| | - Jiaying Shi
- Department of Prosthodontics, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, PR China
| | - Jiayu Zhu
- Department of Prosthodontics, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, PR China
| | - Jiayu Yan
- Department of Prosthodontics, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, PR China
| | - Jing Wang
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, PR China
- Engineering Research Center for Biomedical Materials of Ministry of Education, East China University of Science and Technology, Shanghai, 200237, PR China
| | - Junhua Wu
- Department of Prosthodontics, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, PR China
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14
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Li X, Si Y, Liang J, Li M, Wang Z, Qin Y, Sun L. Enhancing bone regeneration and immunomodulation via gelatin methacryloyl hydrogel-encapsulated exosomes from osteogenic pre-differentiated mesenchymal stem cells. J Colloid Interface Sci 2024; 672:179-199. [PMID: 38838627 DOI: 10.1016/j.jcis.2024.05.209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 05/13/2024] [Accepted: 05/27/2024] [Indexed: 06/07/2024]
Abstract
Mesenchymal stem cell-derived exosomes (MSC-Exos) have emerged as promising candidates for cell-free therapy in tissue regeneration. However, the native osteogenic and angiogenic capacities of MSC-Exos are often insufficient to repair critical-sized bone defects, and the underlying immune mechanisms remain elusive. Furthermore, achieving sustained delivery and stable activity of MSC-Exos at the defect site is essential for optimal therapeutic outcomes. Here, we extracted exosomes from osteogenically pre-differentiated human bone marrow mesenchymal stem cells (hBMSCs) by ultracentrifugation and encapsulated them in gelatin methacryloyl (GelMA) hydrogel to construct a composite scaffold. The resulting exosome-encapsulated hydrogel exhibited excellent mechanical properties and biocompatibility, facilitating sustained delivery of MSC-Exos. Osteogenic pre-differentiation significantly enhanced the osteogenic and angiogenic properties of MSC-Exos, promoting osteogenic differentiation of hBMSCs and angiogenesis of human umbilical vein endothelial cells (HUVECs). Furthermore, MSC-Exos induced polarization of Raw264.7 cells from a pro-inflammatory phenotype to an anti-inflammatory phenotype under simulated inflammatory conditions, thereby creating an immune microenvironment conducive to osteogenesis. RNA sequencing and bioinformatics analysis revealed that MSC-Exos activate the p53 pathway through targeted delivery of internal microRNAs and regulate macrophage polarization by reducing DNA oxidative damage. Our study highlights the potential of osteogenic exosome-encapsulated composite hydrogels for the development of cell-free scaffolds in bone tissue engineering.
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Affiliation(s)
- Xiaorong Li
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China
| | - Yunhui Si
- School of Biomedical Engineering, Sun Yat-sen University, Shenzhen 518107, China.
| | - Jingxian Liang
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China
| | - Mengsha Li
- School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou 510006, China; Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai 519000, China
| | - Zhiwei Wang
- Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai 519000, China
| | - Yinying Qin
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China
| | - Litao Sun
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China.
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15
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Gandolfi S, Sanouj A, Chaput B, Coste A, Sallerin B, Varin A. The role of adipose tissue-derived stromal cells, macrophages and bioscaffolds in cutaneous wound repair. Biol Direct 2024; 19:85. [PMID: 39343924 PMCID: PMC11439310 DOI: 10.1186/s13062-024-00534-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Accepted: 09/12/2024] [Indexed: 10/01/2024] Open
Abstract
Skin healing is a complex and dynamic physiological process that follows mechanical alteration of the skin barrier. Under normal conditions, this complex process can be divided into at least three continuous and overlapping phases: an inflammatory reaction, a proliferative phase that leads to tissue reconstruction and a phase of tissue remodeling. Macrophages critically contribute to the physiological cascade for tissue repair. In fact, as the inflammatory phase progresses, macrophage gene expression gradually shifts from pro-inflammatory M1-like to pro-resolutive M2-like characteristics, which is critical for entry into the repair phase. A dysregulation in this macrophage' shift phenotype leads to the persistence of the inflammatory phase. Mesenchymal stromal cells and specifically the MSC-derived from adipose tissue (ADSCs) are more and more use to treat inflammatory diseases and several studies have demonstrated that ADSCs promote the wound healing thanks to their neoangiogenic, immunomodulant and regenerative properties. In several studies, ADSCs and macrophages have been injected directly into the wound bed, but the delivery of exogenous cells directly to the wound raise the problem of cell engraftment and preservation of pro-resolutive phenotype and viability of the cells. Complementary approaches have therefore been explored, such as the use of biomaterials enriched with therapeutic cell to improve cell survival and function. This review will present a background of the current scaffold models, using adipose derived stromal-cells and macrophage as therapeutic cells for wound healing, through a discussion on the potential impact for future applications in skin regeneration. According to the PRISMA statement, we resumed data from investigations reporting the use ADSCs and bioscaffolds and data from macrophages behavior with functional biomaterials in wound healing models. In the era of tissue engineering, functional biomaterials, that can maintain cell delivery and cellular viability, have had a profound impact on the development of dressings for the treatment of chronic wounds. Promising results have been showed in pre-clinical reports using ADSCs- and macrophages-based scaffolds to accelerate and to improve the quality of the cutaneous healing.
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Affiliation(s)
- S Gandolfi
- FLAMES Team, Restore Institute, Inserm, Toulouse III Paul Sabatier University, 4Bis Av. H. Curien, 31100, Toulouse, France.
- Department of Plastic and Reconstructive Surgery, Toulouse University Hospital, 1 Av. Pr.Jean Poulhès, 31400, Toulouse, France.
| | - A Sanouj
- FLAMES Team, Restore Institute, Inserm, Toulouse III Paul Sabatier University, 4Bis Av. H. Curien, 31100, Toulouse, France
| | - B Chaput
- Department of Plastic and Reconstructive Surgery, Toulouse University Hospital, 1 Av. Pr.Jean Poulhès, 31400, Toulouse, France
| | - A Coste
- FLAMES Team, Restore Institute, Inserm, Toulouse III Paul Sabatier University, 4Bis Av. H. Curien, 31100, Toulouse, France
| | - B Sallerin
- FLAMES Team, Restore Institute, Inserm, Toulouse III Paul Sabatier University, 4Bis Av. H. Curien, 31100, Toulouse, France
- Department of Pharmacology, Toulouse University Hospital, 1 Av Pr.Jean Poulhès, 31400, Toulouse, France
| | - A Varin
- FLAMES Team, Restore Institute, Inserm, Toulouse III Paul Sabatier University, 4Bis Av. H. Curien, 31100, Toulouse, France
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16
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Liang W, Liang B, Yan K, Zhang G, Zhuo J, Cai Y. Low-Intensity Pulsed Ultrasound: A Physical Stimulus with Immunomodulatory and Anti-inflammatory Potential. Ann Biomed Eng 2024; 52:1955-1981. [PMID: 38683473 DOI: 10.1007/s10439-024-03523-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Accepted: 04/20/2024] [Indexed: 05/01/2024]
Abstract
Ultrasound has expanded into the therapeutic field as a medical imaging and diagnostic technique. Low-intensity pulsed ultrasound (LIPUS) is a kind of therapeutic ultrasound that plays a vital role in promoting fracture healing, wound repair, immunomodulation, and reducing inflammation. Its anti-inflammatory effects are manifested by decreased pro-inflammatory cytokines and chemokines, accelerated regression of immune cell invasion, and accelerated damage repair. Although the anti-inflammatory mechanism of LIPUS is not very clear, many in vitro and in vivo studies have shown that LIPUS may play its anti-inflammatory role by activating signaling pathways such as integrin/Focal adhesion kinase (FAK)/Phosphatidylinositol 3-kinase (PI3K)/Serine threonine kinase (Akt), Vascular endothelial growth factor (VEGF)/endothelial nitric oxide synthase (eNOS), or inhibiting signaling pathways such as Toll-like receptors (TLRs)/Nuclear factor kappa-B (NF-κB) and p38-Mitogen-activated protein kinase (MAPK). As a non-invasive physical therapy, the anti-inflammatory and immunomodulatory effects of LIPUS deserve further exploration.
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Affiliation(s)
- Wenxin Liang
- Center of Medicine Clinical Research, Department of Pharmacy, Medical Supplies Center of Chinese PLA General Hospital, 28 Fu Xing Road, Beijing, 100853, People's Republic of China
- College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China
| | - Beibei Liang
- Center of Medicine Clinical Research, Department of Pharmacy, Medical Supplies Center of Chinese PLA General Hospital, 28 Fu Xing Road, Beijing, 100853, People's Republic of China
| | - Kaicheng Yan
- Center of Medicine Clinical Research, Department of Pharmacy, Medical Supplies Center of Chinese PLA General Hospital, 28 Fu Xing Road, Beijing, 100853, People's Republic of China
| | - Guanxuanzi Zhang
- Center of Medicine Clinical Research, Department of Pharmacy, Medical Supplies Center of Chinese PLA General Hospital, 28 Fu Xing Road, Beijing, 100853, People's Republic of China
| | - Jiaju Zhuo
- Center of Medicine Clinical Research, Department of Pharmacy, Medical Supplies Center of Chinese PLA General Hospital, 28 Fu Xing Road, Beijing, 100853, People's Republic of China
- College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China
| | - Yun Cai
- Center of Medicine Clinical Research, Department of Pharmacy, Medical Supplies Center of Chinese PLA General Hospital, 28 Fu Xing Road, Beijing, 100853, People's Republic of China.
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17
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Wang S, Lei H, Mi Y, Ma P, Fan D. Chitosan and hyaluronic acid based injectable dual network hydrogels - Mediating antimicrobial and inflammatory modulation to promote healing of infected bone defects. Int J Biol Macromol 2024; 274:133124. [PMID: 38897505 DOI: 10.1016/j.ijbiomac.2024.133124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 05/09/2024] [Accepted: 06/11/2024] [Indexed: 06/21/2024]
Abstract
In bone defects, infections lead to excessive inflammation, increased bacterial, and bone lysis, resulting in irregular wounds that hinder new bone regeneration. Injectable bioactive materials with adequate antimicrobial activity and strong osteogenic potential are urgently required to remedy irregular defects, eradicate bacteria, and facilitate the generation of new bone tissue. In this research, injectable dual-network composite hydrogels consisting of sulfated chitosan, oxidized hyaluronic acid, β-sodium glycerophosphate, and CuSr doped mesoporous bioactive glass loaded with bone morphogenetic protein (CuSrMBGBMP-2) were utilized for the first time to treat infectious bone defects. Initially, the hydrogel was injected into the wound at 37 °C with minimal invasion to establish a stable state and prevent hydrogel loss. Subsequently, sulfated chitosan eliminated bacteria at the wound site and facilitated cell proliferation with oxidized hyaluronic acid. Additionally, CuSrMBGBMP-2 strengthened antibacterial properties, regulated inflammatory reactions, promoted angiogenesis and osteogenic differentiation, addressing the deficiency in late-stage osteogenesis. Specifically, the injectable dual-network hydrogel based on chitosan and hyaluronic acid is minimally invasive, offering antibacterial, anti-inflammatory, pro-angiogenic, and bone regeneration properties. Therefore, this hydrogel with injectable dual network properties holds great promise for the treatment of bone infections in the future.
