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Sanie-Jahromi F, Sadeghi N, Moayedfard Z, Gharegezloo Z, Nejabat M, Nowroozzadeh MH. Effects of exosomes derived from activated corneal stromal keratocytes on the inflammation, proliferation, neuroprotection and epithelial-mesenchymal transition in retinal pigment epithelium cells. Life Sci 2025; 371:123592. [PMID: 40174671 DOI: 10.1016/j.lfs.2025.123592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Revised: 03/04/2025] [Accepted: 03/24/2025] [Indexed: 04/04/2025]
Abstract
AIMS This study investigated the effects of activated keratocyte-derived exosomes (aKExo) on retinal pigment epithelial (RPE) cells in-vitro, focusing on cell viability, inflammatory cytokine expression, and neuroprotective properties. MATERIALS AND METHODS Keratocytes were cultured, and exosomes were extracted and characterized using transmission electron microscopy (TEM), scanning electron microscopy (SEM), flow cytometry, and dynamic light scattering (DLS). RPE cells, isolated from a human donor, were confirmed via RPE65 expression. aKExo effects on RPE cells were assessed using MTT assay at concentrations from 10-1 (35 μg/mL) to 10-5 (3.5 × 10-3 μg/mL). The optimal aKExo concentration (10-5) enhanced cell viability and exhibited the highest proliferative potential compared to the control group, making it the optimal dose for subsequent experiments including gene expression analysis, and ELISA. KEY FINDINGS aKExo downregulated IL-6 mRNA (0.70 ± 0.06, p = 0.0009) and marginally reduced TGF-β mRNA (0.75 ± 0.16, p = 0.0575). ELISA confirmed a reduction in IL-6 (31.33 ± 5.77 pg/mL vs. 50.22 ± 13.47 pg/mL, p = 0.0894) and TGF-β (8.91 ± 0.16 pg/mL vs. 11.39 ± 1.49 pg/mL, p = 0.0460). No significant changes were observed for IL-1β expression or other epithelial-mesenchymal transition (EMT)-related genes (α-SMA, ZEB-1, β-catenin). Neuroprotective genes NGF (4.34 ± 1.05, p = 0.0053) and CD90 (1.55 ± 0.25, p = 0.0184) were significantly upregulated, while VEGF-A was elevated (1.65 ± 0.15, p = 0.0018). SIGNIFICANCE These findings highlight aKExo's immunomodulatory, neuroprotective, and anti-EMT effects, suggesting potential therapeutic applications for retinal disorders, while noting that VEGF-A upregulation requires further investigation.
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Affiliation(s)
- Fatemeh Sanie-Jahromi
- Poostchi Ophthalmology Research Center, Department of Ophthalmology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Niloofar Sadeghi
- Poostchi Ophthalmology Research Center, Department of Ophthalmology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Moayedfard
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Gharegezloo
- Poostchi Ophthalmology Research Center, Department of Ophthalmology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mahmood Nejabat
- Poostchi Ophthalmology Research Center, Department of Ophthalmology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - M Hossein Nowroozzadeh
- Poostchi Ophthalmology Research Center, Department of Ophthalmology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
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2
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Luo L, Zheng W, Li J, Chen T, Xue W, Lin T, Liu M, Yan Z, Yang J, Li J, Pu J, Wu Y, Hu K, Li S, Huang W. 3D-Printed Titanium Trabecular Scaffolds with Sustained Release of Hypoxia-Induced Exosomes for Dual-Mimetic Bone Regeneration. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2500599. [PMID: 40349160 DOI: 10.1002/advs.202500599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 03/23/2025] [Indexed: 05/14/2025]
Abstract
Current Ti-6Al-4V bone implants lack trabecular structure and pro‑angiogenic cues, both essential for regeneration. Herein, a dual biomimetic strategy is devised that integrates a 3D-printed biomimetic trabecular porous Ti-6Al-4V scaffold (BTPS) with exosome-loaded PEGDA/GelMA hydrogel microspheres (PGHExo) designed for sustained release. BTPS is designed using Voronoi algorithms and imaging data, and replicates the geometry and mechanical properties of natural bone. Hypoxia-induced human umbilical vein endothelial cell (HUVEC) derived exosomes (HExo) are encapsulated in PGHExo microspheres via microfluidic technology, enabling controlled release of HExo, and anchored onto BTPS using polydopamine (pDA) modification (BTPS&pDA@PGHExo). BTPS exhibited an elastic modulus of ≈3.2 GPa and a permeability of 11.52 × 10-8 mm2, mimicking natural bone. In vitro assays demonstrated that BTPS&pDA@PGHExo significantly enhanced osteogenesis and angiogenesis. mRNA-Seq analysis suggested that BTPS&pDA@PGHExo regulates osteogenic and angiogenic gene expression through the activation of pathways including MAPK, mTOR, HIF-1, and VEGF. In vivo, BTPS&pDA@PGHExo improved bone volume, density, and neovascularization in a rabbit model. This dual biomimetic strategy offers a promising clinical solution, addressing the limitations of conventional Ti-6Al-4V scaffolds and providing an innovative approach for personalized bone defect repair.
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Affiliation(s)
- Lincong Luo
- Yue Bei People's Hospital Postdoctoral Innovation Practice Base, Southern Medical University, Guangzhou, Guangdong, 510515, China
- Guangdong Engineering Research Center for Translation of Medical 3D Printing Application, Guangdong Provincial Key Laboratory of Digital Medicine and Biomechanics, National Key Discipline of Human Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Weihan Zheng
- Guangdong Medical Innovation Platform for Translation of 3D Printing Application, The Third Affiliated Hospital of Southern Medical University, Southern Medical University, Guangzhou, Guangdong, 510630, China
| | - Jiaying Li
- Guangdong Engineering Research Center for Translation of Medical 3D Printing Application, Guangdong Provincial Key Laboratory of Digital Medicine and Biomechanics, National Key Discipline of Human Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Tingting Chen
- School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, 350108, China
| | - Wanting Xue
- Guangdong Engineering Research Center for Translation of Medical 3D Printing Application, Guangdong Provincial Key Laboratory of Digital Medicine and Biomechanics, National Key Discipline of Human Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Tao Lin
- Guangdong Engineering Research Center for Translation of Medical 3D Printing Application, Guangdong Provincial Key Laboratory of Digital Medicine and Biomechanics, National Key Discipline of Human Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Mingrui Liu
- School of Basic Medicine, Dali University, Dali, Yunnan, 671003, China
| | - Zi Yan
- Guangdong Medical Innovation Platform for Translation of 3D Printing Application, The Third Affiliated Hospital of Southern Medical University, Southern Medical University, Guangzhou, Guangdong, 510630, China
| | - Jiaxin Yang
- Guangdong Engineering Research Center for Translation of Medical 3D Printing Application, Guangdong Provincial Key Laboratory of Digital Medicine and Biomechanics, National Key Discipline of Human Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Jiamin Li
- School of Basic Medical Sciences, Guangdong Medical University, Dongguan, Guangdong, 523808, China
| | - Jiahao Pu
- School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, 350108, China
| | - Yaobin Wu
- Guangdong Engineering Research Center for Translation of Medical 3D Printing Application, Guangdong Provincial Key Laboratory of Digital Medicine and Biomechanics, National Key Discipline of Human Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Konghe Hu
- Yue Bei People's Hospital Postdoctoral Innovation Practice Base, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Shiyu Li
- Department of Microbiology and Immunology, College of Basic Medicine and Public Hygiene, Jinan University, Guangzhou, Guangdong, 510632, China
| | - Wenhua Huang
- Yue Bei People's Hospital Postdoctoral Innovation Practice Base, Southern Medical University, Guangzhou, Guangdong, 510515, China
- Guangdong Engineering Research Center for Translation of Medical 3D Printing Application, Guangdong Provincial Key Laboratory of Digital Medicine and Biomechanics, National Key Discipline of Human Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China
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3
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Yuan J, Li M, He X, Hou Q, Fu X, Hao J. A thermally stable bioactive chitosan scaffold with pH-responsive exosome adsorption and release function promotes wound healing. Int J Biol Macromol 2025; 306:141552. [PMID: 40024417 DOI: 10.1016/j.ijbiomac.2025.141552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 02/16/2025] [Accepted: 02/25/2025] [Indexed: 03/04/2025]
Abstract
Chitosan is an excellent carrier material for bioactive substances, and its binding ability is affected by the pH value of surrounding environments. Healthy skin is maintained in a slightly acidic environment, whereas the wound healing environment is normally neutral or slightly alkaline. In the present study, the authors proposed developing a thermally stable bioactive chitosan scaffold (T-CS) with pH-responsive exosome adsorption and release functions to promote wound healing. Our results revealed that T-CS could automatically capture exosomes from human umbilical cord mesenchymal stem cells in an acidic environment and release them in alkaline or neutral environments. The exosomes separated by T-CS and the traditional ultracentrifugation (UC) method exhibited similar size and protein markers. Furthermore, the exosomal biological activities of the T-CS (T-CS-E) and UC groups exhibited similar anti-inflammatory, proproliferation, promigration, and proendothelial cell-tube formation effects on human umbilical vein endothelial cells. Similar results were achieved in a mouse model by sustainably releasing exosomes. T-CS-E could facilitate wound healing by enhancing cell proliferation, inhibiting wound inflammation, and promoting vascularization. Therefore, this study developed a T-CS scaffold that integrates exosome isolation and application for wound healing, laying the foundation for future clinical use.
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Affiliation(s)
- Jifang Yuan
- Medical Innovation Research Department, PLA General Hospital and PLA Medical College, Beijing, 100853, China; PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Beijing 100048, China; Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, 2019RU051, Beijing 100048, China
| | - Meirong Li
- Center for Drug Evaluation, National Medical Products Administration, Beijing 100076, China
| | - Xiaofeng He
- Department of Diagnostic Radiology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Qian Hou
- Medical Innovation Research Department, PLA General Hospital and PLA Medical College, Beijing, 100853, China; PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Beijing 100048, China; Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, 2019RU051, Beijing 100048, China.
| | - Xiaobing Fu
- Medical Innovation Research Department, PLA General Hospital and PLA Medical College, Beijing, 100853, China; PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Beijing 100048, China; Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, 2019RU051, Beijing 100048, China.
| | - Jianxiu Hao
- Medical Innovation Research Department, PLA General Hospital and PLA Medical College, Beijing, 100853, China; PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Beijing 100048, China; Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, 2019RU051, Beijing 100048, China; Graduate school of the PLA General Hospital, Beijing 100853, China.
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4
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Long Q, Liu C, Zheng H, Wang M, Liu H, Liu Y, Cao Z, Sun Y, Mo Q, Backman LJ, Zhu J, Hu L, Huang J, Zhang W, Chen J. Enhancing Tendon Regeneration: Investigating the Impact of Topography on the Secretome of Adipose-Derived Stem Cells. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2417447. [PMID: 40091553 PMCID: PMC12079404 DOI: 10.1002/advs.202417447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Indexed: 03/19/2025]
Abstract
Tendons are vital for maintaining integrity and movement, but current treatment options are insufficient for their regeneration after injuries. Previous studies have shown that the secretome from mesenchymal stem cells (MSCs) promoted tendon regeneration. However, limited studies have explored the impact of the physical microenvironment on the secretome's efficacy of MSCs. In this study, it is shown that the topographic orientation regulates the secretome of human adipose-derived stem cells (ADSCs) and promotes tendon regeneration. Conditioned medium (CM) is collected from ADSCs cultured on the scaffolds with different topography. The results show that CM generated from aligned structure group has a potent effect in promoting cell migration and proliferation, tenogenic differentiation, macrophage polarization toward M2 phenotype, tendon structure and mechanical function recovery. Proteomic analysis revealed that the aligned structure can up-regulate the secretion of Extracellular matrix (ECM) proteins while down-regulate proinflammatory factors. This modulation activates the MAPK, GPCR and Integrin signaling pathways which may account for the enhanced effect on tendon regeneration. This study offers a promising and safer non-cell-based treatment option for tendon repair.
