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Ning J, Sah RK, Wang J. Coculture of mesenchymal stem cells and macrophage: A narrative review. J Pharmacol Exp Ther 2025; 392:103531. [PMID: 40154096 DOI: 10.1016/j.jpet.2025.103531] [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: 10/31/2024] [Accepted: 02/24/2025] [Indexed: 04/01/2025] Open
Abstract
Stem cell transplantation is a promising treatment for repairing damaged tissues, but challenges like immune rejection and ethical concerns remain. Mesenchymal stem cells (MSCs) offer high differentiation potential and immune regulatory activity, showing promise in treating diseases such as gynecological, neurological, and kidney disorders. With scientific progress, MSC applications are overcoming traditional treatment limitations. In MSCs-macrophage coculture, MSCs transform macrophages into anti-inflammatory M2 macrophages, reducing inflammation, whereas macrophages enhance MSCs osteogenic differentiation. This coculture is vital for immune modulation and tissue repair, with models varying by contact type and dimensional arrangements. Factors such as coculture techniques and cell ratios influence outcomes. Benefits include improved heart function, wound healing, reduced lung inflammation, and accelerated bone repair. Challenges include optimizing coculture conditions. This study reviews the methodologies, factors, and mechanisms of MSC-macrophage coculture, providing a foundation for tissue engineering applications. SIGNIFICANCE STATEMENT: This review underlines the significant role of mesenchymal stem cell-macrophage coculture, providing a foundation for tissue engineering application.
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Affiliation(s)
- Jun Ning
- Department of General Gynecology II, Gynecology and Obstetrics Center, the First Hospital of Jilin University, Changchun, China
| | - Rajiv Kumar Sah
- Department of Pediatrics, Hematology/Oncology, Baylor College of Medicine, Houston, Texas; Texas Children's Hospital, Houston, Texas
| | - Jing Wang
- Department of Reproductive Medicine, Department of Prenatal Diagnosis, The First Hospital of Jilin University, Changchun, China.
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Hoseinzadeh A, Esmaeili SA, Sahebi R, Melak AM, Mahmoudi M, Hasannia M, Baharlou R. Fate and long-lasting therapeutic effects of mesenchymal stromal/stem-like cells: mechanistic insights. Stem Cell Res Ther 2025; 16:33. [PMID: 39901306 PMCID: PMC11792531 DOI: 10.1186/s13287-025-04158-z] [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: 04/27/2024] [Accepted: 01/21/2025] [Indexed: 02/05/2025] Open
Abstract
A large body of evidence suggests that mesenchymal stromal cells (MSCs) are able to respond rapidly to the cytokine milieu following systemic infusion. This encounter has the potential to dictate their therapeutic efficacy (also referred to as licensing). MSCs are able to rapidly react to cellular damage by migrating to the inflamed tissue and ultimately modifying the inflammatory microenvironment. However, the limited use of MSCs in clinical practice can be attributed to a lack of understanding of the fate of MSCs in patients after administration and long term MSC-derived therapeutic activity. While the known physiological effectors of viable MSCs make a relative contribution, an innate property of MSCs as a therapeutic agent is their caspase-dependent cell death. These mechanisms may be involving the functional reprogramming of myeloid phagocytes via efferocytosis, the process by which apoptotic bodies (ABs) are identified for engulfment by both specialized and non-specialized phagocytic cells. Recent studies have provided evidence that the uptake of ABs with a distinct genetic component can induce changes in gene expression through the process of epigenetic remodeling. This phenomenon, known as 'trained immunity', has a significant impact on immunometabolism processes. It is hypothesized that the diversity of recipient cells within the inflammatory stroma adjacent to MSCs may potentially serve as a biomarker for predicting the clinical outcome of MSC treatment, while also contributing to the variable outcomes observed with MSC-based therapies. Therefore, the long-term reconstructive process of MSCs may potentially be mediated by MSC apoptosis and subsequent phagocyte-mediated efferocytosis.
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Affiliation(s)
- Akram Hoseinzadeh
- Department of Immunology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Seyed-Alireza Esmaeili
- Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Reza Sahebi
- Department of Modern Sciences and Technologies, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Mahmoud Mahmoudi
- Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Maliheh Hasannia
- Cancer Research Center, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Rasoul Baharlou
- Department of Immunology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran.
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Wan Q, Tian L, Wang M, Chen F, Li X, Xiao Y, Chen X, Zhang X. Immunomodulatory effects of calcium phosphate microspheres: influences of particle size on macrophage polarization and secretion patterns. J Mater Chem B 2025; 13:549-561. [PMID: 39564861 DOI: 10.1039/d4tb02249a] [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: 11/21/2024]
Abstract
This study investigated the immunomodulatory effects of calcium phosphate (CaP) microspheres, focusing on how particle size influenced macrophage polarization and cytokine secretion patterns. SEM analysis revealed that HA microspheres predominantly exhibited a spherical shape with distinct sizes and sub-micro-sized pores. The average particle sizes for the S1, S2, and S3 groups were 17.36 μm, 27.59 μm, and 47.14 μm, respectively. In vitro experiments demonstrated that small-sized S1 microspheres were more readily phagocytosed by macrophages, leading to a pro-inflammatory M1 phenotype characterized by increased gene expression of iNos and inflammatory cytokines (IL-1β, IL-6, TNF-α), and a higher proportion of CCR7+ M1 macrophages. In contrast, the larger S2 and S3 microspheres favored an anti-inflammatory M2 phenotype, with higher expression of Arg and anti-inflammatory cytokines (IL-10), and greater proportions of CD206+ M2 macrophages. Additionally, HA microspheres were injected into mouse quadriceps muscles, revealing significant differences in immune cell infiltration and tissue response. The S1 microspheres induced a prolonged and more severe inflammatory response, while the S2 and S3 microspheres were embedded in cell-rich tissue with minimal inflammation or fibrosis. It indicated the potential of larger microspheres (S2 and S3) to create a more favorable immune microenvironment that supported faster and more effective tissue healing. These findings underscore the importance of optimizing microsphere size to achieve desired immunomodulatory effects, thereby enhancing their clinical efficacy.
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Affiliation(s)
- Qiwen Wan
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, 610064, China.
| | - Luoqiang Tian
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, 610064, China.
| | - Menglu Wang
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, 610064, China.
| | - Fuying Chen
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, 610064, China.
| | - Xiangfeng Li
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, 610064, China.
| | - Yumei Xiao
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, 610064, China.
- Research Center for Material Genome Engineering, Sichuan University, Chengdu, 610064, China
- Provincial Engineering Research Center for Biomaterials Genome of Sichuan, Sichuan University, Chengdu, 610064, China
| | - Xuening Chen
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, 610064, China.
- Research Center for Material Genome Engineering, Sichuan University, Chengdu, 610064, China
- Provincial Engineering Research Center for Biomaterials Genome of Sichuan, Sichuan University, Chengdu, 610064, China
| | - Xingdong Zhang
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, 610064, China.
- Research Center for Material Genome Engineering, Sichuan University, Chengdu, 610064, China
- Provincial Engineering Research Center for Biomaterials Genome of Sichuan, Sichuan University, Chengdu, 610064, China
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Xu T, Li C, Liao Y, Zhang X. Causal relationship between circulating levels of cytokines and bone mineral density: A mendelian randomization study. Cytokine 2024; 182:156729. [PMID: 39126768 DOI: 10.1016/j.cyto.2024.156729] [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: 03/19/2024] [Revised: 06/13/2024] [Accepted: 08/05/2024] [Indexed: 08/12/2024]
Abstract
BACKGROUND Numerous studies have shown that various cytokines are important factors affecting bone mineral density (BMD), but the causality between the two remains uncertain. METHODS Genetic variants associated with 41 circulating cytokines from a genome-wide association study (GWAS) in 8,293 Finns were used as instrumental variables (IVs) for a two-sample Mendelian randomization (MR) analysis. Inverse variance weighting (IVW) was employed as the primary method to investigate whether the 41 cytokines were causally associated with BMD at five different sites [total body bone mineral density (TB-BMD), heel bone mineral density (HE-BMD), forearm bone mineral density (FA-BMD), femoral neck bone mineral density (FN-BMD), and lumbar spine bone mineral density (LS-BMD)]. Weighted median and MR-Egger were chosen to further confirm the robustness of the results. We performed MR pleiotropy residual sum and outlier test (MR-PRESSO), MR-Egger regression, and Cochran's Q test to detect pleiotropy and sensitivity testing. RESULTS After Bonferroni correction, two circulating cytokines had a strong causality with BMD at corresponding sites. Genetically predicted circulating hepatocyte growth factor (HGF) levels and HE-BMD were negatively correlated [β (95 % CI) -0.035(-0.055, -0.016), P=0.00038]. Circulating macrophage inflammatory protein-1α (MIP-1α) levels and TB-BMD were negatively correlated [β(95 %CI): -0.058(-0.092, -0.024), P=0.00074]. Weighted median and MR-Egger results were in line with the IVW results. We also found suggestive causal relationship (IVW P<0.05) between seven circulating cytokines and BMD at corresponding sites. No significant pleiotropy or heterogeneity was observed in our study. CONCLUSION Our MR analyses indicated a causal effect between two circulating cytokines and BMD at corresponding sites (HGF and HE-BMD, MIP-1α and TB-BMD), along with suggestive evidence of a potential causality between seven cytokines and BMD at the corresponding sites. These findings would provide insights into the prevention and treatment of osteoporosis, especially immunoporosis.
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Affiliation(s)
- Taichuan Xu
- Department of Spine, Wuxi Affiliated Hospital of Nanjing University of Chinese Medicine, Wuxi, Jiangsu 214072, China
| | - Chao Li
- Department of Spine, Wuxi Affiliated Hospital of Nanjing University of Chinese Medicine, Wuxi, Jiangsu 214072, China
| | - Yitao Liao
- Department of Spine, Wuxi Affiliated Hospital of Nanjing University of Chinese Medicine, Wuxi, Jiangsu 214072, China
| | - Xian Zhang
- Department of Spine, Wuxi Affiliated Hospital of Nanjing University of Chinese Medicine, Wuxi, Jiangsu 214072, China.
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Shan Y, Zhang M, Tao E, Wang J, Wei N, Lu Y, Liu Q, Hao K, Zhou F, Wang G. Pharmacokinetic characteristics of mesenchymal stem cells in translational challenges. Signal Transduct Target Ther 2024; 9:242. [PMID: 39271680 PMCID: PMC11399464 DOI: 10.1038/s41392-024-01936-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 07/04/2024] [Accepted: 07/23/2024] [Indexed: 09/15/2024] Open
Abstract
Over the past two decades, mesenchymal stem/stromal cell (MSC) therapy has made substantial strides, transitioning from experimental clinical applications to commercial products. MSC therapies hold considerable promise for treating refractory and critical conditions such as acute graft-versus-host disease, amyotrophic lateral sclerosis, and acute respiratory distress syndrome. Despite recent successes in clinical and commercial applications, MSC therapy still faces challenges when used as a commercial product. Current detection methods have limitations, leaving the dynamic biodistribution, persistence in injured tissues, and ultimate fate of MSCs in patients unclear. Clarifying the relationship between the pharmacokinetic characteristics of MSCs and their therapeutic effects is crucial for patient stratification and the formulation of precise therapeutic regimens. Moreover, the development of advanced imaging and tracking technologies is essential to address these clinical challenges. This review provides a comprehensive analysis of the kinetic properties, key regulatory molecules, different fates, and detection methods relevant to MSCs and discusses concerns in evaluating MSC druggability from the perspective of integrating pharmacokinetics and efficacy. A better understanding of these challenges could improve MSC clinical efficacy and speed up the introduction of MSC therapy products to the market.