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Affiliation(s)
- Shang Wang
- Engineering Research Center of Western Resource Innovation Medicine Green Manufacturing, Ministry of Education, School of Chemical Engineering, Northwest University, Xi'an 710069, China; Shaanxi Key Laboratory of Degradable Biomedical Materials and Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Xi'an 710069, China; Biotech. & Biomed. Research Institute, Northwest University, Xi'an 710069, China.
| | - Huan Lei
- Engineering Research Center of Western Resource Innovation Medicine Green Manufacturing, Ministry of Education, School of Chemical Engineering, Northwest University, Xi'an 710069, China; Shaanxi Key Laboratory of Degradable Biomedical Materials and Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Xi'an 710069, China; Biotech. & Biomed. Research Institute, Northwest University, Xi'an 710069, China.
| | - Yu Mi
- Engineering Research Center of Western Resource Innovation Medicine Green Manufacturing, Ministry of Education, School of Chemical Engineering, Northwest University, Xi'an 710069, China; Shaanxi Key Laboratory of Degradable Biomedical Materials and Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Xi'an 710069, China; Biotech. & Biomed. Research Institute, Northwest University, Xi'an 710069, China.
| | - Pei Ma
- Engineering Research Center of Western Resource Innovation Medicine Green Manufacturing, Ministry of Education, School of Chemical Engineering, Northwest University, Xi'an 710069, China; Shaanxi Key Laboratory of Degradable Biomedical Materials and Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Xi'an 710069, China; Biotech. & Biomed. Research Institute, Northwest University, Xi'an 710069, China.
| | - Daidi Fan
- Engineering Research Center of Western Resource Innovation Medicine Green Manufacturing, Ministry of Education, School of Chemical Engineering, Northwest University, Xi'an 710069, China; Shaanxi Key Laboratory of Degradable Biomedical Materials and Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Xi'an 710069, China; Biotech. & Biomed. Research Institute, Northwest University, Xi'an 710069, China.
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18
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Chen R, Zou L. Combined analysis of single-cell sequencing and bulk transcriptome sequencing reveals new mechanisms for non-healing diabetic foot ulcers. PLoS One 2024; 19:e0306248. [PMID: 38950058 PMCID: PMC11216623 DOI: 10.1371/journal.pone.0306248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Accepted: 06/13/2024] [Indexed: 07/03/2024] Open
Abstract
Diabetic foot ulcers (DFUs) pose a significant challenge in diabetes care. Yet, a comprehensive understanding of the underlying biological disparities between healing and non-healing DFUs remains elusive. We conducted bioinformatics analysis of publicly available transcriptome sequencing data in an attempt to elucidate these differences. Our analysis encompassed differential analysis to unveil shifts in cell composition and gene expression profiles between non-healing and healing DFUs. Cell communication alterations were explored employing the Cellchat R package. Pseudotime analysis and cytoTRACE allowed us to dissect the heterogeneity within fibroblast subpopulations. Our findings unveiled disruptions in various cell types, localized low-grade inflammation, compromised systemic antigen processing and presentation, and extensive extracellular matrix signaling disarray in non-healing DFU patients. Some of these anomalies partially reverted in healing DFUs, particularly within the abnormal ECM-receptor signaling pathway. Furthermore, we distinguished distinct fibroblast subpopulations in non-healing and healing DFUs, each with unique biological functions. Healing-associated fibroblasts exhibited heightened extracellular matrix (ECM) remodeling and a robust wound healing response, while non-healing-associated fibroblasts showed signs of cellular senescence and complement activation, among other characteristics. This analysis offers profound insights into the wound healing microenvironment, identifies pivotal cell types for DFU healing promotion, and reveals potential therapeutic targets for DFU management.
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Affiliation(s)
- Ran Chen
- Department of Wound Repair Surgery, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Lijun Zou
- Department of Wound Repair Surgery, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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19
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Las Heras K, Garcia-Orue I, Rancan F, Igartua M, Santos-Vizcaino E, Hernandez RM. Modulating the immune system towards a functional chronic wound healing: A biomaterials and Nanomedicine perspective. Adv Drug Deliv Rev 2024; 210:115342. [PMID: 38797316 DOI: 10.1016/j.addr.2024.115342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 05/16/2024] [Accepted: 05/18/2024] [Indexed: 05/29/2024]
Abstract
Chronic non-healing wounds persist as a substantial burden for healthcare systems, influenced by factors such as aging, diabetes, and obesity. In contrast to the traditionally pro-regenerative emphasis of therapies, the recognition of the immune system integral role in wound healing has significantly grown, instigating an approach shift towards immunological processes. Thus, this review explores the wound healing process, highlighting the engagement of the immune system, and delving into the behaviors of innate and adaptive immune cells in chronic wound scenarios. Moreover, the article investigates biomaterial-based strategies for the modulation of the immune system, elucidating how the adjustment of their physicochemical properties or their synergistic combination with other agents such as drugs, proteins or mesenchymal stromal cells can effectively modulate the behaviors of different immune cells. Finally this review explores various strategies based on synthetic and biological nanostructures, including extracellular vesicles, to finely tune the immune system as natural immunomodulators or therapeutic nanocarriers with promising biophysical properties.
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Affiliation(s)
- Kevin Las Heras
- NanoBioCel Research Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV-EHU), Vitoria-Gasteiz, Spain; Bioaraba, NanoBioCel Research Group, Vitoria-Gasteiz, Spain
| | - Itxaso Garcia-Orue
- NanoBioCel Research Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV-EHU), Vitoria-Gasteiz, Spain; Bioaraba, NanoBioCel Research Group, Vitoria-Gasteiz, Spain; Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN). Institute of Health Carlos III, Madrid, Spain
| | - Fiorenza Rancan
- Department of Dermatology, Venereology und Allergology,Clinical Research Center for Hair and Skin Science, Charité - Universitätsmedizin Berlin
| | - Manoli Igartua
- NanoBioCel Research Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV-EHU), Vitoria-Gasteiz, Spain; Bioaraba, NanoBioCel Research Group, Vitoria-Gasteiz, Spain; Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN). Institute of Health Carlos III, Madrid, Spain
| | - Edorta Santos-Vizcaino
- NanoBioCel Research Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV-EHU), Vitoria-Gasteiz, Spain; Bioaraba, NanoBioCel Research Group, Vitoria-Gasteiz, Spain; Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN). Institute of Health Carlos III, Madrid, Spain.
| | - Rosa Maria Hernandez
- NanoBioCel Research Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV-EHU), Vitoria-Gasteiz, Spain; Bioaraba, NanoBioCel Research Group, Vitoria-Gasteiz, Spain; Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN). Institute of Health Carlos III, Madrid, Spain.
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20
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Almansour S, Dunster JL, Crofts JJ, Nelson MR. A systematic evaluation of the influence of macrophage phenotype descriptions on inflammatory dynamics. MATHEMATICAL MEDICINE AND BIOLOGY : A JOURNAL OF THE IMA 2024; 41:81-109. [PMID: 38604176 PMCID: PMC11258393 DOI: 10.1093/imammb/dqae004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 01/18/2024] [Accepted: 03/28/2024] [Indexed: 04/13/2024]
Abstract
Macrophages play a wide range of roles in resolving the inflammatory damage that underlies many medical conditions and have the ability to adopt different phenotypes in response to different environmental stimuli. Categorising macrophage phenotypes exactly is a difficult task, and there is disparity in the literature around the optimal nomenclature to describe these phenotypes; however, what is clear is that macrophages can exhibit both pro- and anti-inflammatory behaviours dependent upon their phenotype, rendering mathematical models of the inflammatory response potentially sensitive to their description of the macrophage populations that they incorporate. Many previous models of inflammation include a single macrophage population with both pro- and anti-inflammatory functions. Here, we build upon these existing models to include explicit descriptions of distinct macrophage phenotypes and examine the extent to which this influences the inflammatory dynamics that the models emit. We analyse our models via numerical simulation in MATLAB and dynamical systems analysis in XPPAUT, and show that models that account for distinct macrophage phenotypes separately can offer more realistic steady state solutions than precursor models do (better capturing the anti-inflammatory activity of tissue resident macrophages), as well as oscillatory dynamics not previously observed. Finally, we reflect on the conclusions of our analysis in the context of the ongoing hunt for potential new therapies for inflammatory conditions, highlighting manipulation of macrophage polarisation states as a potential therapeutic target.
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Affiliation(s)
- Suliman Almansour
- School of Science & Technology, Nottingham Trent University, Nottingham, NG11 8NS, UK
| | - Joanne L Dunster
- Institute for Cardiovascular and Metabolic Research, University of Reading, Reading, RG6 6AS, UK
| | - Jonathan J Crofts
- School of Science & Technology, Nottingham Trent University, Nottingham, NG11 8NS, UK
| | - Martin R Nelson
- School of Science & Technology, Nottingham Trent University, Nottingham, NG11 8NS, UK
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21
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Qiu H, Xiong H, Zheng J, Peng Y, Wang C, Hu Q, Zhao F, Chen K. Sr-Incorporated Bioactive Glass Remodels the Immunological Microenvironment by Enhancing the Mitochondrial Function of Macrophage via the PI3K/AKT/mTOR Signaling Pathway. ACS Biomater Sci Eng 2024; 10:3923-3934. [PMID: 38766805 DOI: 10.1021/acsbiomaterials.4c00228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/22/2024]
Abstract
The repair of critical-sized bone defects continues to pose a challenge in clinics. Strontium (Sr), recognized for its function in bone metabolism regulation, has shown potential in bone repair. However, the underlying mechanism through which Sr2+ guided favorable osteogenesis by modulating macrophages remains unclear, limiting their application in the design of bone biomaterials. Herein, Sr-incorporated bioactive glass (SrBG) was synthesized for further investigation. The release of Sr ions enhanced the immunomodulatory properties and osteogenic potential by modulating the polarization of macrophages toward the M2 phenotype. In vivo, a 3D-printed SrBG scaffold was fabricated and showed consistently improved bone regeneration by creating a prohealing immunological microenvironment. RNA sequencing was performed to explore the underlying mechanisms. It was found that Sr ions might enhance the mitochondrial function of macrophage by activating PI3K/AKT/mTOR signaling, thereby favoring osteogenesis. Our findings demonstrate the relationship between the immunomodulatory role of Sr ions and the mitochondrial function of macrophages. By focusing on the mitochondrial function of macrophages, Sr2+-mediated immunomodulation sheds light on the future design of biomaterials for tissue regenerative engineering.
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Affiliation(s)
- Huanhuan Qiu
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou 510280, China
| | - Huacui Xiong
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou 510280, China
| | - Jiafu Zheng
- Department of Biomedical Engineering, School of Materials Science and Engineering, South China University of Technology, Guangzhou 510641, China
| | - Yuqi Peng
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou 510280, China
| | - Chunhui Wang
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou 510280, China
| | - Qing Hu
- School of Materials Science and Engineering, Jingdezhen Ceramic University, Jingdezhen 333001, China
| | - Fujian Zhao
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou 510280, China
| | - Ke Chen
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou 510280, China
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22
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Özcolak B, Erenay B, Odabaş S, Jandt KD, Garipcan B. Effects of bone surface topography and chemistry on macrophage polarization. Sci Rep 2024; 14:12721. [PMID: 38830871 PMCID: PMC11148019 DOI: 10.1038/s41598-024-62484-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Accepted: 05/17/2024] [Indexed: 06/05/2024] Open
Abstract
Surface structure plays a crucial role in determining cell behavior on biomaterials, influencing cell adhesion, proliferation, differentiation, as well as immune cells and macrophage polarization. While grooves and ridges stimulate M2 polarization and pits and bumps promote M1 polarization, these structures do not accurately mimic the real bone surface. Consequently, the impact of mimicking bone surface topography on macrophage polarization remains unknown. Understanding the synergistic sequential roles of M1 and M2 macrophages in osteoimmunomodulation is crucial for effective bone tissue engineering. Thus, exploring the impact of bone surface microstructure mimicking biomaterials on macrophage polarization is critical. In this study, we aimed to sequentially activate M1 and M2 macrophages using Poly-L-Lactic acid (PLA) membranes with bone surface topographical features mimicked through the soft lithography technique. To mimic the bone surface topography, a bovine femur was used as a model surface, and the membranes were further modified with collagen type-I and hydroxyapatite to mimic the bone surface microenvironment. To determine the effect of these biomaterials on macrophage polarization, we conducted experimental analysis that contained estimating cytokine release profiles and characterizing cell morphology. Our results demonstrated the potential of the hydroxyapatite-deposited bone surface-mimicked PLA membranes to trigger sequential and synergistic M1 and M2 macrophage polarizations, suggesting their ability to achieve osteoimmunomodulatory macrophage polarization for bone tissue engineering applications. Although further experimental studies are required to completely investigate the osteoimmunomodulatory effects of these biomaterials, our results provide valuable insights into the potential advantages of biomaterials that mimic the complex microenvironment of bone surfaces.