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Affiliation(s)
- Qiuzi Long
- Nanjing University of Chinese MedicineNanjing210029China
- Center for Stem Cell and Regenerative MedicineSoutheast UniversityNanjing210009China
- Nanjing Second HospitalNanjing Hospital affiliated to Nanjing University of Chinese MedicineNanjing210003China
| | - Chuanquan Liu
- Center for Stem Cell and Regenerative MedicineSoutheast UniversityNanjing210009China
- School of MedicineSoutheast UniversityNanjing210009China
| | - Haotian Zheng
- Center for Stem Cell and Regenerative MedicineSoutheast UniversityNanjing210009China
- School of MedicineSoutheast UniversityNanjing210009China
| | - Mingyue Wang
- Center for Stem Cell and Regenerative MedicineSoutheast UniversityNanjing210009China
- School of MedicineSoutheast UniversityNanjing210009China
| | - Hanmei Liu
- Nanjing University of Chinese MedicineNanjing210029China
| | - Yue Liu
- Center for Stem Cell and Regenerative MedicineSoutheast UniversityNanjing210009China
- School of MedicineSoutheast UniversityNanjing210009China
| | - Zhicheng Cao
- Center for Stem Cell and Regenerative MedicineSoutheast UniversityNanjing210009China
- School of MedicineSoutheast UniversityNanjing210009China
- Department of Orthopaedic SurgeryInstitute of Digital MedicineNanjing First HospitalNanjing Medical UniversityNanjing210006China
| | - Yuzhi Sun
- Center for Stem Cell and Regenerative MedicineSoutheast UniversityNanjing210009China
- School of MedicineSoutheast UniversityNanjing210009China
- Department of Orthopaedic SurgeryInstitute of Digital MedicineNanjing First HospitalNanjing Medical UniversityNanjing210006China
| | - Qingyun Mo
- Center for Stem Cell and Regenerative MedicineSoutheast UniversityNanjing210009China
- School of MedicineSoutheast UniversityNanjing210009China
| | - Ludvig J. Backman
- Department of Medical and Translational Biology, AnatomyUmeå UniversityUmeå90187Sweden
- Department of Community Medicine and RehabilitationUmeå UniversityUmeå90187Sweden
| | - Jialin Zhu
- Center for Stem Cell and Regenerative MedicineSoutheast UniversityNanjing210009China
- School of MedicineSoutheast UniversityNanjing210009China
| | - Lizhi Hu
- Center for Stem Cell and Regenerative MedicineSoutheast UniversityNanjing210009China
- School of MedicineSoutheast UniversityNanjing210009China
| | - Jinlong Huang
- Nanjing University of Chinese MedicineNanjing210029China
| | - Wei Zhang
- Center for Stem Cell and Regenerative MedicineSoutheast UniversityNanjing210009China
- School of MedicineSoutheast UniversityNanjing210009China
- Jiangsu Key Laboratory for Biomaterials and DevicesSoutheast UniversityNanjing210096China
- China Orthopedic Regenerative Medicine Group (CORMed)Hangzhou310058China
| | - Jialin Chen
- Center for Stem Cell and Regenerative MedicineSoutheast UniversityNanjing210009China
- School of MedicineSoutheast UniversityNanjing210009China
- Jiangsu Key Laboratory for Biomaterials and DevicesSoutheast UniversityNanjing210096China
- Department of OphthalmologyZhongda HospitalSoutheast UniversityNanjing210009China
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5
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Chen C, Zhong W, Zheng H, Zhao W, Wang Y, Shen B. Current state of heart failure treatment: are mesenchymal stem cells and their exosomes a future therapy? Front Cardiovasc Med 2025; 12:1518036. [PMID: 40357434 PMCID: PMC12066684 DOI: 10.3389/fcvm.2025.1518036] [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: 10/27/2024] [Accepted: 04/16/2025] [Indexed: 05/15/2025] Open
Abstract
Heart failure (HF) represents the terminal stage of cardiovascular disease and remains a leading cause of mortality. Epidemiological studies indicate a high prevalence and mortality rate of HF globally. Current treatment options primarily include pharmacological and non-pharmacological approaches. With the development of mesenchymal stem cell (MSC) transplantation technology, increasing research has shown that stem cell therapy and exosomes derived from these cells hold promise for repairing damaged myocardium and improving cardiac function, becoming a hot topic in clinical treatment for HF. However, this approach also presents certain limitations. This review summarizes the mechanisms of HF, current treatment strategies, and the latest progress in the application of MSCs and their exosomes in HF therapy.
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Affiliation(s)
- Chengqian Chen
- Department of Cardiology Center, The First Hospital of Jilin University, Changchun, China
| | - Wentao Zhong
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, China
| | - Hao Zheng
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, China
| | - Wei Zhao
- Department of Cardiology Center, The First Hospital of Jilin University, Changchun, China
| | - Yushi Wang
- Department of Cardiology Center, The First Hospital of Jilin University, Changchun, China
| | - Botao Shen
- Department of Cardiology Center, The First Hospital of Jilin University, Changchun, China
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6
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Kananivand M, Nouri F, Yousefi MH, Pajouhi A, Ghorbani H, Afkhami H, Razavi ZS. Mesenchymal stem cells and their exosomes: a novel approach to skin regeneration via signaling pathways activation. J Mol Histol 2025; 56:132. [PMID: 40208456 DOI: 10.1007/s10735-025-10394-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Accepted: 03/06/2025] [Indexed: 04/11/2025]
Abstract
Accelerating wound healing is a crucial objective in surgical and regenerative medicine. The wound healing process involves three key stages: inflammation, cell proliferation, and tissue repair. Mesenchymal stem cells (MSCs) have demonstrated significant therapeutic potential in promoting tissue regeneration, particularly by enhancing epidermal cell migration and proliferation. However, the precise molecular mechanisms underlying MSC-mediated wound healing remain unclear. This review highlights the pivotal role of MSCs and their exosomes in wound repair, with a specific focus on critical signaling pathways, including PI3K/Akt, WNT/β-catenin, Notch, and MAPK. These pathways regulate essential cellular processes such as proliferation, differentiation, and angiogenesis. Moreover, in vitro and in vivo studies reveal that MSCs accelerate wound closure, enhance collagen deposition, and modulate immune responses, contributing to improved tissue regeneration. Understanding these mechanisms provides valuable insights into MSC-based therapeutic strategies for enhancing wound healing.
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Affiliation(s)
- Maryam Kananivand
- Medical Department, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Fatemeh Nouri
- Department of Biology, School of Basic Sciences, Science and Research Branch, Islamic Azad University (SRBIAU), Tehran, Iran
| | - Mohammad Hasan Yousefi
- Department of Tissue Engineering and Applied Cell Sciences, School of Medicine, Qom University of Medical Sciences, Qom, Iran
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
- Student Research Committee, Qom University of Medical Sciences, Qom, Iran
| | - Ali Pajouhi
- Student Research Committee, USERN Office, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Hakimeah Ghorbani
- Department of Sciences, Faculty of Biological Sciences, Tabriz University of Sciences, Tabriz, Iran
| | - Hamed Afkhami
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran.
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran.
- Department of Medical Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran.
- Student Research Committee, Qom University of Medical Sciences, Qom, Iran.
| | - Zahra Sadat Razavi
- Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran.
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7
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Palamà MEF, Gorgun C, Rovere M, Shaw GM, Reverberi D, Formica M, Quarto E, Barry F, Murphy M, Gentili C. Batch variability and anti-inflammatory effects of iPSC-derived mesenchymal stromal cell extracellular vesicles in osteoarthritis in vitro model. Front Bioeng Biotechnol 2025; 13:1536843. [PMID: 40242358 PMCID: PMC11999995 DOI: 10.3389/fbioe.2025.1536843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Accepted: 03/21/2025] [Indexed: 04/18/2025] Open
Abstract
Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) hold promise as a cell-free therapy for osteoarthritis (OA), due to their immunomodulatory and anti-inflammatory properties. However, the need for large-scale expansion to obtain MSC-EVs for clinical use can lead to senescence-related changes and loss of stem-like properties. In this scenario, induced pluripotent stem cell (iPSC)-derived MSCs (iMSCs) offer the unique opportunity to address obstacles associated with traditional MSC-based therapies. This study used a xeno-free (XFS) medium for long-term expansion of both MSCs and iMSCs, and their EVs comparison. Characterization of both cells and EVs was conducted across different passages, and the anti-inflammatory potential of EVs and iEVs was assessed using an in vitro model of osteoarthritis. Long-term expansion of MSCs resulted in cellular senescence and a reduction in trilineage differentiation capacity by passage five, accompanied by diminished anti-inflammatory properties of EVs. On the other hand, iMSCs exhibited batch-to-batch variability in differentiation and EV biological properties. However, the effects of iMSC-EVs were prolonged compared to MSC-EVs, providing a wider window of activity for therapeutic purposes. Despite this, the variability among iMSC batches poses challenges for their reliability in OA treatment. Further work is needed to overcome these limitations for clinical application.
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Affiliation(s)
| | - Cansu Gorgun
- Department of Experimental Medicine (DIMES), University of Genoa, Genoa, Italy
| | - Matteo Rovere
- Department of Experimental Medicine (DIMES), University of Genoa, Genoa, Italy
| | - Georgina M. Shaw
- Regenerative Medicine Institute (REMEDI), University of Galway (UoG), Galway, Ireland
| | - Daniele Reverberi
- UOC Research-Scientific Direction, Istituto di Scientifico Ricovero e Cura a Carattere, Ospedale Policlinico San Martino, Genoa, Italy
| | - Matteo Formica
- UOC Clinica Ortopedica, Istituto di Scientifico Ricovero e Cura a Carattere, Ospedale Policlinico San Martino, Genoa, Italy
| | - Emanuele Quarto
- UOC Clinica Ortopedica, Istituto di Scientifico Ricovero e Cura a Carattere, Ospedale Policlinico San Martino, Genoa, Italy
| | - Frank Barry
- Regenerative Medicine Institute (REMEDI), University of Galway (UoG), Galway, Ireland
| | - Mary Murphy
- Regenerative Medicine Institute (REMEDI), University of Galway (UoG), Galway, Ireland
| | - Chiara Gentili
- Department of Experimental Medicine (DIMES), University of Genoa, Genoa, Italy
- UOC Oncologia Cellulare, Istituto di Scientifico Ricovero e Cura a Carattere, Ospedale Policlinico San Martino, Genoa, Italy
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8
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Li L, Wang F, Zhu D, Hu S, Cheng K, Li Z. Engineering exosomes and exosome-like nanovesicles for improving tissue targeting and retention. FUNDAMENTAL RESEARCH 2025; 5:851-867. [PMID: 40242543 PMCID: PMC11997600 DOI: 10.1016/j.fmre.2024.03.025] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2023] [Revised: 03/23/2024] [Accepted: 03/29/2024] [Indexed: 04/18/2025] Open
Abstract
Exosomes are natural nano-size particles secreted by human cells, containing numerous bioactive cargos. Serving as crucial mediators of intercellular communication, exosomes are involved in many physiological and pathological processes, such as inflammation, tissue injury, cardiovascular diseases, tumorigenesis and tumor development. Exosomes have exhibited promising results in the diagnosis and treatment of cancer, cardiovascular diseases and others. They are a rapidly growing class of drug delivery vehicles with many advantages over conventional synthetic carriers. Exosomes used in therapeutic applications encounter several challenges, such as the lack of tissue targeting capabilities and short residence time. In this review, we discuss recent advances in exosome engineering to improve tissue targeting and describe the current types of engineered exosome-like nanovesicles, and summarize their preclinical applications in the treatment of diseases. Further, we also highlight the latest engineering strategies developed to extend exosomes retention time in vivo and exosome-like nanovesicles.