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Affiliation(s)
- Yunlong Shan
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
| | - Mengying Zhang
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Enxiang Tao
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Jing Wang
- Jiangsu Renocell Biotech Co. Ltd., Nanjing, China
| | - Ning Wei
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
- Jiangsu Renocell Biotech Co. Ltd., Nanjing, China
| | - Yi Lu
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Qing Liu
- Jiangsu Renocell Biotech Co. Ltd., Nanjing, China
| | - Kun Hao
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
| | - Fang Zhou
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
| | - Guangji Wang
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
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Song T, Zhao F, Yan L, Liu P, Yang J, Ruan C, Li D, Xiao Y, Zhang X. Structure driven bio-responsive ability of injectable nanocomposite hydrogels for efficient bone regeneration. Biomaterials 2024; 309:122601. [PMID: 38713973 DOI: 10.1016/j.biomaterials.2024.122601] [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: 01/10/2024] [Revised: 03/27/2024] [Accepted: 05/02/2024] [Indexed: 05/09/2024]
Abstract
Injectable hydrogels are promising for treatment of bone defects in clinic owing to their minimally invasive procedure. Currently, there is limited emphasis on how to utilize injectable hydrogels to mobilize body's regenerative potential for enhancing bone regeneration. Herein, an injectable bone-mimicking hydrogel (BMH) scaffold assembled from nanocomposite microgel building blocks was developed, in which a highly interconnected microporous structure and an inorganic/organic (methacrylated hydroxyapatite and methacrylated gelatin) interweaved nano structure were well-designed. Compared with hydrogels lacking micro-nano structures or only showing microporous structure, the BMH scaffold enhanced the ingrowth of vessels and promoted the formation of dense cellular networks (including stem cells and M2 macrophages), across the entire scaffold at early stage after subcutaneous implantation. Moreover, the BMH scaffold could not only directly trigger osteogenic differentiation of the infiltrated stem cells, but also provided an instructive osteo-immune microenvironment by inducing macrophages into M2 phenotype. Mechanistically, our results reveal that the nano-rough structure of the BMH plays an essential role in inducing macrophage M2 polarization through activating mechanotransduction related RhoA/ROCK2 pathway. Overall, this work offers an injectable hydrogel with micro-nano structure driven bio-responsive abilities, highlighting harnessing body's inherent regenerative potential to realize bone regeneration.
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Affiliation(s)
- Tao Song
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610065, China; College of Biomedical Engineering, Sichuan University, Chengdu, 610065, China
| | - Fengxin Zhao
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610065, China; College of Biomedical Engineering, Sichuan University, Chengdu, 610065, China
| | - Ling Yan
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610065, China; College of Biomedical Engineering, Sichuan University, Chengdu, 610065, China
| | - Puxin Liu
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610065, China; College of Biomedical Engineering, Sichuan University, Chengdu, 610065, China
| | - Jirong Yang
- Research Center for Human Tissue and Organs Degeneration, Institute of Biomedical and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Changshun Ruan
- Research Center for Human Tissue and Organs Degeneration, Institute of Biomedical and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Dongxiao Li
- Sichuan Academy of Chinese Medicine Science, Chengdu, 610042, China
| | - Yumei Xiao
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610065, China; College of Biomedical Engineering, Sichuan University, Chengdu, 610065, China.
| | - Xingdong Zhang
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610065, China; College of Biomedical Engineering, Sichuan University, Chengdu, 610065, China
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Tan P, Hua Y, Yuan B, Liu X, Chen X, Zeng WN, Zeng Q, Zhu X, Zhang X. PI3K/AKT/mTOR signaling regulates BCP ceramic-induced osteogenesis. J Mater Chem B 2024; 12:7591-7603. [PMID: 38984467 DOI: 10.1039/d4tb01335b] [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: 07/11/2024]
Abstract
An increasing number of studies demonstrate that biphasic calcium phosphate (BCP) ceramics can induce bone regeneration. However, the underlying molecular mechanisms involved are still poorly understood. This work was proposed to investigate how PI3K/AKT/mTOR signaling influenced the osteogenesis mediated by BCP ceramics. The results showed that incubation with BCP ceramics promoted the proliferation of murine bone marrow-derived mesenchymal stem cells (BMSCs) in a time-dependent manner. The resulting cell proliferation was then suppressed by the selective inhibition of either PI3K, AKT, or mTOR signaling activation. Next, we confirmed that BCP ceramics up-regulated the phosphorylation levels of AKT and mTOR in BMSCs, suggesting the ability of BCP ceramics to drive the activation of PI3K/AKT/mTOR signaling in BMSCs. Furthermore, the blockade of PI3K/AKT/mTOR signaling prevented BCP ceramics-induced osteogenic differentiation and pro-angiogenesis of BMSCs by down-regulating the expression of genes encoding OPN, RUNX2 or VEGF. Moreover, the PI3K/AKT/mTOR signaling blockade suppressed stem cell infiltration and new bone formation in the implants following intra-muscular implantation of BCP ceramics in mice. Therefore, our results suggested that PI3K/AKT/mTOR signaling played a critical regulatory role in BCP ceramic-induced osteogenesis.
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Affiliation(s)
- Peijie Tan
- National Engineering Research Center for Biomaterials, Sichuan University, No. 29 Wangjiang Road, Chengdu 610064, China.
| | - Yuchen Hua
- National Engineering Research Center for Biomaterials, Sichuan University, No. 29 Wangjiang Road, Chengdu 610064, China.
| | - Bo Yuan
- National Engineering Research Center for Biomaterials, Sichuan University, No. 29 Wangjiang Road, Chengdu 610064, China.
| | - Xiaoyang Liu
- Orthopedic Research Institution, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xuening Chen
- National Engineering Research Center for Biomaterials, Sichuan University, No. 29 Wangjiang Road, Chengdu 610064, China.
| | - Wei-Nan Zeng
- Orthopedic Research Institution, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Qin Zeng
- National Engineering Research Center for Biomaterials, Sichuan University, No. 29 Wangjiang Road, Chengdu 610064, China.
- NMPA Key Laboratory for Quality Research and Control of Tissue Regenerative Biomaterials & Institute of Regulatory Science for Medical Devices & NMPA Research Base of Regulatory Science for Medical Devices, Sichuan University, Chengdu 610064, China
| | - Xiangdong Zhu
- National Engineering Research Center for Biomaterials, Sichuan University, No. 29 Wangjiang Road, Chengdu 610064, China.
| | - Xingdong Zhang
- National Engineering Research Center for Biomaterials, Sichuan University, No. 29 Wangjiang Road, Chengdu 610064, China.
- NMPA Key Laboratory for Quality Research and Control of Tissue Regenerative Biomaterials & Institute of Regulatory Science for Medical Devices & NMPA Research Base of Regulatory Science for Medical Devices, Sichuan University, Chengdu 610064, China
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Chen F, Liu J, Liu K, Tian L, Li X, Zhu X, Chen X, Zhang X. Osteo-immunomodulatory effects of macrophage-derived extracellular vesicles treated with biphasic calcium phosphate ceramics on bone regeneration. Biomed Mater 2024; 19:045025. [PMID: 38815599 DOI: 10.1088/1748-605x/ad5242] [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: 01/31/2024] [Accepted: 05/30/2024] [Indexed: 06/01/2024]
Abstract
Literature on osteoimmunology has demonstrated that macrophages have a great influence on biomaterial-induced bone formation. However, there are almost no reports clarifying the osteo-immunomodulatory capacity of macrophage-derived extracellular vesicles (EVs). This study comprehensively investigated the effects of EVs derived from macrophages treated with biphasic calcium phosphate (BCP) ceramics (BEVs) on vital events associated with BCP-induced bone formation such as immune response, angiogenesis, and osteogenesis. It was found that compared with EVs derived from macrophages alone (control, CEVs), BEVs preferentially promoted macrophage polarization towards a wound-healing M2 phenotype, enhanced migration, angiogenic differentiation, and tube formation of human umbilical vein endothelial cells, and induced osteogenic differentiation of mesenchymal stem cells. Analysis of 15 differentially expressed microRNAs (DEMs) related to immune, angiogenesis, and osteogenesis suggested that BEVs exhibited good immunomodulatory, pro-angiogenic, and pro-osteogenic abilities, which might be attributed to their specific miRNA cargos. These findings not only deepen our understanding of biomaterial-mediated osteoinduction, but also suggest that EVs derived from biomaterial-treated macrophages hold great promise as therapeutic agents with desired immunomodulatory capacity for bone regeneration.
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Affiliation(s)
- Fuying Chen
- National Engineering Research Center for Biomaterials, Department of Biomedical Engineering, Sichuan University, Chengdu, People's Republic of China
| | - Jiajun Liu
- National Engineering Research Center for Biomaterials, Department of Biomedical Engineering, Sichuan University, Chengdu, People's Republic of China
| | - Keting Liu
- National Engineering Research Center for Biomaterials, Department of Biomedical Engineering, Sichuan University, Chengdu, People's Republic of China
| | - Luoqiang Tian
- National Engineering Research Center for Biomaterials, Department of Biomedical Engineering, Sichuan University, Chengdu, People's Republic of China
| | - Xiangfeng Li
- National Engineering Research Center for Biomaterials, Department of Biomedical Engineering, Sichuan University, Chengdu, People's Republic of China
| | - Xiangdong Zhu
- National Engineering Research Center for Biomaterials, Department of Biomedical Engineering, Sichuan University, Chengdu, People's Republic of China
| | - Xuening Chen
- National Engineering Research Center for Biomaterials, Department of Biomedical Engineering, Sichuan University, Chengdu, People's Republic of China
| | - Xingdong Zhang
- National Engineering Research Center for Biomaterials, Department of Biomedical Engineering, Sichuan University, Chengdu, People's Republic of China
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Zhang FF, Hao Y, Zhang KX, Yang JJ, Zhao ZQ, Liu HJ, Li JT. Interplay between mesenchymal stem cells and macrophages: Promoting bone tissue repair. World J Stem Cells 2024; 16:375-388. [PMID: 38690513 PMCID: PMC11056637 DOI: 10.4252/wjsc.v16.i4.375] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 02/14/2024] [Accepted: 03/19/2024] [Indexed: 04/25/2024] Open
Abstract
The repair of bone tissue damage is a complex process that is well-orchestrated in time and space, a focus and difficulty in orthopedic treatment. In recent years, the success of mesenchymal stem cells (MSCs)-mediated bone repair in clinical trials of large-area bone defects and bone necrosis has made it a candidate in bone tissue repair engineering and regenerative medicine. MSCs are closely related to macrophages. On one hand, MSCs regulate the immune regulatory function by influencing macrophages proliferation, infiltration, and phenotype polarization, while also affecting the osteoclasts differentiation of macrophages. On the other hand, macrophages activate MSCs and mediate the multilineage differentiation of MSCs by regulating the immune microenvironment. The cross-talk between MSCs and macrophages plays a crucial role in regulating the immune system and in promoting tissue regeneration. Making full use of the relationship between MSCs and macrophages will enhance the efficacy of MSCs therapy in bone tissue repair, and will also provide a reference for further application of MSCs in other diseases.
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Affiliation(s)
- Fei-Fan Zhang
- Molecular Biology Lab, Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital), Zhengzhou 450000, Henan Province, China
- Graduate School, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Yang Hao
- Molecular Biology Lab, Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital), Zhengzhou 450000, Henan Province, China
- Graduate School, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China
| | - Kuai-Xiang Zhang
- Molecular Biology Lab, Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital), Zhengzhou 450000, Henan Province, China
- Graduate School, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China
| | - Jiang-Jia Yang
- Molecular Biology Lab, Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital), Zhengzhou 450000, Henan Province, China
- Graduate School, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Zhi-Qiang Zhao
- Molecular Biology Lab, Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital), Zhengzhou 450000, Henan Province, China
| | - Hong-Jian Liu
- Department of Orthopaedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Ji-Tian Li
- Molecular Biology Lab, Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital), Zhengzhou 450000, Henan Province, China
- Graduate School, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
- Graduate School, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China.
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10
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Garcés P, Amaro A, Montecino M, van Zundert B. Inorganic polyphosphate: from basic research to diagnostic and therapeutic opportunities in ALS/FTD. Biochem Soc Trans 2024; 52:123-135. [PMID: 38323662 DOI: 10.1042/bst20230257] [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: 11/22/2023] [Revised: 01/16/2024] [Accepted: 01/17/2024] [Indexed: 02/08/2024]
Abstract
Inorganic polyphosphate (polyP) is a simple, negatively charged biopolymer with chain lengths ranging from just a few to over a thousand ortho-phosphate (Pi) residues. polyP is detected in every cell type across all organisms in nature thus far analyzed. Despite its structural simplicity, polyP has been shown to play important roles in a remarkably broad spectrum of biological processes, including blood coagulation, bone mineralization and inflammation. Furthermore, polyP has been implicated in brain function and the neurodegenerative diseases amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease and Parkinson's disease. In this review, we first address the challenges associated with identifying mammalian polyP metabolizing enzymes, such as Nudt3, and quantifying polyP levels in brain tissue, cultured neural cells and cerebrospinal fluid. Subsequently, we focus on recent studies that unveil how the excessive release of polyP by human and mouse ALS/FTD astrocytes contributes to these devastating diseases by inducing hyperexcitability, leading to motoneuron death. Potential implications of elevated polyP levels in ALS/FTD patients for innovative diagnostic and therapeutic approaches are explored. It is emphasized, however, that caution is required in targeting polyP in the brain due to its diverse physiological functions, serving as an energy source, a chelator for divalent cations and a scaffold for amyloidogenic proteins. Reducing polyP levels, especially in neurons, might thus have adverse effects in brain functioning. Finally, we discuss how activated mast cells and platelets also can significantly contribute to ALS progression, as they can massively release polyP.