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Affiliation(s)
- Birgün Özcolak
- Biomimetic and Bioinspired Biomaterials Research Laboratory, Institute of Biomedical Engineering, Boğaziçi University, 34684, Istanbul, Turkey
- Department of Biomedical Engineering, School of Engineering and Natural Sciences, Istanbul Medipol University, 34810, Istanbul, Turkey
| | - Berkay Erenay
- Biomimetic and Bioinspired Biomaterials Research Laboratory, Institute of Biomedical Engineering, Boğaziçi University, 34684, Istanbul, Turkey
| | - Sedat Odabaş
- Biomaterials and Tissue Engineering Laboratory (bteLAB), Department of Chemistry, Faculty of Science, Ankara University, 06560, Ankara, Turkey
- Interdisciplinary Research Unit for Advanced Materials (INTRAM), Ankara University, 06560, Ankara, Turkey
| | - Klaus D Jandt
- Chair of Materials Science (CMS), Otto Schott Institute of Materials Research, Faculty of Physics and Astronomy, Friedrich Schiller University Jena, Löbdergraben 32, 07743, Jena, Germany
| | - Bora Garipcan
- Biomimetic and Bioinspired Biomaterials Research Laboratory, Institute of Biomedical Engineering, Boğaziçi University, 34684, Istanbul, Turkey.
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23
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Huang J, Wei J, Xia X, Xiao S, Jin S, Zou Q, Zuo Y, Li Y, Li J. A sequential macrophage activation strategy for bone regeneration: A micro/nano strontium-releasing composite scaffold loaded with lipopolysaccharide. Mater Today Bio 2024; 26:101063. [PMID: 38698884 PMCID: PMC11063594 DOI: 10.1016/j.mtbio.2024.101063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Revised: 04/11/2024] [Accepted: 04/14/2024] [Indexed: 05/05/2024] Open
Abstract
Effective tissue repair relies on the orchestration of different macrophage phenotypes, both the M2 phenotype (promotes tissue repair) and M1 phenotype (pro-inflammatory) deserve attention. In this study, we propose a sequential immune activation strategy to mediate bone regeneration, by loading lipopolysaccharide (LPS) onto the surface of a strontium (Sr) ions -contained composite scaffold, which was fabricated by combining Sr-doped micro/nano-hydroxyapatite (HA) and dual degradable matrices of polycaprolactone (PCL) and poly (lactic-co-glycolic acid) (PLGA). Our strategy involves the sequential release of LPS to promote macrophage homing and induce the expression of the pro-inflammatory M1 phenotype, followed by the release of Sr ions to suppress inflammation. In vitro and in vivo experiments demonstrated that, the appropriate pro-inflammatory effects at the initial stage of implantation, along with the anti-inflammatory effects at the later stage, as well as the structural stability of the scaffolds conferred by the composition, can synergistically promote the regeneration and repair of bone defects.
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Affiliation(s)
- Jinhui Huang
- Yunnan Key Laboratory of Stomatology, School and Hospital of Stomatology, Kunming Medical University, Kunming, 650106, China
- Research Center for Nano-Biomaterials, Analytical & Testing Center, Sichuan University, Chengdu, 610064, China
| | - Jiawei Wei
- Research Center for Nano-Biomaterials, Analytical & Testing Center, Sichuan University, Chengdu, 610064, China
| | - Xue Xia
- Research Center for Nano-Biomaterials, Analytical & Testing Center, Sichuan University, Chengdu, 610064, China
| | - Shiqi Xiao
- Research Center for Nano-Biomaterials, Analytical & Testing Center, Sichuan University, Chengdu, 610064, China
| | - Shue Jin
- Research Center for Nano-Biomaterials, Analytical & Testing Center, Sichuan University, Chengdu, 610064, China
| | - Qin Zou
- Research Center for Nano-Biomaterials, Analytical & Testing Center, Sichuan University, Chengdu, 610064, China
| | - Yi Zuo
- Research Center for Nano-Biomaterials, Analytical & Testing Center, Sichuan University, Chengdu, 610064, China
| | - Yubao Li
- Research Center for Nano-Biomaterials, Analytical & Testing Center, Sichuan University, Chengdu, 610064, China
| | - Jidong Li
- Research Center for Nano-Biomaterials, Analytical & Testing Center, Sichuan University, Chengdu, 610064, China
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24
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Iraji Asiabadi A, Esmaeil N, Zargar Kharazi A, Dabiri A, Varshosaz J. Harnessing IL-10 induced anti-inflammatory response in maturing macrophages in presence of electrospun dexamethasone-loaded PLLA scaffold. J Biomed Mater Res B Appl Biomater 2024; 112:e35411. [PMID: 38773758 DOI: 10.1002/jbm.b.35411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 03/19/2024] [Accepted: 04/13/2024] [Indexed: 05/24/2024]
Abstract
The ultimate goal of tissue engineering is to repair and regenerate damaged tissue or organ. Achieving this goal requires blood vessel networks to supply oxygen and nutrients to new forming tissues. Macrophages are part of the immune system whose behavior plays a significant role in angiogenesis and blood vessel formation. On the other hand, macrophages are versatile cells that change their behavior in response to environmental stimuli. Given that implantation of a biomaterial is followed by inflammation; therefore, we reasoned that this inflammatory condition in tissue spaces modulates the final phenotype of macrophages. Also, we hypothesized that anti-inflammatory glucocorticoid dexamethasone improves modulating macrophages behavior. To check these concepts, we investigated the macrophages that had matured in an inflammatory media. Furthermore, we examined macrophages' behavior after maturation on a dexamethasone-containing scaffold and analyzed how the behavioral change of maturing macrophages stimulates other macrophages in the same environment. In this study, the expression of pro-inflammatory markers TNFa and NFκB1 along with pro-healing markers IL-10 and CD163 were investigated to study the behavior of macrophages. Our results showed that macrophages that were matured in the inflammatory media in vitro increase expression of IL-10, which in turn decreased the expression of pro-inflammatory markers TNFa and NFκB in maturing macrophages. Also, macrophages that were matured on dexamethasone-containing scaffolds decreased the expression of IL-10, TNFa, and NFκB and increase the expression of CD163 compared to the control group. Moreover, the modulation of anti-inflammatory response in maturing macrophages on dexamethasone-containing scaffold resulted in increased expression of TNFa and CD163 by other macrophages in the same media. The results obtained in this study, proposing strategies to improve healing through controlling the behavior of maturing macrophages and present a promising perspective for inflammation control using tissue engineering scaffolds.
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Affiliation(s)
- Arash Iraji Asiabadi
- Tissue Engineering and Nanotechnology, School of Advanced Technologies in Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Nafiseh Esmaeil
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Anousheh Zargar Kharazi
- Tissue Engineering and Nanotechnology, School of Advanced Technologies in Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
- Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Arezou Dabiri
- Isfahan Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Jaleh Varshosaz
- Department of Pharmaceutics, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
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25
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Papadopoulos KS, Piperi C, Korkolopoulou P. Clinical Applications of Adipose-Derived Stem Cell (ADSC) Exosomes in Tissue Regeneration. Int J Mol Sci 2024; 25:5916. [PMID: 38892103 PMCID: PMC11172884 DOI: 10.3390/ijms25115916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 05/24/2024] [Accepted: 05/27/2024] [Indexed: 06/21/2024] Open
Abstract
Adipose-derived stem cells (ADSCs) are mesenchymal stem cells with a great potential for self-renewal and differentiation. Exosomes derived from ADSCs (ADSC-exos) can imitate their functions, carrying cargoes of bioactive molecules that may affect specific cellular targets and signaling processes. Recent evidence has shown that ADSC-exos can mediate tissue regeneration through the regulation of the inflammatory response, enhancement of cell proliferation, and induction of angiogenesis. At the same time, they may promote wound healing as well as the remodeling of the extracellular matrix. In combination with scaffolds, they present the future of cell-free therapies and promising adjuncts to reconstructive surgery with diverse tissue-specific functions and minimal adverse effects. In this review, we address the main characteristics and functional properties of ADSC-exos in tissue regeneration and explore their most recent clinical application in wound healing, musculoskeletal regeneration, dermatology, and plastic surgery as well as in tissue engineering.
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Affiliation(s)
- Konstantinos S. Papadopoulos
- Department of Plastic and Reconstructive Surgery, 401 General Military Hospital of Athens, 11525 Athens, Greece;
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Christina Piperi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75 M. Asias Street, 11527 Athens, Greece
| | - Penelope Korkolopoulou
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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26
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Yuan Q, Yang M, Zheng H, Cai Y, Luo P, Wang X, Xu P. M2 Macrophage-Derived Extracellular Vesicles Encapsulated in Hyaluronic Acid Alleviate Osteoarthritis by Modulating Macrophage Polarization. ACS Biomater Sci Eng 2024; 10:3355-3377. [PMID: 38563817 DOI: 10.1021/acsbiomaterials.3c01833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
An imbalance between M1 and M2 macrophage polarization is critical in osteoarthritis (OA) development. We investigated the effect of M2 macrophage-derived extracellular vesicles (M2-EVs) to reprogramme macrophages from the M1 to M2 phenotype for OA treatment. M1 macrophages and mouse OA models were treated with M2-EVs. Proteomic analysis was performed to evaluate macrophage polarization in vitro. The OA models were as follows: destabilization of the medial meniscus (DMM) surgery-induced OA and collagenase-induced OA (CIOA). Hyaluronic acid (HA) was used to deliver M2-EVs. M2-EVs decreased macrophage accumulation, repolarized macrophages from the M1 to M2 phenotype, mitigated synovitis, reduced cartilage degradation, alleviated subchondral bone damage, and improved gait abnormalities in the CIOA and DMM models. Moreover, HA increased the retention time of M2-EVs and enhanced the efficiency of M2-EVs in OA treatment. Furthermore, proteomic analysis demonstrated that M2-EVs exhibited a macrophage reprogramming ability similar to IL-4, and the pathways might be the NOD-like receptor (NLR), TNF, NF-κB, and Toll-like receptor (TLR) signaling pathways. M2-EVs reprogrammed macrophages from the M1 to M2 phenotype, which resulted in beneficial effects on cartilage and attenuation of OA severity. In summary, our study indicated that M2-EV-guided reprogramming of macrophages is a promising treatment strategy for OA.
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Affiliation(s)
- Qiling Yuan
- Department of Joint Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710054, China
| | - Mingyi Yang
- Department of Joint Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710054, China
| | - Haishi Zheng
- Department of Joint Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710054, China
| | - Yongsong Cai
- Department of Joint Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710054, China
| | - Pan Luo
- Department of Joint Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710054, China
| | - Xinyi Wang
- Department of Rehabilitation, Shaanxi Provincial Rehabilitation Hospital, Xi'an, Shaanxi 710065, China
| | - Peng Xu
- Department of Joint Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710054, China
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27
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Huang R, Kang T, Chen S. The role of tumor-associated macrophages in tumor immune evasion. J Cancer Res Clin Oncol 2024; 150:238. [PMID: 38713256 PMCID: PMC11076352 DOI: 10.1007/s00432-024-05777-4] [Citation(s) in RCA: 45] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Accepted: 05/03/2024] [Indexed: 05/08/2024]
Abstract
BACKGROUND Tumor growth is closely linked to the activities of various cells in the tumor microenvironment (TME), particularly immune cells. During tumor progression, circulating monocytes and macrophages are recruited, altering the TME and accelerating growth. These macrophages adjust their functions in response to signals from tumor and stromal cells. Tumor-associated macrophages (TAMs), similar to M2 macrophages, are key regulators in the TME. METHODS We review the origins, characteristics, and functions of TAMs within the TME. This analysis includes the mechanisms through which TAMs facilitate immune evasion and promote tumor metastasis. Additionally, we explore potential therapeutic strategies that target TAMs. RESULTS TAMs are instrumental in mediating tumor immune evasion and malignant behaviors. They release cytokines that inhibit effector immune cells and attract additional immunosuppressive cells to the TME. TAMs primarily target effector T cells, inducing exhaustion directly, influencing activity indirectly through cellular interactions, or suppressing through immune checkpoints. Additionally, TAMs are directly involved in tumor proliferation, angiogenesis, invasion, and metastasis. Developing innovative tumor-targeted therapies and immunotherapeutic strategies is currently a promising focus in oncology. Given the pivotal role of TAMs in immune evasion, several therapeutic approaches have been devised to target them. These include leveraging epigenetics, metabolic reprogramming, and cellular engineering to repolarize TAMs, inhibiting their recruitment and activity, and using TAMs as drug delivery vehicles. Although some of these strategies remain distant from clinical application, we believe that future therapies targeting TAMs will offer significant benefits to cancer patients.