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Affiliation(s)
- Lanya Li
- The Tenth Affiliated Hospital, Southern Medical University (Dongguan People's Hospital), Dongguan 523059, China
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Southern Medical University, Guangdong 510515, China
| | - Fei Wang
- The Tenth Affiliated Hospital, Southern Medical University (Dongguan People's Hospital), Dongguan 523059, China
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Southern Medical University, Guangdong 510515, China
| | - Dashuai Zhu
- Department of Biomedical Engineering, Columbia University, New York 10032, USA
| | - Shiqi Hu
- Department of Biomedical Engineering, Columbia University, New York 10032, USA
| | - Ke Cheng
- Department of Biomedical Engineering, Columbia University, New York 10032, USA
| | - Zhenhua Li
- The Tenth Affiliated Hospital, Southern Medical University (Dongguan People's Hospital), Dongguan 523059, China
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Southern Medical University, Guangdong 510515, China
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9
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Wang X, Xu L, Wu Z, Lou L, Xia C, Miao H, Dai J, Fei W, Wang J. Exosomes of stem cells: a potential frontier in the treatment of osteoarthritis. PRECISION CLINICAL MEDICINE 2025; 8:pbae032. [PMID: 39781279 PMCID: PMC11705996 DOI: 10.1093/pcmedi/pbae032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 11/18/2024] [Accepted: 11/25/2024] [Indexed: 01/12/2025] Open
Abstract
The aging population has led to a global issue of osteoarthritis (OA), which not only impacts the quality of life for patients but also poses a significant economic burden on society. While biotherapy offers hope for OA treatment, currently available treatments are unable to delay or prevent the onset or progression of OA. Recent studies have shown that as nanoscale bioactive substances that mediate cell communication, exosomes from stem cell sources have led to some breakthroughs in the treatment of OA and have important clinical significance. This paper summarizes the mechanism and function of stem cell exosomes in delaying OA and looks forward to the development prospects and challenges of exosomes.
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Affiliation(s)
- Xiaofei Wang
- The Graduate School, Dalian Medical University, Dalian 116044, China
- Department of Orthopedics, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225001, China
| | - Lei Xu
- Department of Orthopedics, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225001, China
| | - Zhimin Wu
- The Graduate School, Dalian Medical University, Dalian 116044, China
- Department of Orthopedics, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225001, China
| | - Linbing Lou
- The Graduate School, Dalian Medical University, Dalian 116044, China
- Department of Orthopedics, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225001, China
| | - Cunyi Xia
- Department of Orthopedics, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225001, China
| | - Haixiang Miao
- Department of Orthopedics, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225001, China
| | - Jihang Dai
- Department of Orthopedics, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225001, China
| | - Wenyong Fei
- Department of Orthopedics, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225001, China
| | - Jingcheng Wang
- Department of Orthopedics, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225001, China
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10
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Mohammad Mirzapour S, Jalali F. Stem cell therapy for regenerating periodontal bony defects: A narrative review. JOURNAL OF ADVANCED PERIODONTOLOGY & IMPLANT DENTISTRY 2025; 17:1-14. [PMID: 40265031 PMCID: PMC12010474 DOI: 10.34172/japid.025.3749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 01/23/2025] [Accepted: 01/26/2025] [Indexed: 04/24/2025]
Abstract
Periodontal bony defects pose a significant challenge in periodontology, necessitating advanced regenerative approaches to restore the lost structures. Stem cell-based therapies have emerged as a promising solution due to their ability to differentiate into various cells, modulating the regenerative microenvironment. This narrative review explores the potential of stem cells derived from multiple sources in treating periodontal bony defects. Additionally, we examine evidence from both animal and human studies, highlighting advancements, clinical outcomes, and limitations. By investigating these findings, this article provides a comprehensive overview of the advantages of stem cell-based therapies compared to other regenerative techniques in addressing periodontal bony defects and discusses the limitations of their translation into routine clinical practice.
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Affiliation(s)
- Samira Mohammad Mirzapour
- Department of Periodontics, Faculty of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Jalali
- Student Research Committee, Faculty of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran
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11
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Kim SY. Extracellular vesicles offer enticing opportunities to target and treat lung inflammation. Thorax 2025; 80:127-128. [PMID: 39900491 DOI: 10.1136/thorax-2024-222696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/11/2025] [Indexed: 02/05/2025]
Affiliation(s)
- Sally Yunsun Kim
- Institute of Pharmaceutical Science, King's College London, London, UK
- National Heart and Lung Institute, Imperial College London, London, UK
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12
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Khanabdali R, Shojaee M, Johnson J, Law SQK, Lim MBL, James PF, Tester A, Kalionis B. Profiling the extracellular vesicles of two human placenta-derived mesenchymal stromal cell populations. Exp Cell Res 2025; 444:114387. [PMID: 39706285 DOI: 10.1016/j.yexcr.2024.114387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 12/15/2024] [Accepted: 12/16/2024] [Indexed: 12/23/2024]
Abstract
Increasing evidence shows extracellular vesicles (EVs) are primarily responsible for the beneficial effects of cell-based therapies. EVs derived from mesenchymal stromal cells (MSCs) show promise as a source of EVs for cell-free therapies. The human placental fetal-maternal interface is a rich and abundant source of MSCs from which EVs can be isolated. This study focusses on chorionic MSCs (CMSC) located on the fetal aspect of the interface and decidual MSCs (DMSC) on the maternal aspect. This study used Ligand-based Exosome Affinity Purification (LEAP) chromatography to isolate EVs from well-characterized placental hTERT-transduced CMSC29 and DMSC23 cell lines, which retain many important stem cell-like properties of primary CMSC and DMSC, respectively. After initial biophysical characterization of the EVs isolated from each cell line, the biological activities and the protein, lipid and small RNA contents of CMSC29-EVs and DMSC23-EVs were compared and assessed. LEAP-purified EVs from both sources were validated at the biophysical level by Spectradyne, Cryo-Transmission Electron Microscopy (Cryo-TEM), and Western blot analysis. EVs from each type were labelled with the live cell stain PKH26 and their in vitro uptake and internalization by human dermal fibroblast cells was assessed, as well as their phosphorylation of the protein kinase B/AKT (AKT) pathway. The protein and lipid contents were analyzed by mass spectrometry and the nucleic acid content by RNA sequencing (RNA-seq). Lastly, the biological activities of the EVs were evaluated in a BioMAP® Diversity PLUS® screen system across a panel of 12 human primary cell-based systems and in vitro cell proliferation. EVs isolated from both DMSC23 and CMSC29 significantly increased proliferation of fibroblasts and showed phosphorylation of the AKT pathway. Protein mass spectrometry analysis identified a large number of proteins including cell surface receptors, cytokines, chemokines, matrix molecules and enzymes in both EV types. Lipidomic analysis identified species including phosphatidylcholine, triacylglycerides and diacylglycerides in both DMSC23 and CMSC29-derived EVs. There were some significant differences in identified microRNAs (miRNAs) between the two EV types. The top differentially expressed miRNAs between the two EV types show pathways association with matrix interaction, transcriptional regulation, proliferation, cellular protein modification processes, and vasculogenesis. Differences were also detected between DMSC23- and CMSC29-EVs in the biological activity they displayed in the BioMAP® Diversity PLUS® screen.
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Affiliation(s)
- Ramin Khanabdali
- Exopharm Ltd, Level 17, 31 Queen Street, Melbourne, VIC, 3000, Australia
| | - Mozhgan Shojaee
- Exopharm Ltd, Level 17, 31 Queen Street, Melbourne, VIC, 3000, Australia
| | - Jancy Johnson
- Exopharm Ltd, Level 17, 31 Queen Street, Melbourne, VIC, 3000, Australia; University of Melbourne Department of Biochemistry and Pharmacology, Parkville, VIC, 3052, Australia
| | - Sam Q K Law
- Exopharm Ltd, Level 17, 31 Queen Street, Melbourne, VIC, 3000, Australia
| | - Melissa B L Lim
- Exopharm Ltd, Level 17, 31 Queen Street, Melbourne, VIC, 3000, Australia
| | - Patrick F James
- Exopharm Ltd, Level 17, 31 Queen Street, Melbourne, VIC, 3000, Australia
| | - Angus Tester
- Exopharm Ltd, Level 17, 31 Queen Street, Melbourne, VIC, 3000, Australia
| | - Bill Kalionis
- Department of Maternal-Fetal Medicine Pregnancy Research Centre, Royal Women's Hospital, Parkville, VIC, 3052, Australia; University of Melbourne Department of Obstetrics and Gynaecology and Newborn Health, Royal Women's Hospital, Parkville, VIC, 3052, Australia.
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13
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Emami A, Arabpour Z, Izadi E. Extracellular vesicles: essential agents in critical bone defect repair and therapeutic enhancement. Mol Biol Rep 2025; 52:113. [PMID: 39798011 DOI: 10.1007/s11033-024-10209-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Accepted: 12/29/2024] [Indexed: 01/13/2025]
Abstract
Bone serves as a fundamental structural component in the body, playing pivotal roles in support, protection, mineral supply, and hormonal regulation. However, critical-sized bone injuries have become increasingly prevalent, necessitating extensive medical interventions due to limitations in the body's capacity for self-repair. Traditional approaches, such as autografts, allografts, and xenografts, have yielded unsatisfactory results. Stem cell therapy emerges as a promising avenue, but challenges like immune rejection and low cell survival rates hinder its widespread clinical implementation. Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) have garnered attention for their regenerative capabilities, which surpass those of MSCs themselves. EVs offer advantages such as reduced immunogenicity, enhanced stability, and simplified storage, positioning them as a promising tool in stem cell-based therapies. This review explores the potential of EV-based therapy in bone tissue regeneration, delving into their biological characteristics, communication mechanisms, and preclinical applications across various physiological and pathological conditions. The mechanisms underlying EV-mediated bone regeneration, including angiogenesis, osteoblast proliferation, mineralization, and immunomodulation, are elucidated. Preclinical studies demonstrate the efficacy of EVs in promoting bone repair and neovascularization, even in pathological conditions like osteoporosis. EVs hold promise as a potential alternative for regenerating bone tissue, particularly in the context of critical-sized bone defects, offering new avenues for effective bone defect repair and management.
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Affiliation(s)
- Asrin Emami
- Iranian Tissue Bank and Research Center, Tehran University of Medical Sciences, Tehran, Iran.
| | - Zohreh Arabpour
- Department of Ophthalmology and Visual Science and University of Illinois, Chicago, IL, 60612, USA
| | - Elaheh Izadi
- Pediatric Cell, and Gene Therapy Research Center Gene, Cell and Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran
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14
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Guo J, Huang Z, Wang Q, Wang M, Ming Y, Chen W, Huang Y, Tang Z, Huang M, Liu H, Jia B. Opportunities and challenges of bacterial extracellular vesicles in regenerative medicine. J Nanobiotechnology 2025; 23:4. [PMID: 39754127 PMCID: PMC11697683 DOI: 10.1186/s12951-024-02935-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 10/16/2024] [Indexed: 01/07/2025] Open
Abstract
Extracellular vesicles (EVs) are membrane-bound vesicles that are shed or secreted from the cell membrane and enveloped by a lipid bilayer. They possess stability, low immunogenicity, and non-cytotoxicity, exhibiting extensive prospects in regenerative medicine (RM). However, natural EVs pose challenges, such as insufficient targeting capabilities, potential biosafety concerns, and limited acquisition pathways. Although engineered EVs demonstrate excellent therapeutic efficacy, challenges such as low production yield and the complexity of engineering modifications constrain their further clinical applications. Bacteria have advantages such as rapid proliferation, diverse gene editing methods, mature cultivation techniques, and relatively easy preparation of bacterial EVs (BEVs), which can be used to effectively address the challenges currently encountered in the field of EVs. This review provides a description of the biogenesis and pathophysiological functions of BEVs, and strategies for optimizing BEVs preparation to attain efficiency and safety are discussed. An analysis of natural characteristics of BEVs is also conducted to explore how to leverage their advantages or mitigate their limitations, thereby overcoming constraints on the application of BEVs in RM. In summary, engineered BEVs possess characteristics such as high production yield, excellent stability, and high drug-delivering capabilities, laying the foundation for their application in RM.
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Affiliation(s)
- Jiming Guo
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhijie Huang
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, Guangdong, China
| | - Qinjing Wang
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, Guangdong, China
| | - Min Wang
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, Guangdong, China
| | - Yue Ming
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, Guangdong, China
| | - Weixing Chen
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, Guangdong, China
| | - Yisheng Huang
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhengming Tang
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, Guangdong, China
| | - Mingshu Huang
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, Guangdong, China
| | - Hongyu Liu
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, Guangdong, China
| | - Bo Jia
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, Guangdong, China.