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Affiliation(s)
- Polett Garcés
- Faculty of Medicine and Faculty of Life Sciences, Institute of Biomedical Sciences (ICB), Universidad Andres Bello, Santiago, Chile
| | - Armando Amaro
- Faculty of Medicine and Faculty of Life Sciences, Institute of Biomedical Sciences (ICB), Universidad Andres Bello, Santiago, Chile
| | - Martin Montecino
- Faculty of Medicine and Faculty of Life Sciences, Institute of Biomedical Sciences (ICB), Universidad Andres Bello, Santiago, Chile
- Millennium Nucleus of Neuroepigenetics and Plasticity (EpiNeuro), Santiago, Chile
| | - Brigitte van Zundert
- Faculty of Medicine and Faculty of Life Sciences, Institute of Biomedical Sciences (ICB), Universidad Andres Bello, Santiago, Chile
- Millennium Nucleus of Neuroepigenetics and Plasticity (EpiNeuro), Santiago, Chile
- Department of Neurology, University of Massachusetts Chan Medical School (UMMS), Worcester, MA, U.S.A
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11
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Qiu M, Tulufu N, Tang G, Ye W, Qi J, Deng L, Li C. Black Phosphorus Accelerates Bone Regeneration Based on Immunoregulation. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2304824. [PMID: 37953457 PMCID: PMC10767454 DOI: 10.1002/advs.202304824] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Revised: 09/25/2023] [Indexed: 11/14/2023]
Abstract
A fundamental understanding of inflammation and tissue healing suggests that the precise regulation of the inflammatory phase, both in terms of location and timing, is crucial for bone regeneration. However, achieving the activation of early inflammation without causing chronic inflammation while facilitating quick inflammation regression to promote bone regeneration continues to pose challenges. This study reveals that black phosphorus (BP) accelerates bone regeneration by building an osteogenic immunological microenvironment. BP amplifies the acute pro-inflammatory response and promotes the secretion of anti-inflammatory factors to accelerate inflammation regression and tissue regeneration. Mechanistically, BP creates an osteoimmune-friendly microenvironment by stimulating macrophages to express interleukin 33 (IL-33), amplifying the inflammatory response at an early stage, and promoting the regression of inflammation. In addition, BP-mediated IL-33 expression directly promotes osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), which further facilitates bone repair. To the knowledge, this is the first study to reveal the immunomodulatory potential of BP in bone regeneration through the regulation of both early-stage inflammatory responses and later-stage inflammation resolution, along with the associated molecular mechanisms. This discovery serves as a foundation for the clinical use of BP and is an efficient approach for managing the immune microenvironment during bone regeneration.
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Affiliation(s)
- Minglong Qiu
- Department of OrthopaedicsShanghai Key Laboratory for Prevention and Treatment of Bone and Joint DiseasesShanghai Institute of Traumatology and OrthopaedicsRuijin HospitalShanghai Jiao Tong University School of Medicine197 Ruijin 2nd RoadShanghai200025P. R. China
| | - Nijiati Tulufu
- Department of OrthopaedicsShanghai Key Laboratory for Prevention and Treatment of Bone and Joint DiseasesShanghai Institute of Traumatology and OrthopaedicsRuijin HospitalShanghai Jiao Tong University School of Medicine197 Ruijin 2nd RoadShanghai200025P. R. China
| | - Guoqing Tang
- Kunshan Hospital of Traditional Chinese MedicineAffiliated Hospital of Yangzhou University388 Zuchongzhi RoadKunshan CityJiangsu Province215300P. R. China
| | - Wenkai Ye
- Department of OrthopaedicsShanghai Key Laboratory for Prevention and Treatment of Bone and Joint DiseasesShanghai Institute of Traumatology and OrthopaedicsRuijin HospitalShanghai Jiao Tong University School of Medicine197 Ruijin 2nd RoadShanghai200025P. R. China
| | - Jin Qi
- Department of OrthopaedicsShanghai Key Laboratory for Prevention and Treatment of Bone and Joint DiseasesShanghai Institute of Traumatology and OrthopaedicsRuijin HospitalShanghai Jiao Tong University School of Medicine197 Ruijin 2nd RoadShanghai200025P. R. China
| | - Lianfu Deng
- Department of OrthopaedicsShanghai Key Laboratory for Prevention and Treatment of Bone and Joint DiseasesShanghai Institute of Traumatology and OrthopaedicsRuijin HospitalShanghai Jiao Tong University School of Medicine197 Ruijin 2nd RoadShanghai200025P. R. China
| | - Changwei Li
- Department of OrthopaedicsShanghai Key Laboratory for Prevention and Treatment of Bone and Joint DiseasesShanghai Institute of Traumatology and OrthopaedicsRuijin HospitalShanghai Jiao Tong University School of Medicine197 Ruijin 2nd RoadShanghai200025P. R. China
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12
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Fan S, Sun X, Su C, Xue Y, Song X, Deng R. Macrophages-bone marrow mesenchymal stem cells crosstalk in bone healing. Front Cell Dev Biol 2023; 11:1193765. [PMID: 37427382 PMCID: PMC10327485 DOI: 10.3389/fcell.2023.1193765] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Accepted: 06/14/2023] [Indexed: 07/11/2023] Open
Abstract
Bone healing is associated with many orthopedic conditions, including fractures and osteonecrosis, arthritis, metabolic bone disease, tumors and periprosthetic particle-associated osteolysis. How to effectively promote bone healing has become a keen topic for researchers. The role of macrophages and bone marrow mesenchymal stem cells (BMSCs) in bone healing has gradually come to light with the development of the concept of osteoimmunity. Their interaction regulates the balance between inflammation and regeneration, and when the inflammatory response is over-excited, attenuated, or disturbed, it results in the failure of bone healing. Therefore, an in-depth understanding of the function of macrophages and bone marrow mesenchymal stem cells in bone regeneration and the relationship between the two could provide new directions to promote bone healing. This paper reviews the role of macrophages and bone marrow mesenchymal stem cells in bone healing and the mechanism and significance of their interaction. Several new therapeutic ideas for regulating the inflammatory response in bone healing by targeting macrophages and bone marrow mesenchymal stem cells crosstalk are also discussed.
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Affiliation(s)
- Siyu Fan
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Xin Sun
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Chuanchao Su
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Yiwen Xue
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Xiao Song
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Runzhi Deng
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
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13
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Wang J, Li H, Fu S, Su Y. Porous BCP ceramics with nanoscale whisker structure accelerate bone regeneration by regulating inflammatory response. BIOMATERIALS ADVANCES 2023; 147:213313. [PMID: 36753873 DOI: 10.1016/j.bioadv.2023.213313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 01/07/2023] [Accepted: 01/19/2023] [Indexed: 01/26/2023]
Abstract
Inflammation-induced by biomaterials is a critical event to determine the success and efficiency of tissue repair. Macrophages are a major population that participates the biomaterial induced inflammation. The response of macrophages depends on the characteristics of biomaterials, thus causing a cascade reaction in subsequent biological processes. In this study, porous biphase calcium phosphate (BCP) ceramics with the different surface structures were constructed to compare the effect of surface structure on bone generation potential, and further reveal the inflammation-involved mechanism. Our results demonstrated that macrophages on three ceramics showed distinct morphologies and spreading areas. The nanoscale whisker structure did induce more bone generation in the mice thigh muscle. The in vitro result revealed that nanoscale whisker structure could drive macrophage polarization towards M1-like phenotype, indicated by a higher expression of pro-inflammatory specific markers (iNOS and CCR7), and mass secretion of TNF-α. Further research indicated that additional TNF-α could promote the osteogenic differentiation of mesenchymal stem cells (MSCs). However, excess addition of TNF-α showed an opposite effect on the osteogenic differentiation of MSCs by initiating the NF-κB signaling pathway, which suppresses the osteogenesis process.
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Affiliation(s)
- Jing Wang
- School of Life Sciences, Northwestern Polytechnical University, Xi'an 710072, China.
| | - Huishan Li
- School of Life Sciences, Northwestern Polytechnical University, Xi'an 710072, China
| | - Shijia Fu
- School of Life Sciences, Northwestern Polytechnical University, Xi'an 710072, China
| | - Yangyang Su
- State Key Laboratory of Solidification Processing, Northwestern Polytechnical University, Xi'an 710072, China
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14
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Pu P, Wu S, Zhang K, Xu H, Guan J, Jin Z, Sun W, Zhang H, Yan B. Mechanical force induces macrophage-derived exosomal UCHL3 promoting bone marrow mesenchymal stem cell osteogenesis by targeting SMAD1. J Nanobiotechnology 2023; 21:88. [PMID: 36915132 PMCID: PMC10012474 DOI: 10.1186/s12951-023-01836-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 03/02/2023] [Indexed: 03/16/2023] Open
Abstract
BACKGROUND Orthodontic tooth movement (OTM), a process of alveolar bone remodelling, is induced by mechanical force and regulated by local inflammation. Bone marrow-derived mesenchymal stem cells (BMSCs) play a fundamental role in osteogenesis during OTM. Macrophages are mechanosensitive cells that can regulate local inflammatory microenvironment and promote BMSCs osteogenesis by secreting diverse mediators. However, whether and how mechanical force regulates osteogenesis during OTM via macrophage-derived exosomes remains elusive. RESULTS Mechanical stimulation (MS) promoted bone marrow-derived macrophage (BMDM)-mediated BMSCs osteogenesis. Importantly, when exosomes from mechanically stimulated BMDMs (MS-BMDM-EXOs) were blocked, the pro-osteogenic effect was suppressed. Additionally, compared with exosomes derived from BMDMs (BMDM-EXOs), MS-BMDM-EXOs exhibited a stronger ability to enhance BMSCs osteogenesis. At in vivo, mechanical force-induced alveolar bone formation was impaired during OTM when exosomes were blocked, and MS-BMDM-EXOs were more effective in promoting alveolar bone formation than BMDM-EXOs. Further proteomic analysis revealed that ubiquitin carboxyl-terminal hydrolase isozyme L3 (UCHL3) was enriched in MS-BMDM-EXOs compared with BMDM-EXOs. We went on to show that BMSCs osteogenesis and mechanical force-induced bone formation were impaired when UCHL3 was inhibited. Furthermore, mothers against decapentaplegic homologue 1 (SMAD1) was identified as the target protein of UCHL3. At the mechanistic level, we showed that SMAD1 interacted with UCHL3 in BMSCs and was downregulated when UCHL3 was suppressed. Consistently, overexpression of SMAD1 rescued the adverse effect of inhibiting UCHL3 on BMSCs osteogenesis. CONCLUSIONS This study suggests that mechanical force-induced macrophage-derived exosomal UCHL3 promotes BMSCs osteogenesis by targeting SMAD1, thereby promoting alveolar bone formation during OTM.
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Affiliation(s)
- Panjun Pu
- Department of Orthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, 210000, China
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, 210000, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, 210000, China
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Shengnan Wu
- Department of Orthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, 210000, China
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, 210000, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, 210000, China
| | - Kejia Zhang
- Department of Orthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, 210000, China
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, 210000, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, 210000, China
| | - Hao Xu
- Department of Orthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, 210000, China
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, 210000, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, 210000, China
| | - Jiani Guan
- Department of Orthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, 210000, China
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, 210000, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, 210000, China
| | - Zhichun Jin
- Department of Orthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, 210000, China
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, 210000, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, 210000, China
| | - Wen Sun
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, 210000, China
| | - Hanwen Zhang
- School of Basic Medical Sciences, Nanjing Medical University, Nanjing, 210000, China.
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, 210000, China.
| | - Bin Yan
- Department of Orthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, 210000, China.
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, 210000, China.
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, 210000, China.