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Affiliation(s)
- Ruizhe Huang
- Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Ting Kang
- Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Siyu Chen
- Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
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Zaid A, Ariel A. Harnessing anti-inflammatory pathways and macrophage nano delivery to treat inflammatory and fibrotic disorders. Adv Drug Deliv Rev 2024; 207:115204. [PMID: 38342241 DOI: 10.1016/j.addr.2024.115204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Revised: 12/08/2023] [Accepted: 02/05/2024] [Indexed: 02/13/2024]
Abstract
Targeting specific organs and cell types using nanotechnology and sophisticated delivery methods has been at the forefront of applicative biomedical sciences lately. Macrophages are an appealing target for immunomodulation by nanodelivery as they are heavily involved in various aspects of many diseases and are highly plastic in their nature. Their continuum of functional "polarization" states has been a research focus for many years yielding a profound understanding of various aspects of these cells. The ability of monocyte-derived macrophages to metamorphose from pro-inflammatory to reparative and consequently to pro-resolving effectors has raised significant interest in its therapeutic potential. Here, we briefly survey macrophages' ontogeny and various polarization phenotypes, highlighting their function in the inflammation-resolution shift. We review their inducing mediators, signaling pathways, and biological programs with emphasis on the nucleic acid sensing-IFN-I axis. We also portray the polarization spectrum of macrophages and the characteristics of their transition between different subtypes. Finally, we highlighted different current drug delivery methods for targeting macrophages with emphasis on nanotargeting that might lead to breakthroughs in the treatment of wound healing, bone regeneration, autoimmune, and fibrotic diseases.
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Affiliation(s)
- Ahmad Zaid
- Department of Biology and Human Biology, University of Haifa, Haifa, 3498838 Israel
| | - Amiram Ariel
- Department of Biology and Human Biology, University of Haifa, Haifa, 3498838 Israel.
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Caballero-Sánchez N, Alonso-Alonso S, Nagy L. Regenerative inflammation: When immune cells help to re-build tissues. FEBS J 2024; 291:1597-1614. [PMID: 36440547 PMCID: PMC10225019 DOI: 10.1111/febs.16693] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 10/29/2022] [Accepted: 11/18/2022] [Indexed: 11/29/2022]
Abstract
Inflammation is an essential immune response critical for responding to infection, injury and maintenance of tissue homeostasis. Upon injury, regenerative inflammation promotes tissue repair by a timed and coordinated infiltration of diverse cell types and the secretion of growth factors, cytokines and lipids mediators. Remarkably, throughout evolution as well as mammalian development, this type of physiological inflammation is highly associated with immunosuppression. For instance, regenerative inflammation is the consequence of an in situ macrophage polarization resulting in a transition from pro-inflammatory to anti-inflammatory/pro-regenerative response. Immune cells are the first responders upon injury, infiltrating the damaged tissue and initiating a pro-inflammatory response depleting cell debris and necrotic cells. After phagocytosis, macrophages undergo multiple coordinated metabolic and transcriptional changes allowing the transition and dictating the initiation of the regenerative phase. Differences between a highly efficient, complete ad integrum tissue repair, such as, acute skeletal muscle injury, and insufficient regenerative inflammation, as the one developing in Duchenne Muscular Dystrophy (DMD), highlight the importance of a coordinated response orchestrated by immune cells. During regenerative inflammation, these cells interact with others and alter the niche, affecting the character of inflammation itself and, therefore, the progression of tissue repair. Comparing acute muscle injury and chronic inflammation in DMD, we review how the same cells and molecules in different numbers, concentration and timing contribute to very different outcomes. Thus, it is important to understand and identify the distinct functions and secreted molecules of macrophages, and potentially other immune cells, during tissue repair, and the contributors to the macrophage switch leveraging this knowledge in treating diseases.
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Affiliation(s)
- Noemí Caballero-Sánchez
- Doctoral School of Molecular Cell and Immunobiology, Faculty of Medicine, University of Debrecen, Hungary
- Department of Biochemistry and Molecular Biology, Nuclear Receptor Research Laboratory, Faculty of Medicine, University of Debrecen, Hungary
| | - Sergio Alonso-Alonso
- Instituto Oftalmológico Fernández-Vega, Oviedo, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
| | - Laszlo Nagy
- Department of Biochemistry and Molecular Biology, Nuclear Receptor Research Laboratory, Faculty of Medicine, University of Debrecen, Hungary
- Departments Medicine and Biological Chemistry, Johns Hopkins University School of Medicine, and Institute for Fundamental Biomedical Research, Johns Hopkins All Children's Hospital, St Petersburg, Florida, USA
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30
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Chen Y, Zhang Y, Jiang M, Ma H, Cai Y. HMOX1 as a therapeutic target associated with diabetic foot ulcers based on single-cell analysis and machine learning. Int Wound J 2024; 21:e14815. [PMID: 38468410 PMCID: PMC10928352 DOI: 10.1111/iwj.14815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Revised: 01/15/2024] [Accepted: 02/12/2024] [Indexed: 03/13/2024] Open
Abstract
Diabetic foot ulcers (DFUs) are a serious chronic complication of diabetes mellitus and a leading cause of disability and death in diabetic patients. However, current treatments remain unsatisfactory. Although macrophages are associated with DFU, their exact role in this disease remains uncertain. This study sought to detect macrophage-related genes in DFU and identify possible therapeutic targets. Single-cell datasets (GSE223964) and RNA-seq datasets (GSM68183, GSE80178, GSE134431 and GSE147890) associated with DFU were retrieved from the gene expression omnibus (GEO) database for this study. Analysis of the provided single-cell data revealed the distribution of macrophage subpopulations in the DFU. Four independent RNA-seq datasets were merged into a single DFU cohort and further analysed using bioinformatics. This included differential expression (DEG) analysis, multiple machine learning algorithms to identify biomarkers and enrichment analysis. Finally, key results were validated using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western bolt. Finally, the findings were validated using RT-qPCR and western blot. We obtained 802 macrophage-related genes in single-cell analysis. Differential expression analysis yielded 743 DEGs. Thirty-seven macrophage-associated DEGs were identified by cross-analysis of marker genes with macrophage-associated DEGs. Thirty-seven intersections were screened and cross-analysed using four machine learning algorithms. Finally, HMOX1 was identified as a potentially valuable biomarker. HMOX1 was significantly associated with biological pathways such as the insulin signalling pathway. The results showed that HMOX1 was significantly overexpressed in DFU samples. In conclusion, the analytical results of this study identified HMOX1 as a potentially valuable biomarker associated with macrophages in DFU. The results of our analysis improve our understanding of the mechanism of macrophage action in this disease and may be useful in developing targeted therapies for DFU.
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Affiliation(s)
- Yiqi Chen
- Department of Burn and Plastic SurgeryAffiliated Hospital of Nantong UniversityNantongChina
| | - Yixin Zhang
- Department of Burn and Plastic SurgeryAffiliated Hospital of Nantong UniversityNantongChina
- Department of Breast SurgeryYantai City Yantai Hill hospitalYantaiChina
| | - Ming Jiang
- Department of Burn and Plastic SurgeryAffiliated Hospital of Nantong UniversityNantongChina
| | - Hong Ma
- Department of Burn and Plastic SurgeryAffiliated Hospital of Nantong UniversityNantongChina
- Department of BurnHanzhong Central HospitalHanZhongChina
| | - Yuhui Cai
- Department of Burn and Plastic SurgeryAffiliated Hospital of Nantong UniversityNantongChina
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31
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Xool-Tamayo J, Arana-Argaez VE, Villa-de la Torre F, Chan-Zapata I, Vargas-Coronado RF, Cauich-Rodríguez JV. Macrophages morphology and cytokine reeducation by ex situ copper thiol complexes. Immunopharmacol Immunotoxicol 2024; 46:20-32. [PMID: 37584252 DOI: 10.1080/08923973.2023.2245559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 08/02/2023] [Indexed: 08/17/2023]
Abstract
OBJECTIVE To study the reeducation effect of copper thiol complexes on macrophage morphology and cytokine expression. METHODS The effect of copper thiol complexes was assessed on murine macrophages by the cell morphology observed through optical microscopy, while the expression of cytokines by protein abundance after stimulation. A viability experiment was performed on PMBC to confirm that copper complexes do not affect other cells. RESULTS The M1 shape was reported after treatment with copper thiol complexes at 1-200 µM, while M2 behavior was documented between 50 and 800 µM. Surprisingly, a thin elongate morphology was observed between 400-800 µM like the M2 shape. The expression of M1 cytokines was noted ranging from 1 to 100 µM, with the highest yield at 1 µM (2243 pg/µL) for the copper-penicillamine complex. M2 production behavior was observed at 1-800 µM, with the highest abundance close to 1150 pg/µL (200-400 µM) was quantified from the copper-cysteine complex. Finally, LCCu complexes did not induce a cytotoxic response on PBMC while exhibiting a high IL-4 and IL-10 production, similar to their gold analogs. CONCLUSIONS The capacity of copper thiol complexes to reeducate M1 to M2 morphoexpression can be promising for cell protection by using copper thiol penicillamine or immuno-regeneration of tissues when using copper thiol cysteine.
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Affiliation(s)
- Jorge Xool-Tamayo
- Departamento de Innovación Biomédica, Centro de Investigación Científica y de Educación Superior de Ensenada (CICESE), Ensenada, México
| | | | | | - Ivan Chan-Zapata
- Laboratorio de Farmacología, Universidad Autónoma de Yucatán (UADY), Mérida, México
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Xiong S, Zhang Y, Zeng J, Zhou J, Liu S, Wei P, Liu H, Yi F, Wan Z, Xiong L, Zhang B, Li J. DLP fabrication of HA scaffold with customized porous structures to regulate immune microenvironment and macrophage polarization for enhancing bone regeneration. Mater Today Bio 2024; 24:100929. [PMID: 38229884 PMCID: PMC10789648 DOI: 10.1016/j.mtbio.2023.100929] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Revised: 11/24/2023] [Accepted: 12/23/2023] [Indexed: 01/18/2024] Open
Abstract
The immune microenvironment plays a pivotal role in osteoanagenesis. Biomaterials can modulate osteogenic efficacy by inducing specific local immune reactions. As 3D-printing technology advances, digital light projection printing has emerged as a promising method for creating large scale, high-precision biomaterial scaffolds. By adjusting the solid content and the sintering conditions during printing, the pore size of biomaterials can be meticulously controlled. Yet, the systematic influence of pore size on the immune microenvironment remains uncharted. We fabricated 3D-printed hydroxyapatite bioceramic scaffolds with three distinct pore sizes: 400 μm, 600 μm, and 800 μm. Our study revealed that scaffolds with a pore size of 600 μm promote macrophage M2 polarization, which is achieved by upregulating interferon-beta and HIF-1α production. When these materials were implanted subcutaneously in rats and within rabbit skulls, we observed that the 600 μm scaffolds notably improved the long-term inflammatory response, fostered vascular proliferation, and augmented new bone growth. This research paves the way for innovative therapeutic strategies for treating large segmental bone defects in clinical settings.