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15
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Torkashvand M, Rezakhani L, Habibi Z, Mikaeili A, Rahmati S. Innovative approaches in lung tissue engineering: the role of exosome-loaded bioscaffolds in regenerative medicine. Front Bioeng Biotechnol 2024; 12:1502155. [PMID: 39758953 PMCID: PMC11695380 DOI: 10.3389/fbioe.2024.1502155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Accepted: 12/04/2024] [Indexed: 01/07/2025] Open
Abstract
Lung diseases account for over four million premature deaths every year, and experts predict that this number will increase in the future. The top cause of death globally is diseases which include conditions like lung cancer asthma and COPD. Treating severe acute lung injury is a complex task because lungs struggle to heal themselves in the presence of swelling inflammation and scarring caused by damage, to the lung tissues. Though achieving lung regeneration, in controlled environments is still an ambition; ongoing studies are concentrating on notable progress, in the field of lung tissue engineering and methods for repairing lung damage. This review delves into methods, for regenerating lungs with a focus on exosome carry bioscaffolds and mesenchymal stem cells among others. It talks about how these new techniques can help repair lung tissue and improve lung function in cases of damage. Also noted is the significance of ex vivo lung perfusion (EVLP), for rejuvenating donor lungs and the healing properties of exosomes in supporting lung regeneration.
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Affiliation(s)
| | - Leila Rezakhani
- Fertility and Infertility Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Department of Tissue Engineering, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Zahra Habibi
- Clinical Research Development Unit, Hajar Hospital, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Abdolhamid Mikaeili
- Medical Biology Research Center, Health Technology Institute, University of Medical Sciences, Kermanshah, Iran
| | - Shima Rahmati
- Cancer Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran
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16
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Nan F, Liu B, Yao C. Discovering the role of microRNAs and exosomal microRNAs in chest and pulmonary diseases: a spotlight on chronic obstructive pulmonary disease. Mol Genet Genomics 2024; 299:107. [PMID: 39527303 DOI: 10.1007/s00438-024-02199-2] [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: 09/20/2024] [Accepted: 10/26/2024] [Indexed: 11/16/2024]
Abstract
Chronic obstructive pulmonary disease (COPD) is a progressive respiratory condition and ranks as the fourth leading cause of mortality worldwide. Despite extensive research efforts, a reliable diagnostic or prognostic tool for COPD remains elusive. The identification of novel biomarkers may facilitate improved therapeutic strategies for patients suffering from this debilitating disease. MicroRNAs (miRNAs), which are small non-coding RNA molecules, have emerged as promising candidates for the prediction and diagnosis of COPD. Studies have demonstrated that dysregulation of miRNAs influences critical cellular and molecular pathways, including Notch, Wnt, hypoxia-inducible factor-1α, transforming growth factor, Kras, and Smad, which may contribute to the pathogenesis of COPD. Extracellular vesicles, particularly exosomes, merit further investigation due to their capacity to transport various biomolecules such as mRNAs, miRNAs, and proteins between cells. This intercellular communication can significantly impact the progression and severity of COPD by modulating signaling pathways in recipient cells. A deeper exploration of circulating miRNAs and the content of extracellular vesicles may lead to the discovery of novel diagnostic and prognostic biomarkers, ultimately enhancing the management of COPD. The current review focus on the pathogenic role of miRNAs and their exosomal counterparts in chest and respiratory diseases, centering COPD.
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Affiliation(s)
- FangYuan Nan
- Thoracic Surgery Department of the First People's Hospital of Jiangxia District, Wuhan, 430200, Hubei Province, China
| | - Bo Liu
- Thoracic Surgery Department of the First People's Hospital of Jiangxia District, Wuhan, 430200, Hubei Province, China
| | - Cheng Yao
- Infectious Diseases Department of the First People's Hospital of Jiangxia District, Wuhan, 430200, Hubei Province, China.
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17
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Zhao Q, Mo Z, Zeng L, Yuan Y, Wang Y, Wang Y. Construction and Evaluation of Hepatic Targeted Drug Delivery System with Hydroxycamptothecin in Stem Cell-Derived Exosomes. Molecules 2024; 29:5174. [PMID: 39519815 PMCID: PMC11547497 DOI: 10.3390/molecules29215174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 10/30/2024] [Accepted: 10/30/2024] [Indexed: 11/16/2024] Open
Abstract
Hydroxycamptothecin (HCPT) is commonly used in the treatment of liver cancer; however, its low water solubility and poor stability significantly limit its clinical application. In recent years, research on exosomes has deepened considerably. Exosomes possess a unique phospholipid bilayer structure, enabling them to traverse tissue barriers, which provides natural advantages as drug carriers. Nevertheless, delivering exosomes safely and efficiently to target cells remains a major challenge. In this study, we utilized the affinity of the SP94 peptide for human liver cancer cell receptors. HCPT was coated with exosomes in our experimental design, and the exosome membrane was modified with SP94 peptide to facilitate drug delivery to liver cancer cells. Exosomes were purified from bone marrow mesenchymal stem cells, and targeted peptides were attached to their surfaces via post-insertion techniques. Subsequently, HCPT was incorporated into the exosomes through electroporation. Using the HepG2 hepatoma cell line, we evaluated a series of in vitro pharmacodynamics and studied pharmacokinetics and tissue distribution in animal models. The results indicated that ligand-targeted, modified drug-carrying exosomes significantly enhance drug bioavailability, prolong retention time in vivo, and facilitate liver targeting. Moreover, this approach reduces drug nephrotoxicity, enhances anti-tumor efficacy, and lays the groundwork for the development of novel liver cancer-targeting agents.
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Affiliation(s)
- Qiongjun Zhao
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China; (Q.Z.); (Z.M.); (L.Z.); (Y.Y.)
| | - Zixuan Mo
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China; (Q.Z.); (Z.M.); (L.Z.); (Y.Y.)
| | - Liuting Zeng
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China; (Q.Z.); (Z.M.); (L.Z.); (Y.Y.)
| | - Yue Yuan
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China; (Q.Z.); (Z.M.); (L.Z.); (Y.Y.)
| | - Yan Wang
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China; (Q.Z.); (Z.M.); (L.Z.); (Y.Y.)
| | - Ying Wang
- Teaching and Experimental Center, Guangdong Pharmaceutical University, Zhongshan 528453, China
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18
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Zhang Y, Wu D, Zhou C, Bai M, Wan Y, Zheng Q, Fan Z, Wang X, Yang C. Engineered extracellular vesicles for tissue repair and regeneration. BURNS & TRAUMA 2024; 12:tkae062. [PMID: 39439545 PMCID: PMC11495891 DOI: 10.1093/burnst/tkae062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 09/12/2024] [Accepted: 09/21/2024] [Indexed: 10/25/2024]
Abstract
Extracellular vesicles (EVs) are heterogeneous membrane-like vesicles secreted by living cells that are involved in many physiological and pathological processes and act as intermediaries of intercellular communication and molecular transfer. Recent studies have shown that EVs from specific sources regulate tissue repair and regeneration by delivering proteins, lipids, and nucleic acids to target cells as signaling molecules. Nanotechnology breakthroughs have facilitated the development and exploration of engineered EVs for tissue repair. Enhancements through gene editing, surface modification, and content modification have further improved their therapeutic efficacy. This review summarizes the potential of EVs in tissue repair and regeneration, their mechanisms of action, and their research progress in regenerative medicine. This review highlights their design logic through typical examples and explores the development prospects of EVs in tissue repair. The aim of this review is to provide new insights into the design of EVs for tissue repair and regeneration applications, thereby expanding their use in regenerative medicine.
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Affiliation(s)
- Yan Zhang
- College of Basic Medicin, Beihua University, No. 3999 Binjiang East Road, Fengman District, Jilin City, Jilin Province, China
- School of Public Health, Beihua University, No. 3999 Binjiang East Road, Fengman District, Jilin City, Jilin Province, China
| | - Dan Wu
- College of Basic Medicin, Beihua University, No. 3999 Binjiang East Road, Fengman District, Jilin City, Jilin Province, China
| | - Chen Zhou
- Department of Laboratory Medicine, The Eighth Affiliated Hospital, Sun Yat-Sen University, No. 3025 Shennan Middle Road, Futian District, Shenzhen, China
| | - Muran Bai
- College of Basic Medicin, Beihua University, No. 3999 Binjiang East Road, Fengman District, Jilin City, Jilin Province, China
| | - Yucheng Wan
- Hospital of Stomatology, Zunyi Medical University, No. 89, Wujiang East Road, Xinpu New District, Zunyi City, Guizhou Province, China
| | - Qing Zheng
- College of Basic Medicin, Beihua University, No. 3999 Binjiang East Road, Fengman District, Jilin City, Jilin Province, China
| | - Zhijin Fan
- Institute for Engineering Medicine, Kunming Medical University, No. 1168 Chunrong West Road, Yuhua Street, Chenggong District, Kunming City, Yunnan Province China
| | - Xianwen Wang
- School of Biomedical Engineering, Research and Engineering Center of Biomedical Materials, Anhui Medical University, No.81 Meishan Road, Shushan District, Hefei 230032, China
| | - Chun Yang
- College of Basic Medicin, Beihua University, No. 3999 Binjiang East Road, Fengman District, Jilin City, Jilin Province, China
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19
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Yue S, Zhai G, Zhao S, Liang X, Liu Y, Zheng J, Chen X, Dong Y. The biphasic role of the infrapatellar fat pad in osteoarthritis. Biomed Pharmacother 2024; 179:117364. [PMID: 39226725 DOI: 10.1016/j.biopha.2024.117364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 08/23/2024] [Accepted: 08/26/2024] [Indexed: 09/05/2024] Open
Abstract
Osteoarthritis (OA) is a progressive degenerative disease resulting in joint deterioration. It is a whole organ disease characterized by cartilage degeneration and varying degrees of synovitis, involving pathological changes in all joint tissues, such as cartilage, subchondral bone, ligaments, meniscus, synovium, and infrapatellar fat pad (IPFP). IPFP is the largest adipose tissue structure in the knee joint and is composed of fat cells, immune cells and blood vessels. Moreover, IPFP is located close to the cartilage and bone surface so that it may reduce the impact of loading and absorb forces generated through the knee joint, and may have a protective role in joint health. IPFP has been shown to release various cytokines and adipokines that play pro-inflammatory and pro-catabolic roles in cartilage, promoting OA progression. Intra-articular injections of IPFP-derived mesenchymal stem cells and exosomes have been shown to reduce pain and prevent OA progression in patients with knee OA. Previous studies have shown that IPFP has a biphasic effect on OA progression. This article reviews the latest research progress of IPFP, discusses the role and mechanism of IPFP in OA, provide new intervention strategies for the treatment of OA. This article will also discuss the handling of IPFP during the procedure of total knee arthroplasty.
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Affiliation(s)
- Songkai Yue
- Department of Orthopedics, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Henan University People's Hospital, Zhengzhou 450003, China
| | - Ganggang Zhai
- Department of Orthopedics, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Henan University People's Hospital, Zhengzhou 450003, China
| | - Siyu Zhao
- Department of Orthopedics, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Henan University People's Hospital, Zhengzhou 450003, China
| | - Xiaming Liang
- Department of Orthopedics, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Henan University People's Hospital, Zhengzhou 450003, China
| | - Yunke Liu
- Department of Orthopedics, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Henan University People's Hospital, Zhengzhou 450003, China
| | - Jia Zheng
- Department of Orthopedics, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Henan University People's Hospital, Zhengzhou 450003, China
| | - Xiaoyang Chen
- Department of Orthopedics, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Henan University People's Hospital, Zhengzhou 450003, China
| | - Yonghui Dong
- Department of Orthopedics, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Henan University People's Hospital, Zhengzhou 450003, China.