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15
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Lee MS, Jeon J, Park S, Lim J, Yang HS. Rationally designed bioactive milk-derived protein scaffolds enhanced new bone formation. Bioact Mater 2023; 20:368-380. [PMID: 35784638 PMCID: PMC9213433 DOI: 10.1016/j.bioactmat.2022.05.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 05/09/2022] [Accepted: 05/23/2022] [Indexed: 12/04/2022] Open
Abstract
Recently, a number of studies reported that casein was composed of various multifunctional bioactive peptides such as casein phosphopeptide and β-casochemotide-1 that bind calcium ions and induce macrophage chemotaxis, which is crucial for bone homeostasis and bone fracture repair by cytokines secreted in the process. We hypothesized that the effects of the multifunctional biopeptides in casein would contribute to improving bone regeneration. Thus, we designed a tissue engineering platform that consisted of casein and polyvinyl alcohol, which was a physical-crosslinked scaffold (milk-derived protein; MDP), via simple freeze-thaw cycles and performed surface modification using 3,4-dihydroxy-l-phenylalanine (DOPA), a mussel adhesive protein, for immobilizing adhesive proteins and cytokines for recruiting cells in vivo (MDP-DOPA). Both the MDP and MDP-DOPA groups proved indirectly contribution of macrophages migration as RAW 264.7 cells were highly migrated toward materials by contained bioactive peptides. We implanted MDP and MDP-DOPA in a mouse calvarial defect orthotopic model and evaluated whether MDP-DOPA showed much faster mineral deposition and higher bone density than that of the no-treatment and MDP groups. The MDP-DOPA group showed the accumulation of host M2 macrophages and mesenchymal stem cells (MSCs) around the scaffold, whereas MDP presented mostly M1 macrophages in the early stage.
Bioactive peptide-containing scaffold was fabricated via simple freeze-thaw cycles, and subsequently, the surface was modified with adhesive protein. We confirmed that the multifunctional biopeptides regulated the migration of macrophages and enhanced osteogenic differentiation. The bioactive peptide-containing scaffold showed much faster and higher mineral deposition in vivo animal studies compared to the other groups.
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Affiliation(s)
- Min Suk Lee
- Department of Nanobiomedical Science & BK21 FOUR NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, 31116, Republic of Korea
- Medical Laser Research Center, College of Medicine, Dankook University, Cheonan, 31116, Republic of Korea
| | - Jin Jeon
- Department of Nanobiomedical Science & BK21 FOUR NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, 31116, Republic of Korea
| | - Sihyeon Park
- Department of Nanobiomedical Science & BK21 FOUR NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, 31116, Republic of Korea
| | - Juhan Lim
- Department of Nanobiomedical Science & BK21 FOUR NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, 31116, Republic of Korea
| | - Hee Seok Yang
- Department of Nanobiomedical Science & BK21 FOUR NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, 31116, Republic of Korea
- Center for Bio-Medical Engineering Core-Facility, Dankook University, Cheonan, 31116, Republic of Korea
- Corresponding author. Department of Nanobiomedical Science & BK21 FOUR NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, 31116, Republic of Korea.
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16
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Xiao L, Shiwaku Y, Hamai R, Baba K, Tsuchiya K, Imazato S, Sasaki K, Suzuki O. Osteogenic capacity of octacalcium phosphate involving macrophage polarization. J Biomed Mater Res A 2022; 111:1006-1020. [PMID: 36573692 DOI: 10.1002/jbm.a.37484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 11/16/2022] [Accepted: 12/08/2022] [Indexed: 12/28/2022]
Abstract
Previous research has found that octacalcium phosphate (OCP) increases macrophage accumulation and alters the initial inflammatory response. However, the role of the immune response induced by OCP in osteogenesis remains unknown. This study investigated the behavior of macrophages and bone regeneration capacity during the early inflammatory stage of OCP-mediated osteogenesis. To assess the change in macrophage polarization and osteogenic capacity, we used a standardized rat defect model filled with OCP or calcium-deficient hydroxyapatite (CDHA)-a material obtained through the hydrolysis of the original OCP. OCP or CDHA granules were incubated with RAW264 cells for 5 days to investigate the effect of physicochemical characteristics on macrophage cytokine/chemokine expression in vitro. Our in vivo results show that due to the OCP implantation, macrophages in the rat tibial defect area tend to polarize to the M2 phenotype (anti-inflammatory) and inhibit the formation of the M1 phenotype (pro-inflammatory). In comparison to CDHA, OCP exhibited superior bone regeneration potential due to its rapid promotion of cortical bone healing and stimulation of macrophage-related growth factors. Furthermore, our in vitro results have shown that OCP regulates the expression of macrophage chemokines over time. Compared to incubation with CDHA, incubation with OCP caused changes in the ionic microenvironment. These findings suggest that the OCP-mediated macrophage polarization and secretion profile not only regulate immune function but also positively affect osteogenesis.
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Affiliation(s)
- Linghao Xiao
- Division of Craniofacial Function Engineering Tohoku University Graduate School of Dentistry Sendai Japan
- Division of Advanced Prosthetic Dentistry Tohoku University Graduate School of Dentistry Sendai Japan
- Department of Advanced Functional Materials Science Osaka University Graduate School of Dentistry Suita Japan
| | - Yukari Shiwaku
- Division of Craniofacial Function Engineering Tohoku University Graduate School of Dentistry Sendai Japan
| | - Ryo Hamai
- Division of Craniofacial Function Engineering Tohoku University Graduate School of Dentistry Sendai Japan
| | - Kazuyoshi Baba
- Department of Orthopedic Surgery Tohoku University Graduate School of Medicine Sendai Japan
| | - Kaori Tsuchiya
- Division of Craniofacial Function Engineering Tohoku University Graduate School of Dentistry Sendai Japan
| | - Satoshi Imazato
- Department of Biomaterials Science Osaka University Graduate School of Dentistry Suita Japan
| | - Keiichi Sasaki
- Division of Advanced Prosthetic Dentistry Tohoku University Graduate School of Dentistry Sendai Japan
| | - Osamu Suzuki
- Division of Craniofacial Function Engineering Tohoku University Graduate School of Dentistry Sendai Japan
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17
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Dong J, Wu B, Tian W. Adipose tissue-derived small extracellular vesicles modulate macrophages to improve the homing of adipocyte precursors and endothelial cells in adipose tissue regeneration. Front Cell Dev Biol 2022; 10:1075233. [PMID: 36561367 PMCID: PMC9763459 DOI: 10.3389/fcell.2022.1075233] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 11/28/2022] [Indexed: 12/12/2022] Open
Abstract
Rapid infiltration of endogenous cells induced by cell-free biomaterials is the first and crucial step in tissue regeneration and macrophage is largely involved. Our previous study reported adipose tissue-derived small extracellular vesicles (sEV-AT) could successfully promote adipose tissue regeneration. However, the role of macrophages in this process was unknown. In this study, we isolated sEV-AT and subcutaneously implanted it into the back of SD rats. The results showed sEV-AT increased macrophage infiltration significantly, which was followed by improving homing of adipocyte precursors (APs) and endothelial cells (ECs). However, when macrophages were depleted by clodronate liposome within 1 week, the homing of APs and ECs, and adipose tissue regeneration were destroyed. In vitro, sEV-AT showed the ability to promote the migration of macrophages directly. Besides, sEV-AT-pretreated macrophages improved the migration of APs and ECs, accompanied by the increase of chemokines (MCP-1, SDF-1, VEGF, and FGF) and the activation of NF-kB signaling pathway. These findings indicated sEV-AT might regulate the secretion of chemokines via activating NF-kB signaling pathway to improve homing of APs and ECs and facilitate adipose tissue regeneration. These findings deepened our understanding of small extracellular vesicle-induced tissue regeneration and laid a theoretical foundation for the clinical application of sEV-AT.
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Affiliation(s)
- Jia Dong
- Department of Stomatology, The People’s Hospital of Longhua Shenzhen, Shenzhen, China
| | - Bin Wu
- Department of Stomatology, The People’s Hospital of Longhua Shenzhen, Shenzhen, China
| | - Weidong Tian
- State Key Laboratory of Oral Disease, National Engineering Laboratory for Oral Regenerative Medicine, National Clinical Research Center for Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, China,Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China,*Correspondence: Weidong Tian,
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18
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Lv B, Wu J, Xiong Y, Xie X, Lin Z, Mi B, Liu G. Functionalized multidimensional biomaterials for bone microenvironment engineering applications: Focus on osteoimmunomodulation. Front Bioeng Biotechnol 2022; 10:1023231. [PMID: 36406210 PMCID: PMC9672076 DOI: 10.3389/fbioe.2022.1023231] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 10/20/2022] [Indexed: 09/26/2023] Open
Abstract
As bone biology develops, it is gradually recognized that bone regeneration is a pathophysiological process that requires the simultaneous participation of multiple systems. With the introduction of osteoimmunology, the interplay between the immune system and the musculoskeletal diseases has been the conceptual framework for a thorough understanding of both systems and the advancement of osteoimmunomodulaty biomaterials. Various therapeutic strategies which include intervention of the surface characteristics or the local delivery systems with the incorporation of bioactive molecules have been applied to create an ideal bone microenvironment for bone tissue regeneration. Our review systematically summarized the current research that is being undertaken in the field of osteoimmunomodulaty bone biomaterials on a case-by-case basis, aiming to inspire more extensive research and promote clinical conversion.
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Affiliation(s)
| | | | | | | | | | - Bobin Mi
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guohui Liu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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19
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Sarsenova M, Kim Y, Raziyeva K, Kazybay B, Ogay V, Saparov A. Recent advances to enhance the immunomodulatory potential of mesenchymal stem cells. Front Immunol 2022; 13:1010399. [PMID: 36211399 PMCID: PMC9537745 DOI: 10.3389/fimmu.2022.1010399] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 09/07/2022] [Indexed: 11/19/2022] Open
Abstract
Considering the unique therapeutic potential of mesenchymal stem cells (MSCs), including their immunosuppressive and immunomodulatory properties as well as their ability to improve tissue regeneration, these cells have attracted the attention of scientists and clinicians for the treatment of different inflammatory and immune system mediated disorders. However, various clinical trials using MSCs for the therapeutic purpose are conflicting and differ from the results of promising preclinical studies. This inconsistency is caused by several factors such as poor migration and homing capacities, low survival rate, low level of proliferation and differentiation, and donor-dependent variation of the cells. Enhancement and retention of persistent therapeutic effects of the cells remain a challenge to overcome in MSC-based therapy. In this review, we summarized various approaches to enhance the clinical outcomes of MSC-based therapy as well as revised current and future perspectives for the creation of cellular products with improved potential for diverse clinical applications.
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Affiliation(s)
- Madina Sarsenova
- Department of Medicine, School of Medicine, Nazarbayev University, Nur-Sultan, Kazakhstan
| | - Yevgeniy Kim
- Department of Medicine, School of Medicine, Nazarbayev University, Nur-Sultan, Kazakhstan
| | - Kamila Raziyeva
- Department of Medicine, School of Medicine, Nazarbayev University, Nur-Sultan, Kazakhstan
| | - Bexultan Kazybay
- Department of Medicine, School of Medicine, Nazarbayev University, Nur-Sultan, Kazakhstan
| | - Vyacheslav Ogay
- Laboratory of Stem Cells, National Center for Biotechnology, Nur-Sultan, Kazakhstan
| | - Arman Saparov
- Department of Medicine, School of Medicine, Nazarbayev University, Nur-Sultan, Kazakhstan
- *Correspondence: Arman Saparov,
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20
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Sun Y, Zhou Q, Du Y, Sun J, Bi W, Liu W, Li R, Wu X, Yang F, Song L, Li N, Cui W, Yu Y. Dual Biosignal-Functional Injectable Microspheres for Remodeling Osteogenic Microenvironment. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2022; 18:e2201656. [PMID: 35419952 DOI: 10.1002/smll.202201656] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Indexed: 06/14/2023]
Abstract
Bone defect regeneration depends on the population and lifespan of M2 macrophages, which are regulated by dual signals generated by the "physical" spatial configuration of biological tissues and "molecular" chemokines. Herein, inspired by the reprogramming of macrophages, immunoengineered porous microspheres are constructed to accelerate bone repair through the regulation of both "physical" and "molecular" signals. The porous structure of injectable poly (l-lactic acid) (PLLA) microspheres prepared by the microfluidic technique provides a "physical signal" for osteogenic differentiation. Additionally, interleukin (IL)-4-loaded liposomes (Ls) are modified on PLLA microspheres through amide bonds to produce IL-4/Ls/PLLA microspheres, providing a "molecular signal" in stimulating the differentiation of macrophages to M2 type. It is confirmed that IL-4/Ls/PLLA microspheres could induce M2-macrophages polarization and potentiate osteoblast proliferation and differentiation while coculturing with macrophages and osteoblasts in vitro. Besides, IL-4/Ls/PLLA microspheres are proved to promote bone defect regeneration by inducing the conversion of M1 macrophages to M2 through dual biosignal-functional regulation in both the calvaria defect and maxillary sinus defect models. Overall, the immuno-reprogrammed IL-4/Ls/PLLA microspheres achieve the precise immuno-reprogramming of macrophages by dual biosignal-functional regulation. This immune reengineering strategy paves a way for clinical bone defect treatment.