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Affiliation(s)
- Shilang Xiong
- Department of Orthopedics, First Affiliated Hospital of Nanchang University, No. 17 Yong Wai Zheng Street, Nanchang, Jiangxi, 330006, China
| | - Yinuo Zhang
- Department of Orthopedics, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai, 200040, China
| | - Jianhua Zeng
- Department of Spine Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Jingyu Zhou
- Department of Orthopedics, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Shiwei Liu
- Department of Orthopedics, Ganzhou People's Hospital No.16, Mei Guan Road, Zhang Gong District, Ganzhou, Jiangxi, 341000, China
| | - Peng Wei
- Department of Orthopedics, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Hantian Liu
- Department of Orthopedics, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Feng Yi
- Department of Orthopedics, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Zongmiao Wan
- Department of Orthopedics, First Affiliated Hospital of Nanchang University, No. 17 Yong Wai Zheng Street, Nanchang, Jiangxi, 330006, China
| | - Long Xiong
- Department of Orthopedics, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Bin Zhang
- Department of Orthopedics, First Affiliated Hospital of Nanchang University, No. 17 Yong Wai Zheng Street, Nanchang, Jiangxi, 330006, China
| | - Jingtang Li
- Department of Traumatology, Jiangxi Provincial People's Hospital the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, China
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Zhou X, Ye C, Jiang L, Zhu X, Zhou F, Xia M, Chen Y. The bone mesenchymal stem cell-derived exosomal miR-146a-5p promotes diabetic wound healing in mice via macrophage M1/M2 polarization. Mol Cell Endocrinol 2024; 579:112089. [PMID: 37863468 DOI: 10.1016/j.mce.2023.112089] [Citation(s) in RCA: 22] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 10/10/2023] [Accepted: 10/12/2023] [Indexed: 10/22/2023]
Abstract
A diabetic wound is a refractory disease that afflicts patients globally. MicroRNA-146a-5p (miR-146a-5p) is reported to represent a potential therapeutic target for diabetic wounds. However, microRNA easily degrades in the wound microenvironment. This study extracted bone marrow mesenchymal stem cell (BMSC)-derived exosomes (EXO). Electroporation technology was used to load miR-146a-5p into EXO (labeled as EXO-miR-146a). The endothelial cells (human umbilical vein endothelial cells [HUVECs]) and macrophages were cocultured in transwell chambers in the presence of high glucose. Cell proliferation, migration, and angiogenesis were measured with cell counting kit 8, scratch, and tube forming assays, respectively. Flow cytometry was introduced to validate the biomarker of macrophages and BMSCs. The expression level of macrophage polarization-related proteins and tumor necrosis factor receptor-associated factor 6 (TRAF6) was assessed with western blotting analysis. The full-thickness skin wound model was developed to verify the in vitro results. EXO-miR-146a promoted the proliferation, migration, and angiogenesis of HUVECs in the hyperglycemic state by suppressing the TRAF6 expression in vitro. Additionally, EXO-miR-146a treatment facilitated M2 but inhibited M1 macrophage polarization. Furthermore, EXO-miR-146a enhances reepithelialization, angiogenesis, and M2 macrophage polarization, thereby accelerating diabetic wound healing in vivo. The EXO-miR-146a facilitated M2 macrophage polarization, proliferation, migration, and angiogenesis of HUVECs through TRAF6, thereby ameliorating intractable diabetic wound healing. These results established the basis for using EXO to deliver drugs and revealed mediators for diabetic wound treatment.
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Affiliation(s)
- Xijie Zhou
- Department of Hand and Microsurgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
| | - Chenhao Ye
- Department of Hand and Microsurgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
| | - Liangfu Jiang
- Department of Hand and Microsurgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
| | - Xuwei Zhu
- Department of Hand and Microsurgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
| | - Feiya Zhou
- Department of Hand and Microsurgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
| | - Meizi Xia
- Department of Nephrology, Wenzhou Geriatric Hospital, Wenzhou, 325000, China.
| | - Yiheng Chen
- Department of Hand and Microsurgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
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Zhang Y, Wei J, Yu X, Chen L, Ren R, Dong Y, Wang S, Zhu M, Ming N, zhu Z, Gao C, Xiong W. CXCL chemokines-mediated communication between macrophages and BMSCs on titanium surface promotes osteogenesis via the actin cytoskeleton pathway. Mater Today Bio 2023; 23:100816. [PMID: 37859997 PMCID: PMC10582501 DOI: 10.1016/j.mtbio.2023.100816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Revised: 09/06/2023] [Accepted: 09/22/2023] [Indexed: 10/21/2023] Open
Abstract
The refined functional cell subtypes in the immune microenvironment of specific titanium (Ti) surface and their collaborative role in promoting bone marrow mesenchymal stem cells (BMSCs) driven bone integration need to be comprehensively characterized. This study employed a simplified co-culture system to investigate the dynamic, temporal crosstalk between macrophages and BMSCs on the Ti surface. The M2-like sub-phenotype of macrophages, characterized by secretion of CXCL chemokines, emerges as a crucial mediator for promoting BMSC osteogenic differentiation and bone integration in the Ti surface microenvironment. Importantly, these two cells maintain their distinct functional phenotypes through a mutually regulatory interplay. The secretion of CXCL3, CXCL6, and CXCL14 by M2-like macrophages plays a pivotal role. The process activates CXCR2 and CCR1 receptors, triggering downstream regulatory effects on the actin cytoskeleton pathway within BMSCs, ultimately fostering osteogenic differentiation. Reciprocally, BMSCs secrete pleiotrophin (PTN), a key player in regulating macrophage differentiation. This secretion maintains the M2-like phenotype via the Sdc3 receptor-mediated cell adhesion molecules pathway. Our findings provide a novel insight into the intricate communication and mutual regulatory mechanisms operating between BMSCs and macrophages on the Ti surface, highlight specific molecular events governing cell-cell interactions in the osteointegration, inform the surface design of orthopedic implants, and advance our understanding of osteointegration.
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Affiliation(s)
- Yayun Zhang
- Department of Orthopedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
- Trauma Center/Department of Emergency and Trauma Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Jiemao Wei
- Department of Orthopedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Xingbang Yu
- Department of Orthopedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Liangxi Chen
- Department of Orthopedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Ranyue Ren
- Department of Orthopedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Yimin Dong
- Department of Orthopedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Sibo Wang
- Department of Orthopedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Meipeng Zhu
- Department of Orthopedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Nannan Ming
- The State Key Laboratory of Refractories and Metallurgy Institute of Advanced Materials and Nanotechnology Wuhan University of Science and Technology, Wuhan, 430081, China
| | - Ziwei zhu
- Department of Orthopedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Chenghao Gao
- Department of Orthopedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
| | - Wei Xiong
- Department of Orthopedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China
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Gong Y, Wang P, Cao R, Wu J, Ji H, Wang M, Hu C, Huang P, Wang X. Exudate Absorbing and Antimicrobial Hydrogel Integrated with Multifunctional Curcumin-Loaded Magnesium Polyphenol Network for Facilitating Burn Wound Healing. ACS NANO 2023; 17:22355-22370. [PMID: 37930078 DOI: 10.1021/acsnano.3c04556] [Citation(s) in RCA: 76] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/07/2023]
Abstract
Burns are among the most common causes of trauma worldwide. Reducing the healing time of deep burn wounds has always been a major challenge. Traditional dressings not only require a lengthy medical procedure but also cause unbearable pain and secondary damage to patients. In this study, we developed an exudate-absorbing and antimicrobial hydrogel with a curcumin-loaded magnesium polyphenol network (Cur-Mg@PP) to promote burn wound healing. That hydrogel was composed of an ε-poly-l-lysine (ε-PLL)/polymer poly(γ-glutamic acid) (γ-PGA) hydrogel (PP) and curcumin-loaded magnesium polyphenol network (Cur-Mg). Because of the strong water absorption property of ε-PLL and γ-PGA, Cur-Mg@PP powder can quickly absorb the wound exudate and transform into a moist and viscous hydrogel, thus releasing payloads such as magnesium ion (Mg2+) and curcumin (Cur). The released Mg2+ and Cur demonstrated good therapeutic efficacy on analgesic, antioxidant, anti-inflammation, angiogenesis, and tissue regeneration. Our findings provide a strategy for accelerating burn wound healing.
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Affiliation(s)
- Yan Gong
- Department of Thoracic Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Pei Wang
- Department of Thoracic Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Ran Cao
- Marshall Laboratory of Biomedical Engineering, International Cancer Center, Laboratory of Evolutionary Theranostics (LET), School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China
| | - Jiayingzi Wu
- Marshall Laboratory of Biomedical Engineering, International Cancer Center, Laboratory of Evolutionary Theranostics (LET), School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China
| | - Haoran Ji
- Department of Thoracic Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Mingsong Wang
- Department of Thoracic Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Chuang Hu
- Department of Thoracic Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Peng Huang
- Marshall Laboratory of Biomedical Engineering, International Cancer Center, Laboratory of Evolutionary Theranostics (LET), School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China
| | - Xiansong Wang
- Department of Thoracic Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
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Qian M, Li S, Xi K, Tang J, Shen X, Liu Y, Guo R, Zhang N, Gu Y, Xu Y, Cui W, Chen L. ECM-engineered electrospun fibers with an immune cascade effect for inhibiting tissue fibrosis. Acta Biomater 2023; 171:308-326. [PMID: 37673231 DOI: 10.1016/j.actbio.2023.08.058] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 08/25/2023] [Accepted: 08/29/2023] [Indexed: 09/08/2023]
Abstract
Tissue regeneration/fibrosis after injury is intricately regulated by the immune cascade reaction and extracellular matrix (ECM). Dysregulated cascade signal could jeopardize tissue homeostasis leading to fibrosis. Bioactive scaffolds mimicking natural ECM microstructure and chemistry could regulate the cascade reaction to achieve tissue regeneration. The current study constructed an ECM-engineered micro/nanofibrous scaffold using self-assembled nanofibrous collagen and decorin (DCN)-loaded microfibers to regulate the immune cascade reaction. The ECM-engineered scaffold promoted anti-inflammatory and pro-regenerative effects, M2 polarization of macrophages, by nanofibrous collagen. The ECM-engineered scaffold could release DCN to inhibit inflammation-associated fibrous angiogenesis. Yet, to prevent excessive M2 activity leading to tissue fibrosis, controlled release of DCN was expected to elicit M1 activity and achieve M1/M2 balance in the repair process. Regulated cascade reaction guided favorable crosstalk between macrophages, endothelial cells and fibroblasts by proximity. Additionally, decorin could also antagonize TGF-β1 via TGF-β/Smad3 pathway to suppress fibrotic activity of fibroblasts. Hence, ECM-engineered scaffolds could exert effective regulation of the immune cascade reaction by microstructure and DCN release and achieve the balance between tissue fibrosis and regeneration. STATEMENT OF SIGNIFICANCE: With the incidence of up to 74.6%, failed back surgery syndrome (FBSS) has been a lingering issue in spine surgery, which poses a heavy socio-economic burden to society. Epidural fibrosis is believed to be responsible for the onset of FBSS. Current biomaterial-based strategies treating epidural fibrosis mainly rely on physical barriers and unidirectional suppression of inflammation. Regulation of the immune cascade reaction for inhibiting fibrosis has not been widely studied. Based on the simultaneous regulation of M1/M2 polarization and intercellular crosstalk, the ECM-engineered micro/nanofibrous scaffolds constructed in the current study could exert an immune cascade effect to coordinate tissue regeneration and inhibit fibrosis. This finding makes a significant contribution in the development of a treatment for epidural fibrosis and FBSS.
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Affiliation(s)
- Ming Qian
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006 PR China
| | - Shun Li
- Center for Rehabilitation Medicine, Department of Pain Management, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, PR China
| | - Kun Xi
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006 PR China
| | - Jincheng Tang
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006 PR China
| | - Xiaofeng Shen
- Department of Orthopaedic Surgery, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, 889 Wuzhong West Road, Suzhou, Jiangsu 215006, PR China
| | - Yong Liu
- Department of Orthopaedic Surgery, Affiliated Jiangyin Hospital of Nantong University, Jiangyin, Jiangsu 215600, PR China
| | - Ran Guo
- Center for Rehabilitation Medicine, Department of Pain Management, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, PR China
| | - Nannan Zhang
- Center for Rehabilitation Medicine, Department of Pain Management, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, PR China
| | - Yong Gu
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006 PR China.
| | - Yun Xu
- Center for Rehabilitation Medicine, Department of Pain Management, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, PR China.
| | - Wenguo Cui
- Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, PR China.
| | - Liang Chen
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006 PR China.