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20
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Cui X, Guo J, Yuan P, Dai Y, Du P, Yu F, Sun Z, Zhang J, Cheng K, Tang J. Bioderived Nanoparticles for Cardiac Repair. ACS NANO 2024; 18:24622-24649. [PMID: 39185722 DOI: 10.1021/acsnano.3c07878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/27/2024]
Abstract
Biobased therapy represents a promising strategy for myocardial repair. However, the limitations of using live cells, including the risk of immunogenicity of allogeneic cells and inconsistent therapeutic efficacy of autologous cells together with low stability, result in an unsatisfactory clinical outcomes. Therefore, cell-free strategies for cardiac tissue repair have been proposed as alternative strategies. Cell-free strategies, primarily based on the paracrine effects of cellular therapy, have demonstrated their potential to inhibit apoptosis, reduce inflammation, and promote on-site cell migration and proliferation, as well as angiogenesis, after an infarction and have been explored preclinically and clinically. Among various cell-free modalities, bioderived nanoparticles, including adeno-associated virus (AAV), extracellular vesicles, cell membrane-coated nanoparticles, and exosome-mimetic nanovesicles, have emerged as promising strategies due to their improved biological function and therapeutic effect. The main focus of this review is the development of existing cellular nanoparticles and their fundamental working mechanisms, as well as the challenges and opportunities. The key processes and requirements for cardiac tissue repair are summarized first. Various cellular nanoparticle modalities are further highlighted, together with their advantages and limitations. Finally, we discuss various delivery approaches that offer potential pathways for researchers and clinicians to translate cell-free strategies for cardiac tissue repair into clinical practice.
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Affiliation(s)
- Xiaolin Cui
- Cardiac and Osteochondral Tissue Engineering (COTE) Group, School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China
| | - Jiacheng Guo
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan 450052, China
- Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan 450052, China
| | - Peiyu Yuan
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan 450052, China
- Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan 450052, China
| | - Yichen Dai
- Cardiac and Osteochondral Tissue Engineering (COTE) Group, School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China
| | - Pengchong Du
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan 450052, China
- Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan 450052, China
| | - Fengyi Yu
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan 450052, China
- Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan 450052, China
| | - Zhaowei Sun
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan 450052, China
- Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan 450052, China
| | - Jinying Zhang
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan 450052, China
- Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan 450052, China
| | - Ke Cheng
- Department of Biomedical Engineering, Columbia University, New York, New York 10027, United States
| | - Junnan Tang
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan 450052, China
- Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan 450052, China
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Zhao Z, Wang C, Liu A, Bai N, Jiang B, Mao Y, Ying T, Dong D, Yi C, Li D. Multiple applications of metal-organic frameworks (MOFs) in the treatment of orthopedic diseases. Front Bioeng Biotechnol 2024; 12:1448010. [PMID: 39295846 PMCID: PMC11408336 DOI: 10.3389/fbioe.2024.1448010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 08/27/2024] [Indexed: 09/21/2024] Open
Abstract
Pharmacologic treatment of orthopedic diseases is a common challenge for clinical orthopedic surgeons, and as an important step in the stepwise treatment of orthopedic diseases, it is often difficult to achieve satisfactory results with existing pharmacologic treatments. Therefore, it is increasingly important to find new ways to effectively improve the treatment pattern of orthopedic diseases as well as to enhance the therapeutic efficacy. It has been found that metal-organic frameworks (MOFs) possess the advantages of high specific surface area, high porosity, chemical stability, tunability of structure and biocompatibility. Therefore, MOFs are expected to improve the conventional traditional treatment modality for bone diseases. This manuscript reviewed the applications of MOFs in the treatment of common clinical bone diseases and look forward to its future development.
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Affiliation(s)
- Ziwen Zhao
- Department of Orthopedics, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- Department of Orthopedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Chenxu Wang
- Department of Orthopedics, The First Affiliated Hospital of Henan University, Kaifeng, China
| | - Aiguo Liu
- Department of Orthopedics, The First Affiliated Hospital of Henan University, Kaifeng, China
| | - Ning Bai
- Department of Gastroenterology, Huaihe Hospital of Henan University, Kaifeng, China
| | - Bo Jiang
- The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Yuanfu Mao
- Department of Orthopedics, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Ting Ying
- Shanghai YangZhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Medicine, Tongji University, Shanghai, China
| | - Daming Dong
- Department of Orthopedics, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Chengqing Yi
- Department of Orthopedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Dejian Li
- Department of Orthopedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
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22
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Rahmani A, Soleymani A, Almukhtar M, Behzad Moghadam K, Vaziri Z, Hosein Tabar Kashi A, Adabi Firoozjah R, Jafari Tadi M, Zolfaghari Dehkharghani M, Valadi H, Moghadamnia AA, Gasser RB, Rostami A. Exosomes, and the potential for exosome-based interventions against COVID-19. Rev Med Virol 2024; 34:e2562. [PMID: 38924213 DOI: 10.1002/rmv.2562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 05/17/2024] [Accepted: 06/08/2024] [Indexed: 06/28/2024]
Abstract
Since late 2019, the world has been devastated by the coronavirus disease 2019 (COVID-19) induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with more than 760 million people affected and ∼seven million deaths reported. Although effective treatments for COVID-19 are currently limited, there has been a strong focus on developing new therapeutic approaches to address the morbidity and mortality linked to this disease. An approach that is currently being investigated is the use of exosome-based therapies. Exosomes are small, extracellular vesicles that play a role in many clinical diseases, including viral infections, infected cells release exosomes that can transmit viral components, such as miRNAs and proteins, and can also include receptors for viruses that facilitate viral entry into recipient cells. SARS-CoV-2 has the ability to impact the formation, secretion, and release of exosomes, thereby potentially facilitating or intensifying the transmission of the virus among cells, tissues and individuals. Therefore, designing synthetic exosomes that carry immunomodulatory cargo and antiviral compounds are proposed to be a promising strategy for the treatment of COVID-19 and other viral diseases. Moreover, exosomes generated from mesenchymal stem cells (MSC) might be employed as cell-free therapeutic agents, as MSC-derived exosomes can diminish the cytokine storm and reverse the suppression of host anti-viral defences associated with COVID-19, and boost the repair of lung damage linked to mitochondrial activity. The present article discusses the significance and roles of exosomes in COVID-19, and explores potential future applications of exosomes in combating this disease. Despite the challenges posed by COVID-19, exosome-based therapies could represent a promising avenue for improving patient outcomes and reducing the impact of this disease.
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Affiliation(s)
- Abolfazl Rahmani
- Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Ali Soleymani
- Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | | | - Kimia Behzad Moghadam
- Independent Researcher, Former University of California, San Francisco (UCSF), San Francisco, California, USA
| | - Zahra Vaziri
- Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Ali Hosein Tabar Kashi
- Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Reza Adabi Firoozjah
- Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Mehrdad Jafari Tadi
- Department of Cell and Molecular Medicine, Rush University Medical Center, Chicago, Illinois, USA
| | - Maryam Zolfaghari Dehkharghani
- Department of Healthcare Administration and Policy, School of Public Health, University of Nevada Las Vegas (UNLV), Las Vegas, Nevada, USA
| | - Hadi Valadi
- Department of Rheumatology and Inflammation Research Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Ali Akbar Moghadamnia
- Department of Pharmacology and Toxicology, Babol University of Medical Sciences, Babol, Iran
- Pharmaceutical Sciences Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Robin B Gasser
- Department of Veterinary Biosciences, Faculty of Science, Melbourne Veterinary School, The University of Melbourne, Parkville, Victoria, Australia
| | - Ali Rostami
- Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
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Jang E, Yu H, Kim E, Hwang J, Yoo J, Choi J, Jeong HS, Jang S. The Therapeutic Effects of Blueberry-Treated Stem Cell-Derived Extracellular Vesicles in Ischemic Stroke. Int J Mol Sci 2024; 25:6362. [PMID: 38928069 PMCID: PMC11203670 DOI: 10.3390/ijms25126362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 05/23/2024] [Accepted: 06/04/2024] [Indexed: 06/28/2024] Open
Abstract
An ischemic stroke, one of the leading causes of morbidity and mortality, is caused by ischemia and hemorrhage resulting in impeded blood supply to the brain. According to many studies, blueberries have been shown to have a therapeutic effect in a variety of diseases. Therefore, in this study, we investigated whether blueberry-treated mesenchymal stem cell (MSC)-derived extracellular vesicles (B-EVs) have therapeutic effects in in vitro and in vivo stroke models. We isolated the extracellular vesicles using cryo-TEM and characterized the particles and concentrations using NTA. MSC-derived extracellular vesicles (A-EVs) and B-EVs were round with a lipid bilayer structure and a diameter of ~150 nm. In addition, A-EVs and B-EVs were shown to affect angiogenesis, cell cycle, differentiation, DNA repair, inflammation, and neurogenesis following KEGG pathway and GO analyses. We investigated the protective effects of A-EVs and B-EVs against neuronal cell death in oxygen-glucose deprivation (OGD) cells and a middle cerebral artery occlusion (MCAo) animal model. The results showed that the cell viability was increased with EV treatment in HT22 cells. In the animal, the size of the cerebral infarction was decreased, and the behavioral assessment was improved with EV injections. The levels of NeuN and neurofilament heavy chain (NFH)-positive cells were also increased with EV treatment yet decreased in the MCAo group. In addition, the number of apoptotic cells was decreased with EV treatment compared with ischemic animals following TUNEL and Bax/Bcl-2 staining. These data suggested that EVs, especially B-EVs, had a therapeutic effect and could reduce apoptotic cell death after ischemic injury.
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Affiliation(s)
- Eunjae Jang
- Department of Physiology, Chonnam National University Medical School, Hwasun-gun 58128, Republic of Korea; (E.J.); (H.Y.); (J.H.); (J.C.)
- Jeonnam Bioindustry Foundation Biopharmaceutical Research Center, Hwasun-gun 58141, Republic of Korea
| | - Hee Yu
- Department of Physiology, Chonnam National University Medical School, Hwasun-gun 58128, Republic of Korea; (E.J.); (H.Y.); (J.H.); (J.C.)
- Jeonnam Bioindustry Foundation Biopharmaceutical Research Center, Hwasun-gun 58141, Republic of Korea
| | - Eungpil Kim
- Infrastructure Project Organization for Global Industrialization of Vaccine, Sejong-si 30121, Republic of Korea;
| | - Jinsu Hwang
- Department of Physiology, Chonnam National University Medical School, Hwasun-gun 58128, Republic of Korea; (E.J.); (H.Y.); (J.H.); (J.C.)
| | - Jin Yoo
- Department of Physical Education, Chonnam National University, Gwangju 61186, Republic of Korea;
| | - Jiyun Choi
- Department of Physiology, Chonnam National University Medical School, Hwasun-gun 58128, Republic of Korea; (E.J.); (H.Y.); (J.H.); (J.C.)
| | - Han-Seong Jeong
- Department of Physiology, Chonnam National University Medical School, Hwasun-gun 58128, Republic of Korea; (E.J.); (H.Y.); (J.H.); (J.C.)
| | - Sujeong Jang
- Department of Physiology, Chonnam National University Medical School, Hwasun-gun 58128, Republic of Korea; (E.J.); (H.Y.); (J.H.); (J.C.)
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24
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Zhang S, Wang S, Chen J, Cui Y, Lu X, Xiong S, Yue C, Yang B. Human dental pulp stem cell-derived exosomes decorated titanium scaffolds for promoting bone regeneration. Colloids Surf B Biointerfaces 2024; 235:113775. [PMID: 38330688 DOI: 10.1016/j.colsurfb.2024.113775] [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: 11/29/2023] [Revised: 01/21/2024] [Accepted: 01/31/2024] [Indexed: 02/10/2024]
Abstract
Exosomes, nanoscale extracellular vesicles crucial for intercellular communication, hold great promise as a therapeutic avenue in cell-free tissue regeneration. In this study, we identified and utilized exosomes to adorn anodized titanium scaffolds, inducing osteogenic differentiation in human dental pulp stem cells (hDPSCs). The osteogenesis of hDPSCs was stimulated by exosomes derived from hDPSCs that underwent various periods of osteogenic differentiation. After purification, these exosomes were loaded onto anodized titanium scaffolds. Notably, the scaffolds loaded with exosomes deriving from osteogenic differentiated hDPSCs demonstrated superior bone tissue regeneration compared to those loaded with exosomes deriving from hDPSCs within 10-week. RNA-sequencing analysis shed light on the underlying mechanism, revealing that the osteogenic exosomes carried specific cargo, which is due to upregulated miRNAs (Hsa-miR-29c-5p, Hsa-miR-378a-5p, Hsa-miR-10b-5p and Hsa-miR-9-3p) associated with osteogenesis. And down-regulated anti-osteogenic miRNA (Hsa-miR-31-3p, Hsa-miR-221-3p, Hsa-miR-183-5p and Hsa-miR-503-5p). In conclusion, the identification and utilization of exosomes derived from osteogenic differentiated stem cells offer a novel and promising strategy for achieving cell-free bone regeneration.