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Affiliation(s)
- Yang Sun
- Department of Stomatology, Zhongshan hospital, Fudan University, No. 180 Fenglin road, Shanghai, 200032, China
| | - Qianrong Zhou
- Department of Stomatology, Zhongshan hospital, Fudan University, No. 180 Fenglin road, Shanghai, 200032, China
| | - Yawei Du
- 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, P. R. China
| | - Jian Sun
- Department of Stomatology, Zhongshan hospital, Fudan University, No. 180 Fenglin road, Shanghai, 200032, China
| | - Wei Bi
- Department of Stomatology, Zhongshan hospital, Fudan University, No. 180 Fenglin road, Shanghai, 200032, China
| | - Wenjuan Liu
- Department of Stomatology, Xuhui Central Hospital, 996 Huaihaizhong Road, Shanghai, 200031, P. R. China
| | - Ruixue Li
- Department of Stomatology, Zhongshan hospital, Fudan University, No. 180 Fenglin road, Shanghai, 200032, China
| | - Xingwen Wu
- Department of Stomatology, Zhongshan hospital, Fudan University, No. 180 Fenglin road, Shanghai, 200032, China
| | - Fei Yang
- Department of Stomatology, Zhongshan hospital, Fudan University, No. 180 Fenglin road, Shanghai, 200032, China
| | - Liang Song
- Department of Stomatology, Zhongshan hospital, Fudan University, No. 180 Fenglin road, Shanghai, 200032, China
| | - Ni Li
- Department of Stomatology, Zhongshan hospital, Fudan University, No. 180 Fenglin road, Shanghai, 200032, 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, P. R. China
| | - Youcheng Yu
- Department of Stomatology, Zhongshan hospital, Fudan University, No. 180 Fenglin road, Shanghai, 200032, China
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21
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Chen F, Tian L, Pu X, Zeng Q, Xiao Y, Chen X, Zhang X. Enhanced ectopic bone formation by strontium-substituted calcium phosphate ceramics through regulation of osteoclastogenesis and osteoblastogenesis. Biomater Sci 2022; 10:5925-5937. [PMID: 36043373 DOI: 10.1039/d2bm00348a] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
To explore how strontium influences osteoclastogenesis and osteoblastogenesis during material-induced ectopic bone formation, porous strontium-substituted biphasic calcium phosphate (Sr-BCP) and BCP ceramics with equivalent pore structures and comparable grain size and porosity were prepared. In vitro results showed that compared with BCP, Sr-BCP inhibited the osteoclastic differentiation of osteoclast precursors by delaying cell fusion, down-regulating the expression of osteoclast marker genes, and reducing the activity of osteoclast specific proteins, possibly due to the activated ERK signaling pathway but the suppressed p38, JNK and AKT signaling pathways. Meanwhile, Sr-BCP promoted the osteogenic differentiation of mesenchymal stem cells (MSCs) by up-regulating the osteogenic gene expression. Sr-BCP also mediated the expression of important osteoblast-osteoclast coupling factors, as evidenced by the increased Opg/Rankl ratio in mMSCs, and the reduced Rank expression and enhanced EphrinB2 expression in osteoclast precursors. Similar results were observed in an in vivo study based on a murine intramuscular implantation model. The sign of ectopic bone formation was only seen in Sr-BCP at 8 weeks. Compared to BCP, Sr-BCP obviously hindered the formation of TRAP- and CTSK-positive multinucleated osteoclast-like cells during the early implantation time up to 6 weeks, which is consistent with the in vivo PCR results. This suggested that Sr-BCP could clearly accelerate the ectopic bone formation by promoting osteogenesis but suppressing osteoclastogenesis, which might be closely related to the expression of osteoblast-osteoclast coupling factors regulated by Sr2+. These findings may help in the design and fabrication of smart bone substitutes with the desired potential for bone regeneration through modulating both osteoclastic resorption and osteoblastic synthesis.
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Affiliation(s)
- Fuying Chen
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, China.
| | - Luoqiang Tian
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, China.
| | - Ximing Pu
- College of Biomedical Engineering, Sichuan University, Chengdu, China
| | - Qin Zeng
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, China.
| | - Yumei Xiao
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, China.
| | - Xuening Chen
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, China.
| | - Xingdong Zhang
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, China.
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22
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Han Y, Yang J, Fang J, Zhou Y, Candi E, Wang J, Hua D, Shao C, Shi Y. The secretion profile of mesenchymal stem cells and potential applications in treating human diseases. Signal Transduct Target Ther 2022; 7:92. [PMID: 35314676 PMCID: PMC8935608 DOI: 10.1038/s41392-022-00932-0] [Citation(s) in RCA: 294] [Impact Index Per Article: 98.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 11/18/2021] [Accepted: 02/20/2022] [Indexed: 02/06/2023] Open
Abstract
AbstractMesenchymal stromal/stem cells (MSCs) possess multi-lineage differentiation and self-renewal potentials. MSCs-based therapies have been widely utilized for the treatment of diverse inflammatory diseases, due to the potent immunoregulatory functions of MSCs. An increasing body of evidence indicates that MSCs exert their therapeutic effects largely through their paracrine actions. Growth factors, cytokines, chemokines, extracellular matrix components, and metabolic products were all found to be functional molecules of MSCs in various therapeutic paradigms. These secretory factors contribute to immune modulation, tissue remodeling, and cellular homeostasis during regeneration. In this review, we summarize and discuss recent advances in our understanding of the secretory behavior of MSCs and the intracellular communication that accounts for their potential in treating human diseases.
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23
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Yang Y, Chu C, Xiao W, Liu L, Man Y, Lin J, Qu Y. Strategies for advanced particulate bone substitutes regulating the osteo-immune microenvironment. Biomed Mater 2022; 17. [PMID: 35168224 DOI: 10.1088/1748-605x/ac5572] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 02/15/2022] [Indexed: 02/05/2023]
Abstract
The usage of bone substitute granule materials has improved the clinical results of alveolar bone deficiencies treatment and thus broadened applications in implant dentistry. However, because of the complicated mechanisms controlling the foreign body response, no perfect solution can avoid the fibrotic encapsulation of materials till now, which may impair the results of bone regeneration, even cause the implant materials rejection. Recently, the concept of 'osteoimmunology' has been stressed. The outcomes of bone regeneration are proved to be related to the bio-physicochemical properties of biomaterials, which allow them to regulate the biological behaviours of both innate and adaptive immune cells. With the development of single cell transcriptome, the truly heterogeneity of osteo-immune cells has been clarifying, which is helpful to overcome the limitations of traditional M1/M2 macrophage nomenclature and drive the advancements of particulate biomaterials applications. This review aims at introducing the mechanisms of optimal osseointegration regulated by immune systems and provides feasible strategies for the design of next generation 'osteoimmune-smart' particulate bone substitute materials in dental clinic.
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Affiliation(s)
- Yang Yang
- Department of Oral Implantology & Department of Prosthodontics & State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, People's Republic of China
| | - Chenyu Chu
- Department of Oral Implantology & Department of Prosthodontics & State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, People's Republic of China
| | - Wenlan Xiao
- Department of Oral Implantology & Department of Prosthodontics & State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, People's Republic of China
| | - Li Liu
- State Key Laboratory of Biotherapy and Laboratory, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu 610041, People's Republic of China
| | - Yi Man
- Department of Oral Implantology & Department of Prosthodontics & State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, People's Republic of China
| | - Jie Lin
- Department of Oral Implantology & Department of Prosthodontics & State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, People's Republic of China
| | - Yili Qu
- Department of Oral Implantology & Department of Prosthodontics & State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, People's Republic of China
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24
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Zhao Q, Liu X, Yu C, Xiao Y. Macrophages and Bone Marrow-Derived Mesenchymal Stem Cells Work in Concert to Promote Fracture Healing: A Brief Review. DNA Cell Biol 2022; 41:276-284. [PMID: 35196145 DOI: 10.1089/dna.2021.0869] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Bone marrow-derived mesenchymal stem cell (BMSC)-based and macrophage-based cell therapy are regarded as promising strategies to promote fracture healing because of incredible osteogenic potential of BMSCs and typical immunomodulatory function of macrophages. Apart from their respective key roles, accumulative evidence has also demonstrated the importance of cross talk between these two cell types in fracture healing process. This review takes a deep insight into the recent research progress of the synergic performance of BMSCs and macrophages by discussing not only the cells own functions but also the relevant impact factors and mechanisms (ambient microenvironment stimulus, miRNAs, etc). The aim of this review is to provide some valuable cues and technique support for the macrophage- and BMSC-related research, which will be helpful to propel BMSC/macrophage-based combined cell therapy for bone fracture treatment.
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Affiliation(s)
- Qing Zhao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Med-X Center for Materials, Sichuan University, Chengdu, China
| | - Xinran Liu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Med-X Center for Materials, Sichuan University, Chengdu, China
| | - Chuanying Yu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Med-X Center for Materials, Sichuan University, Chengdu, China
| | - Yu Xiao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Med-X Center for Materials, Sichuan University, Chengdu, China
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25
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Bacakova L, Novotna K, Hadraba D, Musilkova J, Slepicka P, Beran M. Influence of Biomimetically Mineralized Collagen Scaffolds on Bone Cell Proliferation and Immune Activation. Polymers (Basel) 2022; 14:polym14030602. [PMID: 35160591 PMCID: PMC8838484 DOI: 10.3390/polym14030602] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 01/30/2022] [Accepted: 02/01/2022] [Indexed: 12/21/2022] Open
Abstract
Collagen, as the main component of connective tissue, is frequently used in various tissue engineering applications. In this study, porous sponge-like collagen scaffolds were prepared by freeze-drying and were then mineralized in a simulated body fluid. The mechanical stability was similar in both types of scaffolds, but the mineralized scaffolds (MCS) contained significantly more calcium, magnesium and phosphorus than the unmineralized scaffolds (UCS). Although the MCS contained a lower percentage (~32.5%) of pores suitable for cell ingrowth (113–357 μm in diameter) than the UCS (~70%), the number of human-osteoblast-like MG-63 cells on days 1, 3 and 7 after seeding was higher on MCS than on UCS, and the cells penetrated deeper into the MCS. The cell growth in extracts prepared by eluting the scaffolds for 7 days in a cell culture medium was also markedly higher in the MCS extracts, as indicated by real-time monitoring in the sensory xCELLigence system for 7 days. From this point of view, MCS are more promising for bone tissue engineering than UCS. However, MCS evoked a more pronounced inflammatory response than UCS, as indicated by the production of tumor necrosis factor-alpha (TNF-α) in macrophage-like RAW 264.7 cells in cultures on these scaffolds.
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Affiliation(s)
- Lucie Bacakova
- Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic; (K.N.); (D.H.); (J.M.)
- Correspondence: ; Tel.: +420-2-9644-3743
| | - Katarina Novotna
- Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic; (K.N.); (D.H.); (J.M.)
| | - Daniel Hadraba
- Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic; (K.N.); (D.H.); (J.M.)
| | - Jana Musilkova
- Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic; (K.N.); (D.H.); (J.M.)
| | - Petr Slepicka
- Department of Solid State Engineering, Faculty of Chemical Technology, University of Chemistry and Technology, Technicka 5, 166 28 Prague 6, Czech Republic;
| | - Milos Beran
- Food Research Institute Prague, Radiova 7, 102 31 Prague 10, Czech Republic;
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26
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Chen R, Hao Z, Wang Y, Zhu H, Hu Y, Chen T, Zhang P, Li J. Mesenchymal Stem Cell-Immune Cell Interaction and Related Modulations for Bone Tissue Engineering. Stem Cells Int 2022; 2022:7153584. [PMID: 35154331 PMCID: PMC8825274 DOI: 10.1155/2022/7153584] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 01/03/2022] [Indexed: 12/11/2022] Open
Abstract
Critical bone defects and related delayed union and nonunion are still worldwide problems to be solved. Bone tissue engineering is mainly aimed at achieving satisfactory bone reconstruction. Mesenchymal stem cells (MSCs) are a kind of pluripotent stem cells that can differentiate into bone cells and can be used as one of the key pillars of bone tissue engineering. In recent decades, immune responses play an important role in bone regeneration. Innate immune responses provide a suitable inflammatory microenvironment for bone regeneration and initiate bone regeneration in the early stage of fracture repair. Adaptive immune responses maintain bone regeneration and bone remodeling. MSCs and immune cells regulate each other. All kinds of immune cells and secreted cytokines can regulate the migration, proliferation, and osteogenic differentiation of MSCs, which have a strong immunomodulatory ability to these immune cells. This review mainly introduces the interaction between MSCs and immune cells on bone regeneration and its potential mechanism, and discusses the practical application in bone tissue engineering by modulating this kind of cell-to-cell crosstalk. Thus, an in-depth understanding of these principles of bone immunology can provide a new way for bone tissue engineering.