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Liu Y, Xue M, Han Y, Li Y, Xiao B, Wang W, Yu J, Ye X. Exosomes from M2c macrophages alleviate intervertebral disc degeneration by promoting synthesis of the extracellular matrix via MiR-124/CILP/TGF-β. Bioeng Transl Med 2023; 8:e10500. [PMID: 38023721 PMCID: PMC10658595 DOI: 10.1002/btm2.10500] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 01/16/2023] [Accepted: 01/27/2023] [Indexed: 02/18/2023] Open
Abstract
Immuno-inflammation is highly associated with anabolic and catabolic dysregulation of the extracellular matrix (ECM) in the nucleus pulposus (NP), which dramatically propels intervertebral disc degeneration (IVDD). With the characteristics of tissue remodeling and regeneration, M2c macrophages have attracted great attention in research on immune modulation that rebuilds degenerated tissues. Therefore, we first demonstrated the facilitating effects of M2c macrophages on ECM anabolism of the NP in vitro. We subsequently found that exosomes from M2c macrophages (M2c-Exoss) mediated their metabolic rebalancing effects on the ECM. To determine whether M2c-Exoss served as positive agents protecting the ECM in IVDD, we constructed an M2c-Exos-loaded hyaluronic acid hydrogel (M2c-Exos@HA hydrogel) and implanted it into the degenerated caudal disc of rats. The results of MRI and histological staining indicated that the M2c-Exos@HA hydrogel alleviated IVDD in vivo in the long term. To elucidate the underlying molecular mechanism, we performed 4D label-free proteomics to screen dysregulated proteins in NPs treated with M2c-Exoss. Cartilage intermediate layer protein (CILP) was the key protein responsible for the rebalancing effects of M2c-Exoss on ECM metabolism in the NP. With prediction and verification using luciferase assays and rescue experiments, miR-124-3p was identified as the upstream regulator in M2c-Exoss that regulated CILP and consequently enhanced the activity of the TGF-β/smad3 pathway. In conclusion, we demonstrated ameliorating effects of M2c-Exoss on the imbalance of ECM metabolism in IVDD via the miR-124/CILP/TGF-β regulatory axis, which provides a promising theoretical basis for the application of M2c macrophages and their exosomes in the treatment of IVDD.
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Affiliation(s)
- Yi Liu
- Department of OrthopaedicsSecond Affiliated Hospital of Naval Medical UniversityShanghaiPeople's Republic of China
- Department of OrthopedicsTongren Hospital, Shanghai Jiao Tong University School of MedicineShanghaiPeople's Republic of China
| | - Mintao Xue
- Department of OrthopaedicsSecond Affiliated Hospital of Naval Medical UniversityShanghaiPeople's Republic of China
| | - Yaguang Han
- Department of OrthopaedicsSecond Affiliated Hospital of Naval Medical UniversityShanghaiPeople's Republic of China
| | - Yucai Li
- Department of OrthopedicsTongren Hospital, Shanghai Jiao Tong University School of MedicineShanghaiPeople's Republic of China
| | - Bing Xiao
- Department of OrthopaedicsSecond Affiliated Hospital of Naval Medical UniversityShanghaiPeople's Republic of China
| | - Weiheng Wang
- Department of OrthopaedicsSecond Affiliated Hospital of Naval Medical UniversityShanghaiPeople's Republic of China
| | - Jiangming Yu
- Department of OrthopedicsTongren Hospital, Shanghai Jiao Tong University School of MedicineShanghaiPeople's Republic of China
| | - Xiaojian Ye
- Department of OrthopedicsTongren Hospital, Shanghai Jiao Tong University School of MedicineShanghaiPeople's Republic of China
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Yabuuchi K, Suzuki M, Liang C, Hashimoto Y, Kimura T, Akiyoshi K, Kishida A. Preparation of Cholesterol-Modified Hyaluronic Acid Nanogel-Based Hydrogel and the Inflammatory Evaluation Using Macrophage-like Cells. Gels 2023; 9:866. [PMID: 37998957 PMCID: PMC10671248 DOI: 10.3390/gels9110866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 10/23/2023] [Accepted: 10/25/2023] [Indexed: 11/25/2023] Open
Abstract
Nanogels are candidate biomaterials for tissue engineering and drug delivery. In the present study, a cholesterol-hyaluronic acid hydrogel was developed, and the pro-inflammatory response of macrophages to the hydrogel was investigated to determine its use in biomedical applications. Hyaluronic acid modified with cholesterol (modification rate: 0-15%) and maleimide (Chol-HA) was synthesized. The Chol-HA nanogel was formed through self-assembly via hydrophobic cholesterol interactions in aqueous solution. The Chol-HA hydrogel was formed through chemical crosslinking of the Chol-HA nanogel via a Michael addition reaction between the maleimide and thiol groups of 4arm-PEGSH. We found that the Chol-HA hydrogels with 5, 10, and 15% cholesterol inhibited the pro-inflammatory response of HiBiT-THP-1 cells, suggesting that the cholesterol contributed to the macrophage response. Furthermore, Interleukin 4 (IL-4) encapsulated in the hydrogel of the Chol-HA nanogel enhanced the inhibition of the inflammatory response in HiBiT-THP-1 cells. These results provide useful insights into the biomedical applications of hydrogels.
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Affiliation(s)
- Kohei Yabuuchi
- New Product Development Office, R&D Group, Healthcare Materials Division, Life Innovation SBU, Asahi Kasei Co., Chiyoda-ku, Tokyo 100-0006, Japan
- Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-surugadai, Chiyoda-ku, Tokyo 101-0062, Japan
| | - Mika Suzuki
- Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-surugadai, Chiyoda-ku, Tokyo 101-0062, Japan
| | - Chen Liang
- Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-surugadai, Chiyoda-ku, Tokyo 101-0062, Japan
| | - Yoshihide Hashimoto
- Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-surugadai, Chiyoda-ku, Tokyo 101-0062, Japan
| | - Tsuyoshi Kimura
- Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-surugadai, Chiyoda-ku, Tokyo 101-0062, Japan
| | - Kazunari Akiyoshi
- Department of Immunology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Akio Kishida
- Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-surugadai, Chiyoda-ku, Tokyo 101-0062, Japan
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Li Y, Yang G, Wang Y, Li Y, Zhang S, Li R, Yang L, Wang J, Pei X, Wan Q, Chen J. Osteoimmunity-regulating nanosilicate-reinforced hydrogels for enhancing osseointegration. J Mater Chem B 2023; 11:9933-9949. [PMID: 37822156 DOI: 10.1039/d3tb01509b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/13/2023]
Abstract
Following the introduction of osteo-immunomodulation as a new and important strategy to enhance material osseointegration, achieving an appropriate immune response after biomaterial implantation has become a significant challenge for efficient bone repair. In this study, a nanosilicate-reinforced sodium alginate (SA) hydrogel was fabricated by introducing montmorillonite (MMT) nanoparticles. Meanwhile, an immunogenically bioactive agent, harmine (HM), was loaded and released to induce macrophage differentiation into the M2 type. The fabricated SA/MMT/HM (SMH) hydrogel exhibited improved mechanical stiffness and stability, which also efficiently promoted macrophage anti-inflammatory M2 phenotype polarization and enhanced the secretion of pro-tissue healing cytokines for inducing a favorable immunomodulatory microenvironment for the osteogenic differentiation of bone marrow stromal cells (BMSCs). Furthermore, a rat air-pouch model and a critical-size bone defect model were used and the results showed that the SMH hydrogel increased the proportion of M2 macrophages and markedly reduced local inflammation, while enhancing desirable new bone formation. Transcriptomic analysis revealed that the SMH hydrogel accelerated the M1-to-M2 transition of macrophages by inhibiting relevant inflammatory signaling pathways and activating the PI3K-AKT1 signaling pathway. Taken together, this high-intensity immunomodulatory hydrogel may be a promising biomaterial for bone regeneration and provide a valuable base and positive enlightenment for massive bone defect repair.
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Affiliation(s)
- Yuanyuan Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chengdu 610041, China.
- Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, South Peoples Road, Chengdu 610041, China
- Department of Preventive Dentistry, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, China
| | - Guangmei Yang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chengdu 610041, China.
- Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, South Peoples Road, Chengdu 610041, China
| | - Yuting Wang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chengdu 610041, China.
- Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, South Peoples Road, Chengdu 610041, China
| | - Yahong Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chengdu 610041, China.
- Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, South Peoples Road, Chengdu 610041, China
| | - Shu Zhang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chengdu 610041, China.
- Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, South Peoples Road, Chengdu 610041, China
| | - Ruyi Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chengdu 610041, China.
- Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, South Peoples Road, Chengdu 610041, China
| | - Linxin Yang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chengdu 610041, China.
- Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, South Peoples Road, Chengdu 610041, China
| | - Jian Wang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chengdu 610041, China.
- Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, South Peoples Road, Chengdu 610041, China
| | - Xibo Pei
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chengdu 610041, China.
- Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, South Peoples Road, Chengdu 610041, China
| | - Qianbing Wan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chengdu 610041, China.
- Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, South Peoples Road, Chengdu 610041, China
| | - Junyu Chen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chengdu 610041, China.
- Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, South Peoples Road, Chengdu 610041, China
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Martin KE, Hunckler MD, Chee E, Caplin JD, Barber GF, Kalelkar PP, Schneider RS, García AJ. Hydrolytic hydrogels tune mesenchymal stem cell persistence and immunomodulation for enhanced diabetic cutaneous wound healing. Biomaterials 2023; 301:122256. [PMID: 37517209 PMCID: PMC10529272 DOI: 10.1016/j.biomaterials.2023.122256] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 07/20/2023] [Accepted: 07/23/2023] [Indexed: 08/01/2023]
Abstract
Diabetes is associated with an altered global inflammatory state with impaired wound healing. Mesenchymal stem/stromal cells (MSC) are being explored for treatment of diabetic cutaneous wounds due to their regenerative properties. These cells are commonly delivered by injection, but the need to prolong the retention of MSC at sites of injury has spurred the development of biomaterial-based MSC delivery vehicles. However, controlling biomaterial degradation rates in vivo remains a therapeutic-limiting challenge. Here, we utilize hydrolytically degradable ester linkages to engineer synthetic hydrogels with tunable in vivo degradation kinetics for temporally controlled delivery of MSC. In vivo hydrogel degradation rate can be controlled by altering the ratio of ester to amide linkages in the hydrogel macromers. These hydrolytic hydrogels degrade at rates that enable unencumbered cutaneous wound healing, while enhancing the local persistence MSC compared to widely used protease-degradable hydrogels. Furthermore, hydrogel-based delivery of MSC modulates local immune responses and enhances cutaneous wound repair in diabetic mice. This study introduces a simple strategy for engineering tunable degradation modalities into synthetic biomaterials, overcoming a key barrier to their use as cell delivery vehicles.
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Affiliation(s)
- Karen E Martin
- Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA; Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA
| | - Michael D Hunckler
- Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA; Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA
| | - Eunice Chee
- Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA; Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA
| | - Jeremy D Caplin
- Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA; Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA
| | - Graham F Barber
- Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA; Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA
| | - Pranav P Kalelkar
- Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA; Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA
| | - Rebecca S Schneider
- Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA; School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA, USA
| | - Andrés J García
- Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA; Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA.