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Affiliation(s)
- Siqi Zhang
- Engineering Research Center in Biomaterials, Sichuan University, Chengdu 610064, People's Republic of China; National Engineering Research Center for Biomaterials, Chengdu 610064, People's Republic of China; College of Biomedical Engineering, Sichuan University, Chengdu 610064, People's Republic of China
| | - Simeng Wang
- Engineering Research Center in Biomaterials, Sichuan University, Chengdu 610064, People's Republic of China; National Engineering Research Center for Biomaterials, Chengdu 610064, People's Republic of China; College of Biomedical Engineering, Sichuan University, Chengdu 610064, People's Republic of China
| | - Jun Chen
- Engineering Research Center in Biomaterials, Sichuan University, Chengdu 610064, People's Republic of China; National Engineering Research Center for Biomaterials, Chengdu 610064, People's Republic of China; College of Biomedical Engineering, Sichuan University, Chengdu 610064, People's Republic of China
| | - Yifan Cui
- Engineering Research Center in Biomaterials, Sichuan University, Chengdu 610064, People's Republic of China; National Engineering Research Center for Biomaterials, Chengdu 610064, People's Republic of China; College of Biomedical Engineering, Sichuan University, Chengdu 610064, People's Republic of China
| | - Xugang Lu
- Engineering Research Center in Biomaterials, Sichuan University, Chengdu 610064, People's Republic of China; National Engineering Research Center for Biomaterials, Chengdu 610064, People's Republic of China; College of Biomedical Engineering, Sichuan University, Chengdu 610064, People's Republic of China
| | - Shibing Xiong
- Engineering Research Center in Biomaterials, Sichuan University, Chengdu 610064, People's Republic of China; National Engineering Research Center for Biomaterials, Chengdu 610064, People's Republic of China; College of Biomedical Engineering, Sichuan University, Chengdu 610064, People's Republic of China
| | - Chongxia Yue
- Engineering Research Center in Biomaterials, Sichuan University, Chengdu 610064, People's Republic of China; National Engineering Research Center for Biomaterials, Chengdu 610064, People's Republic of China; NMPA Key Laboratory for Quality Research and Control of Tissue Regenerative Biomaterial & Institute of Regulatory Science for Medical Devices & NMPA Research Base of Regulatory Science for Medical Devices, Sichuan University, Chengdu 610064, People's Republic of China; College of Biomedical Engineering, Sichuan University, Chengdu 610064, People's Republic of China.
| | - Bangcheng Yang
- Engineering Research Center in Biomaterials, Sichuan University, Chengdu 610064, People's Republic of China; National Engineering Research Center for Biomaterials, Chengdu 610064, People's Republic of China; College of Biomedical Engineering, Sichuan University, Chengdu 610064, People's Republic of China.
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25
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Miron RJ, Zhang Y. Understanding exosomes: Part 1-Characterization, quantification and isolation techniques. Periodontol 2000 2024; 94:231-256. [PMID: 37740431 DOI: 10.1111/prd.12520] [Citation(s) in RCA: 24] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 07/21/2023] [Accepted: 07/25/2023] [Indexed: 09/24/2023]
Abstract
Exosomes are the smallest subset of extracellular signaling vesicles secreted by most cells with a diameter in the range of 30-150 nm. Their use has gained great momentum recently due to their ability to be utilized as diagnostic tools with a vast array of therapeutic applications. Over 5000 publications are currently being published yearly on this topic, and this number is only expected to dramatically increase as novel therapeutic strategies continue to be investigated. This review article first focuses on understanding exosomes, including their cellular origin, biogenesis, function, and characterization. Thereafter, overviews of the quantification methods and isolation techniques are given with discussion over their potential use as novel therapeutics in regenerative medicine.
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Affiliation(s)
- Richard J Miron
- Department of Periodontology, University of Bern, Bern, Switzerland
| | - Yufeng Zhang
- Department of Oral Implantology, University of Wuhan, Wuhan, China
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26
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Kmiotek-Wasylewska K, Łabędź-Masłowska A, Bobis-Wozowicz S, Karnas E, Noga S, Sekuła-Stryjewska M, Woźnicka O, Madeja Z, Dawn B, Zuba-Surma EK. Induced pluripotent stem cell-derived extracellular vesicles enriched with miR-126 induce proangiogenic properties and promote repair of ischemic tissue. FASEB J 2024; 38:e23415. [PMID: 38243682 DOI: 10.1096/fj.202301836r] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 12/15/2023] [Accepted: 12/27/2023] [Indexed: 01/21/2024]
Abstract
Emerging evidence suggests that stem cell-derived extracellular vesicles (EVs) may induce pro-regenerative effects in ischemic tissues by delivering bioactive molecules, including microRNAs. Recent studies have also shown pro-regenerative benefits of EVs derived from induced pluripotent stem (iPS) cells. However, the underlying mechanisms of EV benefits and the role of their transferred regulatory molecules remain incompletely understood. Accordingly, we investigated the effects of human iPS-derived EVs (iPS-EVs) enriched in proangiogenic miR-126 (iPS-miR-126-EVs) on functional properties of human endothelial cells (ECs) in vitro. We also examined the outcomes following EV injection in a murine model of limb ischemia in vivo. EVs were isolated from conditioned media from cultures of unmodified and genetically modified human iPS cells overexpressing miR-126. The iPS-miR-126-EVs were enriched in miR-126 when compared with control iPS-EVs and effectively transferred miR-126 along with other miRNAs to recipient ECs improving their functional properties essential for ischemic tissue repair, including proliferation, metabolic activity, cell survival, migration, and angiogenic potential. Injection of iPS-miR-126-EVs in vivo in a murine model of acute limb ischemia promoted angiogenesis, increased perfusion, and enhanced functional recovery. These observations corresponded with elevated expression of genes for several proangiogenic factors in ischemic tissues following iPS-miR-126-EV transplantation. These results indicate that innate pro-regenerative properties of iPS-EVs may be further enhanced by altering their molecular composition via controlled genetic modifications. Such iPS-EVs overexpressing selected microRNAs, including miR-126, may represent a novel acellular tool for therapy of ischemic tissues in vivo.
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Affiliation(s)
- Katarzyna Kmiotek-Wasylewska
- Faculty of Biochemistry, Biophysics and Biotechnology, Department of Cell Biology, Jagiellonian University, Kraków, Poland
| | - Anna Łabędź-Masłowska
- Faculty of Biochemistry, Biophysics and Biotechnology, Department of Cell Biology, Jagiellonian University, Kraków, Poland
| | - Sylwia Bobis-Wozowicz
- Faculty of Biochemistry, Biophysics and Biotechnology, Department of Cell Biology, Jagiellonian University, Kraków, Poland
| | - Elżbieta Karnas
- Faculty of Biochemistry, Biophysics and Biotechnology, Department of Cell Biology, Jagiellonian University, Kraków, Poland
| | - Sylwia Noga
- Faculty of Biochemistry, Biophysics and Biotechnology, Department of Cell Biology, Jagiellonian University, Kraków, Poland
- Malopolska Centre of Biotechnology, Laboratory of Stem Cell Biotechnology, Jagiellonian University, Kraków, Poland
| | - Małgorzata Sekuła-Stryjewska
- Malopolska Centre of Biotechnology, Laboratory of Stem Cell Biotechnology, Jagiellonian University, Kraków, Poland
| | - Olga Woźnicka
- Faculty of Biology, Institute of Zoology and Biomedical Research, Department of Cell Biology and Imaging, Jagiellonian University, Kraków, Poland
| | - Zbigniew Madeja
- Faculty of Biochemistry, Biophysics and Biotechnology, Department of Cell Biology, Jagiellonian University, Kraków, Poland
| | - Buddhadeb Dawn
- Department of Internal Medicine, Kirk Kerkorian School of Medicine, University of Nevada, Las Vegas, Las Vegas, Nevada, USA
| | - Ewa K Zuba-Surma
- Faculty of Biochemistry, Biophysics and Biotechnology, Department of Cell Biology, Jagiellonian University, Kraków, Poland
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Chakraborty A, Badhe RV, Abbas M, Chauhan A, Jaiswal A, Fareed R, Kumar V, Duan Y, Dutta N. Role of exosomal RNA in wound healing and tissue repair. EXOSOMAL RNA 2024:295-323. [DOI: 10.1016/b978-0-443-14008-2.00001-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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28
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Cha SG, Rhim WK, Kim JY, Lee EH, Lee SY, Park JM, Lee JE, Yoon H, Park CG, Kim BS, Kwon TG, Lee Y, Lee DR, Han DK. Kidney tissue regeneration using bioactive scaffolds incorporated with differentiating extracellular vesicles and intermediate mesoderm cells. Biomater Res 2023; 27:126. [PMID: 38049879 PMCID: PMC10696796 DOI: 10.1186/s40824-023-00471-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Accepted: 11/24/2023] [Indexed: 12/06/2023] Open
Abstract
BACKGROUND To overcome the limitations of current alternative therapies for chronic kidney disease (CKD), tissue engineering-mediated regeneration strategies have demonstrated the possibilities for complete kidney tissue regeneration. Given the challenges associated with the reproducibility of renal basal cells, the incorporation of intermediate mesoderm (IM) cells and bioactive materials to control bioactivities of cells with supported scaffolds should be considered as a viable approach to enable the regeneration of the complex kidney structure via renal differentiation. METHODS We developed PMEZ scaffolds by combining crucial bioactive components, such as ricinoleic acid-grafted Mg(OH)2 (M), extracellular matrix (E), and alpha lipoic acid-conjugated ZnO (Z) integrated into biodegradable porous PLGA (P) platform. Additionally, we utilized differentiating extracellular vesicles (dEV) isolated during intermediate mesoderm differentiation into kidney progenitor cells, and IM cells were serially incorporated to facilitate kidney tissue regeneration through their differentiation into kidney progenitor cells in the 3/4 nephrectomy mouse model. RESULTS The use of differentiating extracellular vesicles facilitated IM differentiation into kidney progenitor cells without additional differentiation factors. This led to improvements in various regeneration-related bioactivities including tubule and podocyte regeneration, anti-fibrosis, angiogenesis, and anti-inflammation. Finally, implanting PMEZ/dEV/IM scaffolds in mouse injury model resulted in the restoration of kidney function. CONCLUSIONS Our study has demonstrated that utilizing biodegradable PLGA-based scaffolds, which include multipotent cells capable of differentiating into various kidney progenitor cells along with supporting components, can facilitate kidney tissue regeneration in the mouse model that simulates CKD through 3/4 nephrectomy.