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Affiliation(s)
- Renxin Chen
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Zhuowen Hao
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Yi Wang
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Hongzhen Zhu
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Yingkun Hu
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Tianhong Chen
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Peng Zhang
- Department of Orthopedics, Suzhou Science and Technology Town Hospital, The Affiliated Suzhou Science and Technology Town Hospital of Nanjing Medical University, Suzhou 215153, China
| | - Jingfeng Li
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
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27
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Svensson S, Palmer M, Svensson J, Johansson A, Engqvist H, Omar O, Thomsen P. Monocytes and pyrophosphate promote mesenchymal stem cell viability and early osteogenic differentiation. JOURNAL OF MATERIALS SCIENCE. MATERIALS IN MEDICINE 2022; 33:11. [PMID: 35032239 PMCID: PMC8761140 DOI: 10.1007/s10856-021-06639-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Accepted: 12/18/2021] [Indexed: 06/14/2023]
Abstract
Pyrophosphate-containing calcium phosphate implants promote osteoinduction and bone regeneration. The role of pyrophosphate for inflammatory cell-mesenchymal stem cell (MSC) cross-talk during osteogenesis is not known. In the present work, the effects of lipopolysaccharide (LPS) and pyrophosphate (PPi) on primary human monocytes and on osteogenic gene expression in human adipose-derived MSCs were evaluated in vitro, using conditioned media transfer as well as direct effect systems. Direct exposure to pyrophosphate increased nonadherent monocyte survival (by 120% without LPS and 235% with LPS) and MSC viability (LDH) (by 16-19% with and without LPS). Conditioned media from LPS-primed monocytes significantly upregulated osteogenic genes (ALP and RUNX2) and downregulated adipogenic (PPAR-γ) and chondrogenic (SOX9) genes in recipient MSCs. Moreover, the inclusion of PPi (250 μM) resulted in a 1.2- to 2-fold significant downregulation of SOX9 in the recipient MSCs, irrespective of LPS stimulation or culture media type. These results indicate that conditioned media from LPS-stimulated inflammatory monocytes potentiates the early MSCs commitment towards the osteogenic lineage and that direct pyrophosphate exposure to MSCs can promote their viability and reduce their chondrogenic gene expression. These results are the first to show that pyrophosphate can act as a survival factor for both human MSCs and primary monocytes and can influence the early MSC gene expression. Graphical abstract.
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Affiliation(s)
- Sara Svensson
- Department of Biomaterials, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Michael Palmer
- Department of Engineering Sciences, Applied Materials Science Section, Uppsala University, Uppsala, Sweden
| | - Johan Svensson
- Department of Statistics, Umeå School of Business, Economics and Statistics, Umeå University, Umeå, Sweden
| | - Anna Johansson
- Department of Biomaterials, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Håkan Engqvist
- Department of Engineering Sciences, Applied Materials Science Section, Uppsala University, Uppsala, Sweden
| | - Omar Omar
- Department of Biomedical Dental Sciences, College of Dentistry, Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia
| | - Peter Thomsen
- Department of Biomaterials, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
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28
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Li X, Zhou Q, Wu Y, Feng C, Yang X, Wang L, Xiao Y, Zhang K, Zhu X, Liu L, Song Y, Zhang X. Enhanced bone regenerative properties of calcium phosphate ceramic granules in rabbit posterolateral spinal fusion through a reduction of grain size. Bioact Mater 2021; 11:90-106. [PMID: 34938915 PMCID: PMC8665272 DOI: 10.1016/j.bioactmat.2021.10.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 10/02/2021] [Accepted: 10/03/2021] [Indexed: 02/05/2023] Open
Abstract
Osteoinductivity is a crucial factor to determine the success and efficiency of posterolateral spinal fusion (PLF) by employing calcium phosphate (Ca-P) bioceramics. In this study, three kinds of Ca-P ceramics with microscale to nanoscale gain size (BCP-control, BCP-micro and BCP-nano) were prepared and their physicochemical properties were characterized. BCP-nano had the spherical shape and nanoscale gain size, BCP-micro had the spherical shape and microscale gain size, and BCP-control (BAM®) had the irregular shape and microscale gain size. The obtained BCP-nano with specific nanotopography could well regulate in vitro protein adsorption and osteogenic differentiation of MC3T3 cells. In vivo rabbit PLF procedures further confirmed that nanotopography of BCP-nano might be responsible for the stronger bone regenerative ability comparing with BCP-micro and BCP-control. Collectedly, due to nanocrystal similarity with natural bone apatite, BCP-nano has excellent efficacy in guiding bone regeneration of PLF, and holds great potentials to become an alternative to standard bone grafts for future clinical applications.
The nanocrystal of porous BCP ceramic spheres is similar to natural bone apatite. BCP nanoceramics is conducive to protein adsorption and osteogenic differentiation of MC3T3 cells. Osteoindutivity of BCP ceramics is a crucial factor to determine the sucess and efficiency of PLF. BCP ceramic spheres with nanotopography hold great potential in clinical PLF applications.
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Affiliation(s)
- Xiangfeng Li
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, 610064, China
| | - Quan Zhou
- Department of Orthopaedic Surgery, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Yonghao Wu
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, 610064, China
| | - Cong Feng
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, 610064, China
| | - Xi Yang
- Department of Orthopaedic Surgery, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Linnan Wang
- Department of Orthopaedic Surgery, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Yumei Xiao
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, 610064, China
| | - Kai Zhang
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, 610064, China
| | - Xiangdong Zhu
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, 610064, China
| | - Limin Liu
- Department of Orthopaedic Surgery, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Yueming Song
- Department of Orthopaedic Surgery, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Xingdong Zhang
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, 610064, China
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Liu X, Ouyang L, Chen L, Qiao Y, Ma X, Xu G, Liu X. Hydroxyapatite composited PEEK with 3D porous surface enhances osteoblast differentiation through mediating NO by macrophage. Regen Biomater 2021; 9:rbab076. [PMID: 35480864 PMCID: PMC9039504 DOI: 10.1093/rb/rbab076] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 11/21/2021] [Accepted: 11/30/2021] [Indexed: 11/14/2022] Open
Abstract
The adverse immune response mediated by macrophages is one of the main factors that are prone to lead poor osseointegration of polyetheretherketone (PEEK) implants in clinic. Hence, endowing PEEK with immunomodulatory ability to avoid the adverse immune response becomes a promising strategy to promote bone repair. In this work, sulfonation and hydrothermal treatment were used to fabricate a 3D porous surface on PEEK and hydroxyapatite (HA) composited PEEK. The HA composited PEEK with 3D porous surface inhibited macrophages polarizing to M1 phenotype and downregulated inducible nitric oxide synthase protein expression, which led to a nitric oxide concentration reduction in culture medium of mouse bone marrow mesenchymal stem cells (mBMSCs) under co-culture condition. The decrease of nitric oxide concentration could help to increase bone formation-related OSX and ALP genes expressions and decrease bone resorption-related MMP-9 and MMP-13 genes expressions via cAMP-PKA-RUNX2 pathway in mBMSCs. In summary, the HA composited PEEK with 3D porous surface has the potential to promote osteogenesis of PEEK through immunomodulation, which provides a promising strategy to improve the bone repair ability of PEEK.
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Affiliation(s)
- Xingdan Liu
- State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Dingxi Road 1295, Shanghai 200050, China
- Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Yuquan Road 19, Beijing 100049, China
| | - Liping Ouyang
- Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 Xianxia Road, Shanghai 200336, China
| | - Lan Chen
- School of Materials Science, and Engineering & Henan Key Laboratory of Advanced Magnesium Alloy & Key Laboratory of Materials Processing and Mold Technology (Ministry of Education), Zhengzhou University, Science Avenue 100, Zhengzhou 450001, China
| | - Yuqin Qiao
- State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Dingxi Road 1295, Shanghai 200050, China
- Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Yuquan Road 19, Beijing 100049, China
| | - Xiaohan Ma
- State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Dingxi Road 1295, Shanghai 200050, China
- Cixi Center of Biomaterials Surface Engineering, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Wenwei Road 345, Ningbo 315300, China
| | - Guohua Xu
- Department of Orthopedic Surgery, Spine Center, Changzheng Hospital, Naval Medical University, No.415 Fengyang Road, Shanghai 200003, China
| | - Xuanyong Liu
- State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Dingxi Road 1295, Shanghai 200050, China
- Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Yuquan Road 19, Beijing 100049, China
- Cixi Center of Biomaterials Surface Engineering, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Wenwei Road 345, Ningbo 315300, China
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30
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Wu J, Tang Y, Pu X, Wang M, Chen F, Chen X, Zhu X, Zhang X. The role of micro-vibration parameters in inflammatory responses of macrophages cultured on biphasic calcium phosphate ceramics and the resultant influence on osteogenic differentiation of mesenchymal stem cells. J Mater Chem B 2021; 9:8003-8013. [PMID: 34476430 DOI: 10.1039/d1tb00898f] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Although in vitro studies have shown that biomaterials and mechanical stimuli can mediate inflammatory responses or regulate osteogenesis of MSCs, the underlying behaviour of the inflammatory response of macrophages on biomaterials mediated by mechanical stimuli, which regulates osteogenesis, is relatively unknown. Thus, it is imperative to explore the role of bionic mechanical stimulation in the biomaterial-mediated inflammatory response of macrophages. In this study, we used osteoinductive biphasic calcium phosphate (BCP) ceramics as the model biomaterial and chose micro-vibration stimulation (MVs) with three variable parameters (frequency, magnitude, and time). Based on orthogonal experiments, nine combinations of MVs parameters were generated, and their effects on the BCP-mediated macrophage inflammatory response were investigated. MVs significantly affected the gene expression and cytokine secretion of macrophages grown on BCP ceramics and further influenced the behaviour of bone marrow mesenchymal stem cells (BMMSCs) in a paracrine manner. Moreover, frequency seemed to be the most dominant factor (compared with magnitude and time) in regulating the inflammatory response of macrophages. The optimal combination of MVs parameters (frequency 10 Hz, magnitude 0.45 g, and time 60 min) could induce a healing-associated M2 phenotype, as evidenced by the downregulated pro-inflammatory gene (Il-1β, and Tnf-α) expression, the upregulated anti-inflammatory gene (Il10) expression, and the inhibited pro-inflammatory cytokine (Il-1β and Tnf-α) secretion of macrophages grown on BCP ceramics, and its conditioned medium (CM) could further promote osteogenic differentiation of BMMSCs. These findings provide valuable insights into the mechanical stimulus-mediated macrophage inflammatory response and osteogenesis in the presence of osteoinductive BCP ceramics and allow accurate evaluation of the biological performance of biomaterials in vitro, in order to optimize bone substitute materials to achieve the desired clinical performance.
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Affiliation(s)
- Jinjie Wu
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China.
| | - Yitao Tang
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China.
| | - Ximing Pu
- College of Materials and Engineering, Sichuan University, Chengdu 610064, China
| | - Menglu Wang
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China.
| | - Fuying Chen
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China.
| | - Xuening Chen
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China.
| | - Xiangdong Zhu
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China.
| | - Xingdong Zhang
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China.