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41
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Dai Y, Xin L, Hu S, Xu S, Huang D, Jin X, Chen J, Chan RWS, Ng EHY, Yeung WSB, Ma L, Zhang S. A construct of adipose-derived mesenchymal stem cells-laden collagen scaffold for fertility restoration by inhibiting fibrosis in a rat model of endometrial injury. Regen Biomater 2023; 10:rbad080. [PMID: 37808957 PMCID: PMC10551231 DOI: 10.1093/rb/rbad080] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 08/28/2023] [Accepted: 08/29/2023] [Indexed: 10/10/2023] Open
Abstract
Severe endometrium damage causes pathological conditions such as thin endometrium and intrauterine adhesion, resulting in uterine factor infertility. Mesenchymal stem cell (MSC) therapy is a promising strategy in endometrial repair; yet, exogenous MSCs still raise concerns for safety and ethical issues. Human adipose-derived mesenchymal stem cells (ADMSCs) residing in adipose tissue have high translational potentials due to their autologous origin. To harness the high translation potentials of ADMSC in clinical endometrium regeneration, here we constructed an ADMSCs composited porous scaffold (CS/ADMSC) and evaluated its effectiveness on endometrial regeneration in a rat endometrium-injury model. We found that CS/ADMSC intrauterine implantation (i) promoted endometrial thickness and gland number, (ii) enhanced tissue angiogenesis, (iii) reduced fibrosis and (iv) restored fertility. We ascertained the pro-proliferation, pro-angiogenesis, immunomodulating and anti-fibrotic effects of CS/ADMSC in vitro and revealed that the CS/ADMSC influenced extracellular matrix composition and organization by a transcriptomic analysis. Our results demonstrated the effectiveness of CS/ADMSC for endometrial regeneration and provided solid proof for our future clinical study.
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Affiliation(s)
- Yangyang Dai
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China
- Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou 310016, China
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, China
| | - Liaobing Xin
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China
- Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou 310016, China
| | - Sentao Hu
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, China
| | - Shiqian Xu
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China
- Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou 310016, China
| | - Dong Huang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China
- Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou 310016, China
| | - Xiaoying Jin
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China
- Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou 310016, China
| | - Jianmin Chen
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China
- Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou 310016, China
| | - Rachel Wah Shan Chan
- Department of Obstetrics and Gynaecology, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR 999077, China
- Shenzhen Key Laboratory of Fertility Regulation, The University of Hong Kong Shenzhen Hospital, Shenzhen 518000, China
| | - Ernest Hung Yu Ng
- Department of Obstetrics and Gynaecology, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR 999077, China
- Shenzhen Key Laboratory of Fertility Regulation, The University of Hong Kong Shenzhen Hospital, Shenzhen 518000, China
| | - William Shu Biu Yeung
- Department of Obstetrics and Gynaecology, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR 999077, China
- Shenzhen Key Laboratory of Fertility Regulation, The University of Hong Kong Shenzhen Hospital, Shenzhen 518000, China
| | - Lie Ma
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, China
| | - Songying Zhang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China
- Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou 310016, China
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Cui J, Zhang YJ, Li X, Luo JJ, Zhao LL, Xie XY, Ding W, Luo JC, Qin TW. Decellularized tendon scaffolds loaded with collagen targeted extracellular vesicles from tendon-derived stem cells facilitate tendon regeneration. J Control Release 2023; 360:842-857. [PMID: 37478916 DOI: 10.1016/j.jconrel.2023.07.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 07/15/2023] [Accepted: 07/18/2023] [Indexed: 07/23/2023]
Abstract
Stem cell-based treatment of tendon injuries remains to have some inherent issues. Extracellular vesicles derived from stem cells have shown promising achievements in tendon regeneration, though their retention in vivo is low. This study reports on the use of a collagen binding domain (CBD) to bind extracellular vesicles, obtained from tendon-derived stem cells (TDSCs), to collagen. CBD-extracellular vesicles (CBD-EVs) were coupled to decellularized bovine tendon sheets (DBTS) to fabricate a bio-functionalized scaffold (CBD-EVs-DBTS). Our results show that thus obtained bio-functionalized scaffolds facilitate the proliferation, migration and tenogenic differentiation of stem cells in vitro. Furthermore, the scaffolds promote endogenous stem cell recruitment to the defects, facilitate collagen deposition and improve the biomechanics of injured tendons, thus resulting in functional regeneration of tendons.
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Affiliation(s)
- Jing Cui
- Department of Orthopedic Surgery and Orthopedic Research Institute, Laboratory of Stem Cell and Tissue Engineering, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Yan-Jing Zhang
- Department of Orthopedic Surgery and Orthopedic Research Institute, Laboratory of Stem Cell and Tissue Engineering, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Xuan Li
- Department of Orthopedic Surgery and Orthopedic Research Institute, Laboratory of Stem Cell and Tissue Engineering, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Jia-Jiao Luo
- Department of Orthopedic Surgery and Orthopedic Research Institute, Laboratory of Stem Cell and Tissue Engineering, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Lei-Lei Zhao
- Department of Orthopedic Surgery and Orthopedic Research Institute, Laboratory of Stem Cell and Tissue Engineering, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Xin-Yue Xie
- Department of Orthopedic Surgery and Orthopedic Research Institute, Laboratory of Stem Cell and Tissue Engineering, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Wei Ding
- Department of Orthopedic Surgery and Orthopedic Research Institute, Laboratory of Stem Cell and Tissue Engineering, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Jing-Cong Luo
- Department of Orthopedic Surgery and Orthopedic Research Institute, Laboratory of Stem Cell and Tissue Engineering, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Ting-Wu Qin
- Department of Orthopedic Surgery and Orthopedic Research Institute, Laboratory of Stem Cell and Tissue Engineering, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
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Geng K, Ma X, Jiang Z, Gu J, Huang W, Wang W, Xu Y, Xu Y. WDR74 facilitates TGF-β/Smad pathway activation to promote M2 macrophage polarization and diabetic foot ulcer wound healing in mice. Cell Biol Toxicol 2023; 39:1577-1591. [PMID: 35982296 DOI: 10.1007/s10565-022-09748-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 07/06/2022] [Indexed: 11/02/2022]
Abstract
Diabetic foot ulcer (DFU) is a devastating component of diabetes progression, leading to decreased quality of life and increased mortality in diabetic patients. The underlying mechanism of DFU is not completely understood. Hence, this study aims to elucidate the mechanism involved in wound healing in mouse models of DFU. Gain- and loss-of-function studies were performed to study the roles that WDR74 and TGF-β play in mouse models of DFU and primary bone marrow-derived mouse macrophages. M1 and M2 macrophage phenotypic markers, extracellular matrix (ECM) components, and angiogenic makers were determined by RT-qPCR and/or Western blot analysis. Localization of these proteins was determined by immunofluorescence staining and/or immunohistochemistry. Interaction between WDR74 with Smad2/3 in macrophages was detected by co-immunoprecipitation. We found that WDR74 and M2 macrophages were decreased in wound tissues from DFU mice. TGF-β/Smad pathway activation increased the expression of M2 macrophage markers (arginase-1 and YM1), IL-4, while decreased expression of M1 macrophage marker (iNOS). TGF-β/Smad pathway activation also increased the production of ECM and promoted the wound closure in diabetic mice. We also noticed that WDR74 overexpression increased Smad2/3 phosphorylation, elevated the population of M2 macrophage and ECM production, and alleviated DFU. LY2109761 treatment normalized effects of TGF-β or WDR74 overexpression. In conclusion, WDR74 promoted M2 macrophage polarization, leading to improved DFU in mice, through activation of the TGF-β/Smad pathway. Graphical Headlights 1. WDR74 promotes M2 macrophage polarization and ECM production. 2. WDR74 activates the TGF-β/Smad signaling pathway. 3. TGF-β/Smad activation promotes M2 macrophage polarization in murine DFU. 4. WDR74 enhances wound healing in murine DFU.
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Affiliation(s)
- Kang Geng
- Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macao
- Department of Endocrinology and Metabolism, Metabolic Vascular Disease Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Nephropathy, Luzhou, Sichuan, People's Republic of China
- Department of Plastic and Burn Surgery, National Key Clinical Construction Specialty, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People's Republic of China
| | - Xiumei Ma
- Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macao
- Department of Endocrinology and Metabolism, Metabolic Vascular Disease Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Nephropathy, Luzhou, Sichuan, People's Republic of China
| | - Zongzhe Jiang
- Department of Endocrinology and Metabolism, Metabolic Vascular Disease Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Nephropathy, Luzhou, Sichuan, People's Republic of China
| | - Junling Gu
- Endocrinology Department, The Second People's Hospital of Yibin, West China Yibin Hospital, Sichuan University, Yibin, Sichuan, People's Republic of China
| | - Wei Huang
- Department of Endocrinology and Metabolism, Metabolic Vascular Disease Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Nephropathy, Luzhou, Sichuan, People's Republic of China
| | - Weiming Wang
- Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macao
- Department of General Surgery (Vascular Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People's Republic of China
| | - Yong Xu
- Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macao.
- Department of Endocrinology and Metabolism, Metabolic Vascular Disease Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Nephropathy, Luzhou, Sichuan, People's Republic of China.
| | - Youhua Xu
- Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macao.
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Protzman NM, Mao Y, Long D, Sivalenka R, Gosiewska A, Hariri RJ, Brigido SA. Placental-Derived Biomaterials and Their Application to Wound Healing: A Review. Bioengineering (Basel) 2023; 10:829. [PMID: 37508856 PMCID: PMC10376312 DOI: 10.3390/bioengineering10070829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 06/20/2023] [Accepted: 07/03/2023] [Indexed: 07/30/2023] Open
Abstract
Chronic wounds are associated with considerable patient morbidity and present a significant economic burden to the healthcare system. Often, chronic wounds are in a state of persistent inflammation and unable to progress to the next phase of wound healing. Placental-derived biomaterials are recognized for their biocompatibility, biodegradability, angiogenic, anti-inflammatory, antimicrobial, antifibrotic, immunomodulatory, and immune privileged properties. As such, placental-derived biomaterials have been used in wound management for more than a century. Placental-derived scaffolds are composed of extracellular matrix (ECM) that can mimic the native tissue, creating a reparative environment to promote ECM remodeling, cell migration, proliferation, and differentiation. Reliable evidence exists throughout the literature to support the safety and effectiveness of placental-derived biomaterials in wound healing. However, differences in source (i.e., anatomical regions of the placenta), preservation techniques, decellularization status, design, and clinical application have not been fully evaluated. This review provides an overview of wound healing and placental-derived biomaterials, summarizes the clinical results of placental-derived scaffolds in wound healing, and suggests directions for future work.
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Affiliation(s)
- Nicole M Protzman
- Healthcare Analytics, LLC, 78 Morningside Dr., Easton, PA 18045, USA
| | - Yong Mao
- Laboratory for Biomaterials Research, Department of Chemistry and Chemical Biology, Rutgers University, 145 Bevier Rd., Piscataway, NJ 08854, USA
| | - Desiree Long
- Research & Development, Degenerative Diseases, Celularity Inc., 170 Park Ave., Florham Park, NJ 07932, USA
| | - Raja Sivalenka
- Research & Development, Degenerative Diseases, Celularity Inc., 170 Park Ave., Florham Park, NJ 07932, USA
| | - Anna Gosiewska
- Research & Development, Degenerative Diseases, Celularity Inc., 170 Park Ave., Florham Park, NJ 07932, USA
| | - Robert J Hariri
- Research & Development, Degenerative Diseases, Celularity Inc., 170 Park Ave., Florham Park, NJ 07932, USA
| | - Stephen A Brigido
- Research & Development, Degenerative Diseases, Celularity Inc., 170 Park Ave., Florham Park, NJ 07932, USA
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Sung S, Steele LA, Risser GE, Spiller KL. Biomaterial-Assisted Macrophage Cell Therapy for Regenerative Medicine. Adv Drug Deliv Rev 2023:114979. [PMID: 37394101 DOI: 10.1016/j.addr.2023.114979] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 06/27/2023] [Accepted: 06/29/2023] [Indexed: 07/04/2023]
Abstract
Although most tissue types are capable of some form of self-repair and regeneration, injuries that are larger than a critical threshold or those occurring in the setting of certain diseases can lead to impaired healing and ultimately loss of structure and function. The immune system plays an important role in tissue repair and must be considered in the design of therapies in regenerative medicine. In particular, macrophage cell therapy has emerged as a promising strategy that leverages the reparative roles of these cells. Macrophages are critical for successful tissue repair and accomplish diverse functions throughout all phases of the process by dramatically shifting in phenotypes in response to microenvironmental cues. Depending on their response to various stimuli, they may release growth factors, support angiogenesis, and facilitate extracellular matrix remodeling. However, this ability to rapidly shift phenotype is also problematic for macrophage cell therapy strategies, because adoptively transferred macrophages fail to maintain therapeutic phenotypes following their administration to sites of injury or inflammation. Biomaterials are a potential way to control macrophage phenotype in situ while also enhancing their retention at sites of injury. Cell delivery systems incorporated with appropriately designed immunomodulatory signals have potential to achieve tissue regeneration in intractable injuries where traditional therapies have failed. Here we explorecurrent challenges in macrophage cell therapy, especially retention and phenotype control, how biomaterials may overcome them, and opportunities for next generation strategies. Biomaterials will be an essential tool to advance macrophage cell therapy for widespread clinical applications.