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Affiliation(s)
- Seung-Gyu Cha
- Department of Biomedical Science, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam- si, 13488, Gyeonggi-do, Republic of Korea
| | - Won-Kyu Rhim
- Department of Biomedical Science, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam- si, 13488, Gyeonggi-do, Republic of Korea
| | - Jun Yong Kim
- Department of Biomedical Science, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam- si, 13488, Gyeonggi-do, Republic of Korea
- Department of Biomedical Engineering, SKKU Institute for Convergence, Sungkyunkwan University (SKKU), 2066 Seobu-ro, Jangan-gu, Suwon-si, 16419, Gyeonggi-do, Republic of Korea
- Intelligent Precision of Healthcare Convergence, SKKU Institute for Convergence, Sungkyunkwan University (SKKU), 2066 Seobu-ro, Jangan-gu, Suwon-si, 16419, Gyeonggi-do, Republic of Korea
| | - Eun Hye Lee
- Joint Institute for Regenerative Medicine, Kyungpook National University, Jung-gu, Daegu, 41944, Republic of Korea
| | - Seung Yeon Lee
- Department of Biomedical Science, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam- si, 13488, Gyeonggi-do, Republic of Korea
| | - Jeong Min Park
- Department of Biomedical Science, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam- si, 13488, Gyeonggi-do, Republic of Korea
| | - Jeoung Eun Lee
- Bundang Medical Center, CHA Advanced Research Institute, CHA University, Sungnam- si, 13488, Gyeonggi-do, Republic of Korea
| | - Hyeji Yoon
- Department of Chemistry and Nanoscience, Ewha Womans University, Seodaemun-gu, Seoul, Republic of Korea
| | - Chun Gwon Park
- Department of Biomedical Engineering, SKKU Institute for Convergence, Sungkyunkwan University (SKKU), 2066 Seobu-ro, Jangan-gu, Suwon-si, 16419, Gyeonggi-do, Republic of Korea
- Intelligent Precision of Healthcare Convergence, SKKU Institute for Convergence, Sungkyunkwan University (SKKU), 2066 Seobu-ro, Jangan-gu, Suwon-si, 16419, Gyeonggi-do, Republic of Korea
| | - Bum Soo Kim
- Joint Institute for Regenerative Medicine, Kyungpook National University, Jung-gu, Daegu, 41944, Republic of Korea
- Department of Urology, School of Medicine, Kyungpook National University, Jung-gu, Daegu, 41944, Republic of Korea
| | - Tae Gyun Kwon
- Joint Institute for Regenerative Medicine, Kyungpook National University, Jung-gu, Daegu, 41944, Republic of Korea
- Department of Urology, School of Medicine, Kyungpook National University, Jung-gu, Daegu, 41944, Republic of Korea
| | - Youngmi Lee
- Department of Chemistry and Nanoscience, Ewha Womans University, Seodaemun-gu, Seoul, Republic of Korea
| | - Dong Ryul Lee
- Department of Biomedical Science, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam- si, 13488, Gyeonggi-do, Republic of Korea
- Bundang Medical Center, CHA Advanced Research Institute, CHA University, Sungnam- si, 13488, Gyeonggi-do, Republic of Korea
| | - Dong Keun Han
- Department of Biomedical Science, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam- si, 13488, Gyeonggi-do, Republic of Korea.
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Wang Y, Shi G, Huang TCT, Li J, Long Z, Reisdorf R, Shin AY, Amadio P, Behfar A, Zhao C, Moran SL. Enhancing Functional Recovery after Segmental Nerve Defect Using Nerve Allograft Treated with Plasma-Derived Exosome. Plast Reconstr Surg 2023; 152:1247-1258. [PMID: 36912739 DOI: 10.1097/prs.0000000000010389] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/14/2023]
Abstract
BACKGROUND Nerve injuries can result in detrimental functional outcomes. Currently, autologous nerve graft offers the best outcome for segmental peripheral nerve injury. Allografts are alternatives, but do not have comparable results. This study evaluated whether plasma-derived exosome can improve nerve regeneration and functional recovery when combined with decellularized nerve allografts. METHODS The effect of exosomes on Schwann cell proliferation and migration were evaluated. A rat model of sciatic nerve repair was used to evaluate the effect on nerve regeneration and functional recovery. A fibrin sealant was used as the scaffold for exosome. Eighty-four Lewis rats were divided into autograft, allograft, and allograft with exosome groups. Gene expression of nerve regeneration factors was analyzed on postoperative day 7. At 12 and 16 weeks, rats were subjected to maximum isometric tetanic force and compound muscle action potential. Nerve specimens were then analyzed by means of histology and immunohistochemistry. RESULTS Exosomes were readily taken up by Schwann cells that resulted in improved Schwann cell viability and migration. The treated allograft group had functional recovery (compound muscle action potential, isometric tetanic force) comparable to that of the autograft group. Similar results were observed in gene expression analysis of nerve regenerating factors. Histologic analysis showed no statistically significant differences between treated allograft and autograft groups in terms of axonal density, fascicular area, and myelin sheath thickness. CONCLUSIONS Plasma-derived exosome treatment of decellularized nerve allograft may provide comparable clinical outcomes to that of an autograft. This can be a promising strategy in the future as an alternative for segmental peripheral nerve repair. CLINICAL RELEVANCE STATEMENT Off-the-shelf exosomes may improve recovery in nerve allografts.
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Affiliation(s)
- Yicun Wang
- From the Department of Orthopedics, Jinling Hospital, School of Medicine, Nanjing University
- Division of Plastic Surgery, Department of Surgery
- Department of Orthopedic Surgery
| | - Guidong Shi
- Department of Orthopedic Surgery
- Tianjin Medical University
| | | | - Jialun Li
- Division of Plastic Surgery, Department of Surgery
- Department of Plastic Surgery, Wuhan Union Hospital, Huazhong University of Science and Technology
| | | | | | | | | | - Atta Behfar
- Center for Regenerative Medicine
- Department of Cardiovascular Medicine, Mayo Clinic
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Wojtasińska A, Kućmierz J, Tokarek J, Dybiec J, Rodzeń A, Młynarska E, Rysz J, Franczyk B. New Insights into Cardiovascular Diseases Treatment Based on Molecular Targets. Int J Mol Sci 2023; 24:16735. [PMID: 38069058 PMCID: PMC10706703 DOI: 10.3390/ijms242316735] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Revised: 11/07/2023] [Accepted: 11/13/2023] [Indexed: 12/18/2023] Open
Abstract
Cardiovascular diseases (CVDs) which consist of ischemic heart disease, stroke, heart failure, peripheral arterial disease, and several other cardiac and vascular conditions are one of the most common causes of death worldwide and often co-occur with diabetes mellitus and lipid disorders which worsens the prognosis and becomes a therapeutic challenge. Due to the increasing number of patients with CVDs, we need to search for new risk factors and pathophysiological changes to create new strategies for preventing, diagnosing, and treating not only CVDs but also comorbidities like diabetes mellitus and lipid disorders. As increasing amount of patients suffering from CVDs, there are many therapies which focus on new molecular targets like proprotein convertase subtilisin/kexin type 9 (PCSK9), angiopoietin-like protein 3, ATP-citrate lyase, or new technologies such as siRNA in treatment of dyslipidemia or sodium-glucose co-transporter-2 and glucagon-like peptide-1 in treatment of diabetes mellitus. Both SGLT-2 inhibitors and GLP-1 receptor agonists are used in the treatment of diabetes, however, they proved to have a beneficial effect in CVDs as well. Moreover, a significant amount of evidence has shown that exosomes seem to be associated with myocardial ischaemia and that exosome levels correlate with the severity of myocardial injury. In our work, we would like to focus on the above mechanisms. The knowledge of them allows for the appearance of new strategies of treatment among patients with CVDs.
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Affiliation(s)
- Armanda Wojtasińska
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Joanna Kućmierz
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Julita Tokarek
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Jill Dybiec
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Anna Rodzeń
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Ewelina Młynarska
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Jacek Rysz
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Beata Franczyk
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
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Yang F, Li Z, Cai Z, He Y, Ke C, Wang J, Lin M, Li L. Pluronic F-127 Hydrogel Loaded with Human Adipose-Derived Stem Cell-Derived Exosomes Improve Fat Graft Survival via HIF-1α-Mediated Enhancement of Angiogenesis. Int J Nanomedicine 2023; 18:6781-6796. [PMID: 38026529 PMCID: PMC10658963 DOI: 10.2147/ijn.s435106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Accepted: 11/09/2023] [Indexed: 12/01/2023] Open
Abstract
Purpose Autologous fat grafting is playing an increasingly important role in plastic surgery. However, high absorption and low survival of autologous fat grafts limit their clinical application. This study aimed to investigate whether human adipose-derived stem cell-derived exosomes (hASC-Exos) encapsulated in a PF-127 hydrogel can improve the survival of autologous fat grafts and to elucidate the underlying mechanisms. Patients and Methods Exosomes were isolated from hASCs and identified using transmission electron microscopy, nanoparticle tracking analysis and Western blotting. We performed functional assays in vitro to assess the effect of hASC-Exos on proliferation, migration, and tube formation as well as their regulatory role in the HIF-1α/VEGF signaling pathway. hASC-Exos encapsulated in the PF-127 hydrogel were used as an in vivo autologous fat graft model. The effects of the PF-127 hydrogel/hASC-Exos and the role of the HIF-1α/VEGF signaling pathway in promoting angiogenesis in an autologous fat grafting model were assessed. Results hASC-Exos were taken up by human umbilical vein endothelial cells and enhanced their proliferation, migration, and tubule formation in vitro. The effects of hASC-Exos on promoting angiogenesis were mediated by the HIF-1α/VEGF signaling pathway. Moreover, we fabricated a PF-127 hydrogel for the sustained release of hASC-Exos, and in vivo results showed that hASC-Exos encapsulated in PF-127 hydrogel improved the survival of autologous fat grafts. Conclusion Our findings indicated that hASC-Exos encapsulated in PF-127 hydrogel serve as a key regulator of angiogenesis by activating the HIF-1α/VEGF signaling pathway and provide a promising strategy for autologous fat grafting treatment.
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Affiliation(s)
- Fangfang Yang
- Department of Plastic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China
| | - Zihao Li
- Department of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China
| | - Zhongming Cai
- Department of Plastic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China
| | - Yucang He
- Department of Plastic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China
| | - Chen Ke
- Department of Plastic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China
| | - Jingping Wang
- Department of Plastic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China
| | - Ming Lin
- Department of Obstetrics and Gynecology, Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China
| | - Liqun Li
- Department of Plastic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China
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Yang B, Lin Y, Huang Y, Zhu N, Shen YQ. Extracellular vesicles modulate key signalling pathways in refractory wound healing. BURNS & TRAUMA 2023; 11:tkad039. [PMID: 38026441 PMCID: PMC10654481 DOI: 10.1093/burnst/tkad039] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Revised: 05/10/2023] [Accepted: 06/22/2023] [Indexed: 12/01/2023]
Abstract
Chronic wounds are wounds that cannot heal properly due to various factors, such as underlying diseases, infection or reinjury, and improper healing of skin wounds and ulcers can cause a serious economic burden. Numerous studies have shown that extracellular vesicles (EVs) derived from stem/progenitor cells promote wound healing, reduce scar formation and have significant advantages over traditional treatment methods. EVs are membranous particles that carry various bioactive molecules from their cellular origins, such as cytokines, nucleic acids, enzymes, lipids and proteins. EVs can mediate cell-to-cell communication and modulate various physiological processes, such as cell differentiation, angiogenesis, immune response and tissue remodelling. In this review, we summarize the recent advances in EV-based wound healing, focusing on the signalling pathways that are regulated by EVs and their cargos. We discuss how EVs derived from different types of stem/progenitor cells can promote wound healing and reduce scar formation by modulating the Wnt/β-catenin, phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin, vascular endothelial growth factor, transforming growth factor β and JAK-STAT pathways. Moreover, we also highlight the challenges and opportunities for engineering or modifying EVs to enhance their efficacy and specificity for wound healing.
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Affiliation(s)
- Bowen Yang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, Renmin South Road, Wuhou District, Chengdu 610041, China
| | - Yumeng Lin
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, Renmin South Road, Wuhou District, Chengdu 610041, China
| | - Yibo Huang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, Renmin South Road, Wuhou District, Chengdu 610041, China
| | - Nanxi Zhu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, Renmin South Road, Wuhou District, Chengdu 610041, China
| | - Ying-Qiang Shen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, Renmin South Road, Wuhou District, Chengdu 610041, China
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Zhang M, Wan L, Li R, Li X, Zhu T, Lu H. Engineered exosomes for tissue regeneration: from biouptake, functionalization and biosafety to applications. Biomater Sci 2023; 11:7247-7267. [PMID: 37794789 DOI: 10.1039/d3bm01169k] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/06/2023]
Abstract
Exosomes are increasingly recognized as important effector molecules that regulate intercellular signaling pathways. Notably, certain types of exosomes can induce therapeutic responses, including cell proliferation, angiogenesis, and tissue repair. The use of exosomes in therapy is a hot spot in current research, especially in regenerative medicine. Despite the therapeutic potential, problems have hindered their success in clinical applications. These shortcomings include low concentration, poor targeting and limited loading capability. To fully realize their therapeutic potential, certain modifications are needed in native exosomes. In the present review, we summarize the exosome modification and functionalization strategies. In addition, we provide an overview of potential clinical applications and highlight the issues associated with the biosafety and biocompatibility of engineered exosomes in applications.