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Yao Z, Chen P, Fan L, Chen P, Zhang X, Yu B. CCL2 is a critical mechano-responsive mediator in crosstalk between osteoblasts and bone mesenchymal stromal cells. FASEB J 2021; 35:e21851. [PMID: 34547121 DOI: 10.1096/fj.202002808rr] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 07/24/2021] [Accepted: 07/28/2021] [Indexed: 12/23/2022]
Abstract
It has been known that moderate mechanical loading, like that caused by exercise, promotes bone formation. However, its underlying mechanisms remain elusive. Here we showed that moderate running dramatically improved trabecular bone in mice tibias with an increase in bone volume fraction and trabecular number and a decrease in trabecular pattern factor. Results of immunohistochemical and histochemical staining revealed that moderate running mainly increased the number of osteoblasts but had no effect on osteoclasts. In addition, we observed a dramatic increase in the number of colony forming unit-fibroblast in endosteal bone marrow and the percentage of CD45- Leptin receptor+ (CD45- LepR+ ) endosteal mesenchymal progenitors. Bioinformatics analysis of the transcriptional data from gene expression omnibus (GEO) database identified chemokine c-c-motif ligands (CCL2) as a critical candidate induced by mechanical loading. Interestingly, we found that CCL2 was up-regulated mainly in osteoblastic cells in the tibia of mice after moderate running. Further, we found that mechanical loading up-regulated the expression of CCL2 by activating ERK1/2 pathway, thereby stimulating migration of endosteal progenitors. Finally, neutralizing CCL2 abolished the recruitment of endosteal progenitors and the increased bone formation in mice after 4 weeks running. These results therefore uncover an unknown connection between osteoblasts and endosteal progenitors recruited in the increased bone formation induced by mechanical loading.
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Affiliation(s)
- Zilong Yao
- Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China.,Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China
| | - Pengyu Chen
- Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China.,Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China
| | - Liuyi Fan
- Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China.,Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China
| | - Peisheng Chen
- Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China.,Department of Orthopedics, Fuzhou Second Hospital Affiliated to Xiamen University, Fuzhou, China
| | - Xianrong Zhang
- Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China.,Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China
| | - Bin Yu
- Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China.,Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China
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Mestres G, Carter SSD, Hailer NP, Diez-Escudero A. A practical guide for evaluating the osteoimmunomodulatory properties of biomaterials. Acta Biomater 2021; 130:115-137. [PMID: 34087437 DOI: 10.1016/j.actbio.2021.05.038] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 04/29/2021] [Accepted: 05/20/2021] [Indexed: 12/17/2022]
Abstract
Biomaterials offer a promising approach to repair bone defects. Whereas traditional studies predominantly focused on optimizing the osteogenic capacity of biomaterials, less focus has been on the immune response elicited by them. However, the immune and skeletal systems extensively interact, a concept which is referred to as 'osteoimmunology'. This realization has fuelled the development of biomaterials with favourable osteoimmunomodulatory (OIM) properties, aiming to modulate the immune response and to support bone regeneration, thereby affecting the success of an implant. Given the plethora of in vitro assays used to evaluate the OIM properties of biomaterials, it may be challenging to select the right methods to produce conclusive results. In this review, we aim to provide a comprehensive and practical guide for researchers interested in studying the OIM properties of biomaterials in vitro. After a concise overview of the concept of osteoimmunology, emphasis is put on the methodologies that are regularly used to evaluate the OIM properties of biomaterials. First, a description of the most commonly used cell types and cell culture media is provided. Second, typical experimental set-ups and their relevant characteristics are discussed. Third, a detailed overview of the generally used methodologies and readouts, including cell type-specific markers and time points of analysis, is given. Finally, we highlight the promise of advanced approaches, namely microarrays, bioreactors and microfluidic-based systems, and the potential that these may offer to the osteoimmunology field. STATEMENT OF SIGNIFICANCE: Osteoimmunology focuses on the connection and communication between the skeletal and immune systems. This interaction has been recognized to play an important role in the clinical success of biomaterials, which has resulted in an increasing amount of research on the osteoimmunomodulatory (OIM) properties of biomaterials. However, the amount of literature makes it challenging to extract the information needed to design experiments from beginning to end, and to compare obtained results to existing work. This article intends to serve as a guide for those aiming to learn more about the commonly used experimental approaches in the field. We cover early-stage choices, such as cell types and experimental set-ups, but also discuss specific assays, including cell markers and time points of analysis.
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Affiliation(s)
- Gemma Mestres
- Division of Microsystems Technology, Department of Materials Science and Engineering, Science for Life Laboratory, Uppsala University, 751 22 Uppsala, Sweden.
| | - Sarah-Sophia D Carter
- Division of Microsystems Technology, Department of Materials Science and Engineering, Science for Life Laboratory, Uppsala University, 751 22 Uppsala, Sweden
| | - Nils P Hailer
- Ortholab, Department of Surgical Sciences-Orthopaedics, Uppsala University, 751 85 Uppsala, Sweden
| | - Anna Diez-Escudero
- Ortholab, Department of Surgical Sciences-Orthopaedics, Uppsala University, 751 85 Uppsala, Sweden
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Zhou G, Sun S, Yuan Q, Zhang R, Jiang P, Li G, Wang Y, Li X. Multiple-Tissue and Multilevel Analysis on Differentially Expressed Genes and Differentially Correlated Gene Pairs for HFpEF. Front Genet 2021; 12:668702. [PMID: 34306013 PMCID: PMC8296822 DOI: 10.3389/fgene.2021.668702] [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: 02/17/2021] [Accepted: 05/12/2021] [Indexed: 11/15/2022] Open
Abstract
Heart failure with preserved ejection fraction (HFpEF) is a complex disease characterized by dysfunctions in the heart, adipose tissue, and cerebral arteries. The elucidation of the interactions between these three tissues in HFpEF will improve our understanding of the mechanism of HFpEF. In this study, we propose a multilevel comparative framework based on differentially expressed genes (DEGs) and differentially correlated gene pairs (DCGs) to investigate the shared and unique pathological features among the three tissues in HFpEF. At the network level, functional enrichment analysis revealed that the networks of the heart, adipose tissue, and cerebral arteries were enriched in the cell cycle and immune response. The networks of the heart and adipose tissues were enriched in hemostasis, G-protein coupled receptor (GPCR) ligand, and cancer-related pathway. The heart-specific networks were enriched in the inflammatory response and cardiac hypertrophy, while the adipose-tissue-specific networks were enriched in the response to peptides and regulation of cell adhesion. The cerebral-artery-specific networks were enriched in gene expression (transcription). At the module and gene levels, 5 housekeeping DEGs, 2 housekeeping DCGs, 6 modules of merged protein–protein interaction network, 5 tissue-specific hub genes, and 20 shared hub genes were identified through comparative analysis of tissue pairs. Furthermore, the therapeutic drugs for HFpEF-targeting these genes were examined using molecular docking. The combination of multitissue and multilevel comparative frameworks is a potential strategy for the discovery of effective therapy and personalized medicine for HFpEF.
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Affiliation(s)
- Guofeng Zhou
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Shaoyan Sun
- School of Mathematics and Statistics, Ludong University, Yantai, China
| | - Qiuyue Yuan
- CEMS, NCMIS, MDIS, Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing, China.,School of Mathematical Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Run Zhang
- School of Mathematics and Statistics, Ludong University, Yantai, China
| | - Ping Jiang
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Guangyu Li
- CEMS, NCMIS, MDIS, Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing, China
| | - Yong Wang
- CEMS, NCMIS, MDIS, Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing, China.,School of Mathematical Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Xiao Li
- Department of Cardiovascular, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
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Sharkeev YP, Komarova EG, Chebodaeva VV, Sedelnikova MB, Zakharenko AM, Golokhvast KS, Litvinova LS, Khaziakhmatova OG, Malashchenko VV, Yurova KA, Gazatova ND, Kozlov IG, Khlusova MY, Zaitsev KV, Khlusov IA. Amorphous-Crystalline Calcium Phosphate Coating Promotes In Vitro Growth of Tumor-Derived Jurkat T Cells Activated by Anti-CD2/CD3/CD28 Antibodies. MATERIALS (BASEL, SWITZERLAND) 2021; 14:3693. [PMID: 34279263 PMCID: PMC8269898 DOI: 10.3390/ma14133693] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 06/24/2021] [Accepted: 06/25/2021] [Indexed: 12/29/2022]
Abstract
A modern trend in traumatology, orthopedics, and implantology is the development of materials and coatings with an amorphous-crystalline structure that exhibits excellent biocopatibility. The structure and physico-chemical and biological properties of calcium phosphate (CaP) coatings deposited on Ti plates using the micro-arc oxidation (MAO) method under different voltages (200, 250, and 300 V) were studied. Amorphous, nanocrystalline, and microcrystalline statesof CaHPO4 and β-Ca2P2O7 were observed in the coatings using TEM and XRD. The increase in MAO voltage resulted in augmentation of the surface roughness Ra from 2.5 to 6.5 µm, mass from 10 to 25 mg, thickness from 50 to 105 µm, and Ca/P ratio from 0.3 to 0.6. The electrical potential (EP) of the CaP coatings changed from -456 to -535 mV, while the zeta potential (ZP) decreased from -53 to -40 mV following an increase in the values of the MAO voltage. Numerous correlations of physical and chemical indices of CaP coatings were estimated. A decrease in the ZP magnitudes of CaP coatings deposited at 200-250 V was strongly associated with elevated hTERT expression in tumor-derived Jurkat T cells preliminarily activated with anti-CD2/CD3/CD28 antibodies and then contacted in vitro with CaP-coated samples for 14 days. In turn, in vitro survival of CD4+ subsets was enhanced, with proinflammatory cytokine secretion of activated Jurkat T cells. Thus, the applied MAO voltage allowed the regulation of the physicochemical properties of amorphous-crystalline CaP-coatings on Ti substrates to a certain extent. This method may be used as a technological mechanism to trigger the behavior of cells through contact with micro-arc CaP coatings. The possible role of negative ZP and Ca2+ as effectors of the biological effects of amorphous-crystalline CaP coatings is discussed. Micro-arc CaP coatings should be carefully tested to determine their suitability for use in patients with chronic lymphoid malignancies.
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Affiliation(s)
- Yurii P Sharkeev
- Laboratory of Physics of Nanostructured Biocomposites, Institute of Strength Physics and Materials Science, Siberian Branch of Russian Academy of Sciences, 634055 Tomsk, Russia
- Research School of High-Energy Physics, National Research Tomsk Polytechnic University, 634050 Tomsk, Russia
| | - Ekaterina G Komarova
- Laboratory of Physics of Nanostructured Biocomposites, Institute of Strength Physics and Materials Science, Siberian Branch of Russian Academy of Sciences, 634055 Tomsk, Russia
| | - Valentina V Chebodaeva
- Laboratory of Physics of Nanostructured Biocomposites, Institute of Strength Physics and Materials Science, Siberian Branch of Russian Academy of Sciences, 634055 Tomsk, Russia
| | - Mariya B Sedelnikova
- Laboratory of Physics of Nanostructured Biocomposites, Institute of Strength Physics and Materials Science, Siberian Branch of Russian Academy of Sciences, 634055 Tomsk, Russia
| | | | - Kirill S Golokhvast
- School of Engineering, Far Eastern Federal University, 690090 Vladivostok, Russia
| | - Larisa S Litvinova
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236029 Kaliningrad, Russia
| | - Olga G Khaziakhmatova
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236029 Kaliningrad, Russia
| | - Vladimir V Malashchenko
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236029 Kaliningrad, Russia
| | - Kristina A Yurova
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236029 Kaliningrad, Russia
| | - Natalia D Gazatova
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236029 Kaliningrad, Russia
| | - Ivan G Kozlov
- Department of Organization and Management in the Sphere of Circulation of Medicines, Institute of Postgraduate Education, I.M. Sechenov Federal State Autonomous Educational University of Higher Education-First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 119991 Moscow, Russia
| | - Marina Y Khlusova
- Department of Pathophysiology, Siberian State Medical University, 634050 Tomsk, Russia
| | - Konstantin V Zaitsev
- Siberian Federal Scientific and Clinical Center of the Federal Medical-Biological Agency, 636070 Seversk, Russia
| | - Igor A Khlusov
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, 236029 Kaliningrad, Russia
- Research School of Chemistry and Applied Biomedical Sciences, National Research Tomsk Polytechnic University, 634050 Tomsk, Russia
- Department of Morphology and General Pathology, Siberian State Medical University, 634050 Tomsk, Russia
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Li M, Guo X, Qi W, Wu Z, de Bruijn JD, Xiao Y, Bao C, Yuan H. Macrophage polarization plays roles in bone formation instructed by calcium phosphate ceramics. J Mater Chem B 2021; 8:1863-1877. [PMID: 32067012 DOI: 10.1039/c9tb02932j] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
To investigate the roles of macrophages in material-instructed bone formation, two calcium phosphate (TCP) ceramics with the same chemistry but various scales of surface topography were employed in this study. After being implanted subcutaneously in FVB mice for 8 weeks, TCPs (TCP ceramics with submicron surface topography) gave rise to bone formation, while TCPb (TCP ceramics with micron surface topography) did not, showing the crucial role of surface topography scale in material-instructed bone formation. Depletion of macrophages with liposomal clodronate (LipClod) blocked such bone formation instructed by TCPs, confirming the role of macrophages in material-instructed bone formation. Macrophage cells (i.e. RAW 264.7 cells) cultured on TCPs in vitro polarized to tissue repair macrophages as evidenced by gene expression and cytokine production, while polarizing to pro-inflammatory macrophages on TCPb. Submicron surface topography of TCP ceramics directed macrophage polarization via PI3K/AKT pathways with the synergistic regulation of integrin β1. Finally, the tissue repair macrophage polarization on TCPs resulted in osteogenic differentiation of mesenchymal stem cells in vitro. At early implantation in FVB mice, TCPs recruited more macrophages which polarized towards tissue repair macrophages with time. The present data demonstrate the important roles of macrophage polarization in bone formation instructed by calcium phosphate ceramics.