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Affiliation(s)
- Samuel Sung
- School of Biomedical Engineering, Science, and Health Systems, Drexel University, Philadelphia, PA, USA
| | - Lindsay A Steele
- School of Biomedical Engineering, Science, and Health Systems, Drexel University, Philadelphia, PA, USA
| | - Gregory E Risser
- School of Biomedical Engineering, Science, and Health Systems, Drexel University, Philadelphia, PA, USA
| | - Kara L Spiller
- School of Biomedical Engineering, Science, and Health Systems, Drexel University, Philadelphia, PA, USA
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Cheng C, Li H, Liu J, Wu L, Fang Z, Xu G. MCP-1-Loaded Poly(l-lactide- co-caprolactone) Fibrous Films Modulate Macrophage Polarization toward an Anti-inflammatory Phenotype and Improve Angiogenesis. ACS Biomater Sci Eng 2023. [PMID: 37367696 DOI: 10.1021/acsbiomaterials.3c00476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/28/2023]
Abstract
Tissue engineering approaches such as the electrospinning technique can fabricate nanofibrous scaffolds which are widely used for small-diameter vascular grafting. However, foreign body reaction (FBR) and lack of endothelial coverage are still the main cause of graft failure after the implantation of nanofibrous scaffolds. Macrophage-targeting therapeutic strategies have the potential to address these issues. Here, we fabricate a monocyte chemotactic protein-1 (MCP-1)-loaded coaxial fibrous film with poly(l-lactide-co-ε-caprolactone) (PLCL/MCP-1). The PLCL/MCP-1 fibrous film can polarize macrophages toward anti-inflammatory M2 macrophages through the sustained release of MCP-1. Meanwhile, these specific functional polarization macrophages can mitigate FBR and promote angiogenesis during the remodeling of implanted fibrous films. These studies indicate that MCP-1-loaded PLCL fibers have a higher potential to modulate macrophage polarity, which provides a new strategy for small-diameter vascular graft designing.
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Affiliation(s)
- Can Cheng
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P. R. China
- Department of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, P. R. China
| | - Heng Li
- Department of Comprehensive Surgery, Anhui Provincial Cancer Hospital, West District of The First Affiliated Hospital of USTC, Hefei, Anhui 230001, P. R. China
| | - Jingwen Liu
- Anhui Provincial Hospital Health Management Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, P. R. China
| | - Liang Wu
- Department of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, P. R. China
| | - Zhengdong Fang
- Department of Vascular Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, P. R. China
| | - Geliang Xu
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P. R. China
- Department of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, P. R. China
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Xu N, Gao Y, Li Z, Chen Y, Liu M, Jia J, Zeng R, Luo G, Li J, Yu Y. Immunoregulatory hydrogel decorated with Tannic acid/Ferric ion accelerates diabetic wound healing via regulating Macrophage polarization. CHEMICAL ENGINEERING JOURNAL 2023; 466:143173. [DOI: 10.1016/j.cej.2023.143173] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Sun D, Zhang G, Xie M, Wang Y, Liang X, Tu M, Su Z, Zeng R. Softness enhanced macrophage-mediated therapy of inhaled apoptotic-cell-inspired nanosystems for acute lung injury. J Nanobiotechnology 2023; 21:172. [PMID: 37248505 DOI: 10.1186/s12951-023-01930-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 05/14/2023] [Indexed: 05/31/2023] Open
Abstract
Engineered nanosystems offer a promising strategy for macrophage-targeted therapies for various diseases, and their physicochemical parameters including surface-active ligands, size and shape are widely investigated for improving their therapeutic efficacy. However, little is known about the synergistic effect of elasticity and surface-active ligands. Here, two kinds of anti-inflammatory N-acetylcysteine (NAC)-loaded macrophage-targeting apoptotic-cell-inspired phosphatidylserine (PS)-containing nano-liposomes (PSLipos) were constructed, which had similar size and morphology but different Young's modulus (E) (H, ~ 100 kPa > Emacrophage vs. L, ~ 2 kPa < Emacrophage). Interestingly, these PSLipos-NAC showed similar drug loading and encapsulation efficiency, and in vitro slow-release behavior of NAC, but modulus-dependent interactions with macrophages. Softer PSLipos-L-NAC could resist macrophage capture, but remarkably prolong their targeting effect period on macrophages via durable binding to macrophage surface, and subsequently more effectively suppress inflammatory response in macrophages and then hasten inflammatory lung epithelial cell wound healing. Especially, pulmonary administration of PSLipos-L-NAC could significantly reduce the inflammatory response of M1-like macrophages in lung tissue and promote lung injury repair in a bleomycin-induced acute lung injury (ALI) mouse model, providing a potential therapeutic approach for ALI. The results strongly suggest that softness may enhance ligand-directed macrophage-mediated therapeutic efficacy of nanosystems, which will shed new light on the design of engineered nanotherapeutics.
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Affiliation(s)
- Dazheng Sun
- Department of Materials Science and Engineering, College of Chemistry and Materials, Jinan University, Guangzhou, 510632, P. R. China
| | - Guanglin Zhang
- Department of Materials Science and Engineering, College of Chemistry and Materials, Jinan University, Guangzhou, 510632, P. R. China
- Henry Fok Colloge of Biology and Agriculture, Shaoguan University, Shaoguan, 512005, P. R. China
| | - Mingyang Xie
- Department of Materials Science and Engineering, College of Chemistry and Materials, Jinan University, Guangzhou, 510632, P. R. China
| | - Yina Wang
- Guangdong Provincial Key Laboratory of Bioengineering Medicine, Department of Cell Biology, Jinan University, Guangzhou, 510632, P. R. China
- National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, 510632, P. R. China
| | - Xiangchao Liang
- Department of Materials Science and Engineering, College of Chemistry and Materials, Jinan University, Guangzhou, 510632, P. R. China
| | - Mei Tu
- Department of Materials Science and Engineering, College of Chemistry and Materials, Jinan University, Guangzhou, 510632, P. R. China
| | - Zhijian Su
- Guangdong Provincial Key Laboratory of Bioengineering Medicine, Department of Cell Biology, Jinan University, Guangzhou, 510632, P. R. China.
- National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, 510632, P. R. China.
| | - Rong Zeng
- Department of Materials Science and Engineering, College of Chemistry and Materials, Jinan University, Guangzhou, 510632, P. R. China.
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Zhao C, Yang C, Lou Q, Yan J, Wang X, Chang J. The memory effect of micro/nano-structures activating osteogenic differentiation of BMSCs. J Mater Chem B 2023; 11:3816-3822. [PMID: 37092687 DOI: 10.1039/d3tb00337j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/08/2023]
Abstract
Degradable bioceramics such as hydroxyapatite (HA) are usually used as bone grafts due to their excellent osteoconductive ability. Recent studies have proved that decorated micro/nano-structures on HA could enhance its osteogenic capacity by directly activating osteogenic differentiation of bone marrow-derived stem cells (BMSCs) or by indirectly activating the osteoimmune microenvironment. However, it is still unclear whether the degradation process of HA affects the activation effect of micro/nano-structures. In this study, we first demonstrate that the enhanced osteogenic properties activated by micro/nano-structures could be memorized and continue to play a role even after the removal of micro/nano-structures. More interestingly, this topography-triggered osteogenic memory effect (TTOME) could be regulated through the stimulation time, indicating the importance of the rational maintenance of micro/nano-structures as well as the degradation process of bioceramics. These findings provide a perspective of the design of bone implants with a biodegradable surface topography.
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Affiliation(s)
- Cancan Zhao
- State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, P. R. China.
- Department of Oral & Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai 200011, P. R. China.
| | - Chen Yang
- Joint Centre of Translational Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
- Zhejiang Engineering Research Center for Tissue Repair Materials, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325000, China
| | - Qun Lou
- Department of Oral & Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai 200011, P. R. China.
| | - Jiashu Yan
- Department of Oral & Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai 200011, P. R. China.
| | - Xudong Wang
- Department of Oral & Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai 200011, P. R. China.
| | - Jiang Chang
- State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, P. R. China.
- Joint Centre of Translational Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
- Zhejiang Engineering Research Center for Tissue Repair Materials, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325000, China
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Risser GE, Machour M, Hernaez-Estrada B, Li D, Levenberg S, Spiller KL. Effects of Interleukin-4 (IL-4)-releasing microparticles and adoptive transfer of macrophages on immunomodulation and angiogenesis. Biomaterials 2023; 296:122095. [PMID: 36989737 PMCID: PMC10085857 DOI: 10.1016/j.biomaterials.2023.122095] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 02/16/2023] [Accepted: 03/16/2023] [Indexed: 03/29/2023]
Abstract
Macrophages are major regulators of angiogenesis in response to injury, but the mechanisms behind their diverse and phenotypically specific functions are still poorly understood. In particular, the effects of interleukin-4 (IL-4) on macrophage behavior have been well studied in vitro, but it remains unclear whether the release of IL-4 from biomaterials can be used to control macrophage phenotype and subsequent effects on angiogenesis in vivo. We used the murine hindlimb ischemia model to investigate the effects of IL-4-releasing poly(lactic-co-glycolic acid) microparticles co-delivered with IL-4-polarized macrophages on host macrophage phenotype and angiogenesis in vivo. We established a minimum dose of IL-4 required to modulate macrophage phenotype in vivo and evaluated effects on macrophage subpopulation diversity using multidimensional flow cytometry and pseudotime analysis. The delivery of IL-4-releasing microparticles did not affect the density or size of blood vessels as measured by immunohistochemical (IHC) analysis, but it did increase perfused tissue volume as measured by 3D microcomputed tomography (microCT). In contrast, the co-delivery of IL-4-releasing microparticles and exogenously IL-4-polarized macrophages increased the size of blood vessels as measured by IHC, but without effects on perfused tissue volume via microCT. These effects occurred in spite of low recovery of adoptively transferred macrophages at 4 days after administration. Spatial analysis of macrophage-blood vessel interactions via IHC showed that macrophages closely interacted with blood vessels, which was slightly influenced by treatment, and that blood vessel size was positively correlated with number of macrophages in close proximity. Altogether, these findings indicate that delivery of IL-4-releasing microparticles and exogenously IL-4-polarized macrophages can be beneficial for angiogenesis, but further mechanistic investigations are required.
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Affiliation(s)
- Gregory E Risser
- School of Biomedical Engineering, Sciences and Health Systems, Drexel University, Philadelphia, PA, USA
| | - Majd Machour
- Department of Biomedical Engineering, Technion-Israel Institute of Technology, Haifa, Israel
| | - Beatriz Hernaez-Estrada
- School of Biomedical Engineering, Sciences and Health Systems, Drexel University, Philadelphia, PA, USA
| | - Dong Li
- Shanghai Key Tissue Engineering Laboratory, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shulamit Levenberg
- Department of Biomedical Engineering, Technion-Israel Institute of Technology, Haifa, Israel
| | - Kara L Spiller
- School of Biomedical Engineering, Sciences and Health Systems, Drexel University, Philadelphia, PA, USA.
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