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Affiliation(s)
- Mingzheng Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, Ren Min Nan Rd, Chengdu, 610041, Sichuan, China.
| | - Xiaodong Guo
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, Ren Min Nan Rd, Chengdu, 610041, Sichuan, China.
| | - Wenting Qi
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, Ren Min Nan Rd, Chengdu, 610041, Sichuan, China.
| | - Zhenzhen Wu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, Ren Min Nan Rd, Chengdu, 610041, Sichuan, China.
| | - Joost D de Bruijn
- School of Engineering and Materials Science, Queen Mary University of London, UK
| | - Yu Xiao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, Ren Min Nan Rd, Chengdu, 610041, Sichuan, China.
| | - Chongyun Bao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, Ren Min Nan Rd, Chengdu, 610041, Sichuan, China.
| | - Huipin Yuan
- Kuros Biosciences BV, Prof. Bronkhorstlaan 10, 3723 MB Bilthoven, The Netherlands and MERLN Institute, Maastricht University, The Netherlands
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Xing H, Li R, Qing Y, Ying B, Qin Y. Biomaterial-based osteoimmunomodulatory strategies via the TLR4-NF-κB signaling pathway: A review. APPLIED MATERIALS TODAY 2021; 22:100969. [DOI: 10.1016/j.apmt.2021.100969] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Wang J, Su Y, Xu L, Li D. Micro-patterned surface construction on BCP ceramics and the regulation on inflammation-involved osteogenic differentiation. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2020; 116:111220. [DOI: 10.1016/j.msec.2020.111220] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 06/09/2020] [Accepted: 06/18/2020] [Indexed: 02/07/2023]
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Costimulatory Effect of Rough Calcium Phosphate Coating and Blood Mononuclear Cells on Adipose-Derived Mesenchymal Stem Cells In Vitro as a Model of In Vivo Tissue Repair. MATERIALS 2020; 13:ma13194398. [PMID: 33023124 PMCID: PMC7579197 DOI: 10.3390/ma13194398] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 09/26/2020] [Accepted: 09/29/2020] [Indexed: 02/07/2023]
Abstract
Calcium phosphate (CaP) materials do not always induce ectopic vascularization and bone formation; the reasons remain unclear, and there are active discussions of potential roles for post-implantation hematoma, circulating immune and stem cells, and pericytes, but studies on adipose-derived stem cells (AMSCs) in this context are lacking. The rough (average surface roughness Ra = 2-5 µm) scaffold-like CaP coating deposited on pure titanium plates by the microarc oxidation method was used to investigate its subcutaneous vascularization in CBA/CaLac mice and in vitro effect on cellular and molecular crosstalk between human blood mononuclear cells (hBMNCs) and AMSCs (hAMSCs). Postoperative hematoma development on the CaP surface lasting 1-3 weeks may play a key role in the microvessel elongation and invasion into the CaP relief at the end of the 3rd week of injury and BMNC migration required for enhanced wound healing in mice. Satisfactory osteogenic and chondrogenic differentiation but poor adipogenic differentiation of hAMSCs on the rough CaP surface were detected in vitro by differential cell staining. The fractions of CD73+ (62%), CD90+ (0.24%), and CD105+ (0.41%) BMNCs may be a source of autologous circulating stem/progenitor cells for the subcutis reparation, but allogenic hBMNC participation is mainly related to the effects of CD4+ T cells co-stimulated with CaP coating on the in vitro recruitment of hAMSCs, their secretion of angiogenic and osteomodulatory molecules, and the increase in osteogenic features within the period of in vivo vascularization. Cellular and molecular crosstalk between BMNCs and AMSCs is a model of effective subcutis repair. Rough CaP surface enhanced angio- and osteogenic signaling between cells. We believe that preconditioning and/or co-transplantation of hAMSCs with hBMNCs may broaden their potential in applications related to post-implantation tissue repair and bone bioengineering caused by microarc CaP coating.
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Chen X, Wang M, Chen F, Wang J, Li X, Liang J, Fan Y, Xiao Y, Zhang X. Correlations between macrophage polarization and osteoinduction of porous calcium phosphate ceramics. Acta Biomater 2020; 103:318-332. [PMID: 31857257 DOI: 10.1016/j.actbio.2019.12.019] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 12/09/2019] [Accepted: 12/13/2019] [Indexed: 01/08/2023]
Abstract
The host immune response is critical for in situ osteogenesis, but correlations between local inflammatory reactions and biomaterial osteoinduction are still poorly understood. This study used a murine intramuscular implantation model to demonstrate that calcium phosphate ceramics with different phase compositions exhibited divergent osteoinductivities. The osteoinductive potential of each ceramic was closely associated with the immunomodulatory capacity of the material, and especially with the regulation of macrophage polarization and functional status. Biphasic calcium phosphate (BCP) ceramics with superior osteoinductive potential enhanced the fraction of CD206+ M2 macrophages, up-regulated expression of M2 phenotypic markers in vitro, and increased the ARG+ M2 population in vivo. This suggested that BCP ceramics could ameliorate long-term inflammation and build a pro-osteogenic microenvironment. However, β-tricalcium phosphate (β-TCP) ceramics with no obvious osteoinductivity increased the fraction of CCR7+ M1 macrophages, promoted the secretion of M1 phenotypic markers in vitro, and maintained a high proportion of iNOS+ M1 macrophages in vivo. It indicated that β-TCP ceramics could exacerbate inflammation and inhibit ectopic bone formation. Hydroxyapatite ceramics with an intermediate osteoinductivity exhibited a moderate amount of both M1 and M2 macrophages. These findings highlight the critical role of macrophage polarization in biomaterial-dependent osteoinduction, which not only deepens our understanding of osteoinductive mechanisms but also provides a strategy to design bone substitutes by endowing materials with the proper immunomodulatory abilities to achieve the desired clinic performance. STATEMENT OF SIGNIFICANCE: Calcium phosphate (CaP) ceramics with osteoinductive capacities are able to induce ectopic bone formation in non-osseous sites. However, its underlying mechanism is largely unknown. Previous studies have demonstrated an indispensable role of macrophages in osteogenesis, inspiring us that local inflammatory reaction may affect material-dependent osteoinduction. This study indicated that CaP ceramics with different phase composition could present divergent osteoinductive capacities through modulating polarization and functional status of macrophages, as biphasic calcium phosphate with potent osteoinductivity ameliorated long-term inflammation and induced a healing-associated M2 phenotype to initiate bone formation. These findings not only get an insight into the mechanism of CaP-involved osteoinduction, but also help the design of tissue-inducing implants by endowing biomaterials with proper immunomodulatory ability.
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Affiliation(s)
- Xuening Chen
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China
| | - Menglu Wang
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China
| | - Fuying Chen
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China
| | - Jing Wang
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China
| | - Xiangfeng Li
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China
| | - Jie Liang
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China.
| | - Yujiang Fan
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China
| | - Yumei Xiao
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China.
| | - Xingdong Zhang
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China
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40
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Humbert P, Brennan MÁ, Davison N, Rosset P, Trichet V, Blanchard F, Layrolle P. Immune Modulation by Transplanted Calcium Phosphate Biomaterials and Human Mesenchymal Stromal Cells in Bone Regeneration. Front Immunol 2019; 10:663. [PMID: 31001270 PMCID: PMC6455214 DOI: 10.3389/fimmu.2019.00663] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Accepted: 03/11/2019] [Indexed: 12/22/2022] Open
Abstract
A wide variety of biomaterials have been developed as both stabilizing structures for the injured bone and inducers of bone neoformation. They differ in chemical composition, shape, porosity, and mechanical properties. The most extensively employed and studied subset of bioceramics are calcium phosphate materials (CaPs). These materials, when transplanted alongside mesenchymal stem cells (MSCs), lead to ectopic (intramuscular and subcutaneous) and orthotopic bone formation in preclinical studies, and effective fracture healing in clinical trials. Human MSC transplantation in pre-clinical and clinical trials reveals very low engraftment in spite of successful clinical outcomes and their therapeutic actions are thought to be primarily through paracrine mechanisms. The beneficial role of transplanted MSC could rely on their strong immunomodulatory effect since, even without long-term engraftment, they have the ability to alter both the innate and adaptive immune response which is critical to facilitate new bone formation. This study presents the current knowledge of the immune response to the implantation of CaP biomaterials alone or in combination with MSC. In particular the central role of monocyte-derived cells, both macrophages and osteoclasts, in MSC-CaP mediated bone formation is emphasized. Biomaterial properties, such as macroporosity and surface microstructure, dictate the host response, and the ultimate bone healing cascade. Understanding intercellular communications throughout the inflammation, its resolution and the bone regeneration phase, is crucial to improve the current therapeutic strategies or develop new approaches.
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Affiliation(s)
- Paul Humbert
- Laboratory Phy-Os, Inserm UMR1238, University of Nantes, Nantes, France
| | - Meadhbh Á. Brennan
- Laboratory Phy-Os, Inserm UMR1238, University of Nantes, Nantes, France
- Harvard School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, United States
| | - Noel Davison
- MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Maastricht, Netherlands
- Instructure Labs, B.V., The Hague, Netherlands
| | - Philippe Rosset
- Laboratory Phy-Os, Inserm UMR1238, University of Nantes, Nantes, France
- Centre Hospitalier Universitaire de Tours, Tours, France
| | - Valérie Trichet
- Laboratory Phy-Os, Inserm UMR1238, University of Nantes, Nantes, France
| | | | - Pierre Layrolle
- Laboratory Phy-Os, Inserm UMR1238, University of Nantes, Nantes, France
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Lee J, Byun H, Madhurakkat Perikamana SK, Lee S, Shin H. Current Advances in Immunomodulatory Biomaterials for Bone Regeneration. Adv Healthc Mater 2019; 8:e1801106. [PMID: 30328293 DOI: 10.1002/adhm.201801106] [Citation(s) in RCA: 186] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 09/19/2018] [Indexed: 12/14/2022]
Abstract
Biomaterials with suitable surface modification strategies are contributing significantly to the rapid development of the field of bone tissue engineering. Despite these encouraging results, utilization of biomaterials is poorly translated to human clinical trials potentially due to lack of knowledge about the interaction between biomaterials and the body defense mechanism, the "immune system". The highly complex immune system involves the coordinated action of many immune cells that can produce various inflammatory and anti-inflammatory cytokines. Besides, bone fracture healing initiates with acute inflammation and may later transform to a regenerative or degenerative phase mainly due to the cross-talk between immune cells and other cells in the bone regeneration process. Among various immune cells, macrophages possess a significant role in the immune defense, where their polarization state plays a key role in the wound healing process. Growing evidence shows that the macrophage polarization state is highly sensitive to the biomaterial's physiochemical properties, and advances in biomaterial research now allow well controlled surface properties. This review provides an overview of biomaterial-mediated modulation of the immune response for regulating key bone regeneration events, such as osteogenesis, osteoclastogenesis, and inflammation, and it discusses how these strategies can be utilized for future bone tissue engineering applications.
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Affiliation(s)
- Jinkyu Lee
- Department of Bioengineering; Hanyang University; 222 Wangsimni-ro Seongdong-gu Seoul 04763 Republic of Korea
| | - Hayeon Byun
- Department of Bioengineering; Hanyang University; 222 Wangsimni-ro Seongdong-gu Seoul 04763 Republic of Korea
| | | | - Sangmin Lee
- Department of Bioengineering; Hanyang University; 222 Wangsimni-ro Seongdong-gu Seoul 04763 Republic of Korea
| | - Heungsoo Shin
- Department of Bioengineering; Hanyang University; 222 Wangsimni-ro Seongdong-gu Seoul 04763 Republic of Korea
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