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Affiliation(s)
- Mu Zhang
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, China.
| | - Lei Wan
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, China.
| | - Ruiqi Li
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, China.
| | - Xiaoling Li
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, China.
| | - Taifu Zhu
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, China.
| | - Haibin Lu
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, China.
- The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, 510900, China
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Wei G, Li C, Jia X, Xie J, Tang Z, Jin M, Chen Q, Sun Y, He S, Li X, Chen Y, Zheng H, Liao W, Liao Y, Bin J, Huang S. Extracellular vesicle-derived CircWhsc1 promotes cardiomyocyte proliferation and heart repair by activating TRIM59/STAT3/Cyclin B2 pathway. J Adv Res 2023; 53:199-218. [PMID: 36587763 PMCID: PMC10658329 DOI: 10.1016/j.jare.2022.12.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 12/22/2022] [Accepted: 12/26/2022] [Indexed: 12/31/2022] Open
Abstract
INTRODUCTION Extracellular vesicles (EVs)-mediated cell-to-cell communication is crucial for hypoxia-induced cell proliferation and tissue repair, but its function in endogenous cardiac regeneration is still unknown. OBJECTIVES Herein, we aimed to determine whether hypoxia-inducible circWhsc1 in endothelial EVs promoted cardiomyocyte (CM) proliferation and cardiac regeneration. METHODS RNA-sequence data was used to identify EV circRNAs that were involved into endogenous cardiac regeneration. Quantitative polymerase chain reactions were conducted to determine circRNA expression in tissue, cells and EVs. Gain- and loss-of-function assays were performed to explore the function of EV-derived circWhsc1 during cardiac regeneration. Western blotting and RNA pulldown assays were used to investigate its underlying mechanism. RESULTS We found that circWhsc1 was enriched in neonatal mouse hearts, particularly in cardiac ECs, and was further upregulated both in ECs and EC-derived EVs under hypoxic conditions. When cocultured with hypoxia-preconditioned neonatal ECs or their secreted EVs, both neonatal and adult CMs exhibited an increased proliferation rate and G2/M ratio, which could be attenuated by knockdown of circWhsc1 in ECs. In vivo, EC-restricted overexpression of circWhsc1 and EV-mediated delivery of circWhsc1 induced CM proliferation, alleviated cardiac fibrosis and restored cardiac function following myocardial infarction in adult mice. Mechanistic studies revealed that EV-derived circWhsc1 activated TRIM59 by enhancing its phosphorylation, thereby reinforcing the binding of TRIM59 to STAT3, phosphorylating STAT3 and inducing CM proliferation. CONCLUSION The current study demonstrated that hypoxia-inducible circWhsc1 in EC-derived EVs induces CM proliferation and heart regeneration. EC-CM communication mediated by EV-derived circWhsc1 might represent a prospective therapeutic target for inducing cardiac repair post-myocardial infarction.
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Affiliation(s)
- Guoquan Wei
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China
| | - Chuling Li
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China
| | - Xiaoqian Jia
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China
| | - Jingfang Xie
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China
| | - Zhenquan Tang
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China
| | - Ming Jin
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China
| | - Qiqi Chen
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China
| | - Yili Sun
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China
| | - Sisi He
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China
| | - Xinzhong Li
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China
| | - Yanmei Chen
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China
| | - Hao Zheng
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China
| | - Wangjun Liao
- Department of Oncology, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China
| | - Yulin Liao
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China
| | - Jianping Bin
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China.
| | - Senlin Huang
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515 Guangzhou, China.
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Shao H, Zhang Q, Sun M, Wu M, Sun X, Wang Q, Tong S. Effects of hydroxyapatite-coated porous titanium scaffolds functionalized by exosomes on the regeneration and repair of irregular bone. Front Bioeng Biotechnol 2023; 11:1283811. [PMID: 38026868 PMCID: PMC10644107 DOI: 10.3389/fbioe.2023.1283811] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 10/18/2023] [Indexed: 12/01/2023] Open
Abstract
As a traditional bone implant material, titanium (Ti) and its alloys have the disadvantages of lack of biological activity and susceptibility to stress shielding effect. Adipose stem cells (ADSCs) and exosomes were combined with the scaffold material in the current work to effectively create a hydroxyapatite (HA) coated porous titanium alloy scaffold that can load ADSCs and release exosomes over time. The composite made up for the drawbacks of traditional titanium alloy materials with higher mechanical characteristics and a quicker rate of osseointegration. Exosomes (Exos) are capable of promoting the development of ADSCs in porous titanium alloy scaffolds with HA coating, based on experimental findings from in vitro and in vivo research. Additionally, compared to pure Ti implants, the HA scaffolds loaded with adipose stem cell exosomes demonstrated improved bone regeneration capability and bone integration ability. It offers a theoretical foundation for the combined use of stem cell treatment and bone tissue engineering, as well as a design concept for the creation and use of novel clinical bone defect repair materials.
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Affiliation(s)
- Hanyu Shao
- Department of Plastic Surgery, First Hospital of China Medical University, Shenyang, China
| | - Qiyue Zhang
- Liaoning Provincial Key Laboratory of Oral Diseases, School and Hospital of Stomatology, China Medical University, Shenyang, China
| | - Mingman Sun
- Department of Plastic Surgery, First Hospital of China Medical University, Shenyang, China
| | - Ming Wu
- Department of Plastic Surgery, First Hospital of China Medical University, Shenyang, China
| | - Xu Sun
- Department of Plastic Surgery, First Hospital of China Medical University, Shenyang, China
| | - Qiang Wang
- Liaoning Provincial Key Laboratory of Oral Diseases, School and Hospital of Stomatology, China Medical University, Shenyang, China
| | - Shuang Tong
- Department of Plastic Surgery, First Hospital of China Medical University, Shenyang, China
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Ding JY, Chen MJ, Wu LF, Shu GF, Fang SJ, Li ZY, Chu XR, Li XK, Wang ZG, Ji JS. Mesenchymal stem cell-derived extracellular vesicles in skin wound healing: roles, opportunities and challenges. Mil Med Res 2023; 10:36. [PMID: 37587531 PMCID: PMC10433599 DOI: 10.1186/s40779-023-00472-w] [Citation(s) in RCA: 55] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 07/24/2023] [Indexed: 08/18/2023] Open
Abstract
Skin wounds are characterized by injury to the skin due to trauma, tearing, cuts, or contusions. As such injuries are common to all human groups, they may at times represent a serious socioeconomic burden. Currently, increasing numbers of studies have focused on the role of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) in skin wound repair. As a cell-free therapy, MSC-derived EVs have shown significant application potential in the field of wound repair as a more stable and safer option than conventional cell therapy. Treatment based on MSC-derived EVs can significantly promote the repair of damaged substructures, including the regeneration of vessels, nerves, and hair follicles. In addition, MSC-derived EVs can inhibit scar formation by affecting angiogenesis-related and antifibrotic pathways in promoting macrophage polarization, wound angiogenesis, cell proliferation, and cell migration, and by inhibiting excessive extracellular matrix production. Additionally, these structures can serve as a scaffold for components used in wound repair, and they can be developed into bioengineered EVs to support trauma repair. Through the formulation of standardized culture, isolation, purification, and drug delivery strategies, exploration of the detailed mechanism of EVs will allow them to be used as clinical treatments for wound repair. In conclusion, MSC-derived EVs-based therapies have important application prospects in wound repair. Here we provide a comprehensive overview of their current status, application potential, and associated drawbacks.
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Affiliation(s)
- Jia-Yi Ding
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Institute of Imaging Diagnosis and Minimally Invasive Intervention Research, the Fifth Affiliated Hospital of Wenzhou Medical University, Zhejiang, 323000, Lishui, China
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Min-Jiang Chen
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Institute of Imaging Diagnosis and Minimally Invasive Intervention Research, the Fifth Affiliated Hospital of Wenzhou Medical University, Zhejiang, 323000, Lishui, China
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Ling-Feng Wu
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Clinical College of the Affiliated Central Hospital, School of Medicine, Lishui University, Lishui, 323000, Zhejiang, China
| | - Gao-Feng Shu
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Institute of Imaging Diagnosis and Minimally Invasive Intervention Research, the Fifth Affiliated Hospital of Wenzhou Medical University, Zhejiang, 323000, Lishui, China
- Clinical College of the Affiliated Central Hospital, School of Medicine, Lishui University, Lishui, 323000, Zhejiang, China
| | - Shi-Ji Fang
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Institute of Imaging Diagnosis and Minimally Invasive Intervention Research, the Fifth Affiliated Hospital of Wenzhou Medical University, Zhejiang, 323000, Lishui, China
- Clinical College of the Affiliated Central Hospital, School of Medicine, Lishui University, Lishui, 323000, Zhejiang, China
| | - Zhao-Yu Li
- Department of Overseas Education College, Jimei University, Xiamen, 361021, Fujian, China
| | - Xu-Ran Chu
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Department of Medicine II, Internal Medicine, Cardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus-Liebig University Giessen, 35392, Giessen, Germany
- Pulmonary and Critical Care, Department of Medicine V, Internal Medicine, Infectious Diseases and Infection Control, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus-Liebig University Giessen, 35392, Giessen, Germany
| | - Xiao-Kun Li
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
| | - Zhou-Guang Wang
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Institute of Imaging Diagnosis and Minimally Invasive Intervention Research, the Fifth Affiliated Hospital of Wenzhou Medical University, Zhejiang, 323000, Lishui, China.
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
| | - Jian-Song Ji
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Institute of Imaging Diagnosis and Minimally Invasive Intervention Research, the Fifth Affiliated Hospital of Wenzhou Medical University, Zhejiang, 323000, Lishui, China.
- Clinical College of the Affiliated Central Hospital, School of Medicine, Lishui University, Lishui, 323000, Zhejiang, China.
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Skelton AM, Cohen DJ, Boyan BD, Schwartz Z. Osteoblast-Derived Matrix Vesicles Exhibit Exosomal Traits and a Unique Subset of microRNA: Their Caveolae-Dependent Endocytosis Results in Reduced Osteogenic Differentiation. Int J Mol Sci 2023; 24:12770. [PMID: 37628952 PMCID: PMC10454939 DOI: 10.3390/ijms241612770] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 08/08/2023] [Accepted: 08/11/2023] [Indexed: 08/27/2023] Open
Abstract
Matrix vesicles (MVs) are nano-sized extracellular vesicles that are anchored in the extracellular matrix (ECM). In addition to playing a role in biomineralization, osteoblast-derived MVs were recently suggested to have regulatory duties. The aims of this study were to establish the characteristics of osteoblast-derived MVs in the context of extracellular vesicles like exosomes, assess their role in modulating osteoblast differentiation, and examine their mechanism of uptake. MVs were isolated from the ECM of MG63 human osteoblast-like cell cultures and characterized via enzyme activity, transmission electron microscopy, nanoparticle tracking analysis, Western blot, and small RNA sequencing. Osteoblasts were treated with MVs from two different culture conditions (growth media [GM]; osteogenic media [OM]) to evaluate their effects on the differentiation and production of inflammatory markers and on macrophage polarization. MV endocytosis was assessed using a lipophilic, fluorescent dye and confocal microscopy with the role of caveolae determined using methyl-β-cyclodextrin. MVs exhibited a four-fold enrichment in alkaline phosphatase specific activity compared to plasma membranes; were 50-150 nm in diameter; possessed exosomal markers CD63, CD81, and CD9 and endosomal markers ALIX, TSG101, and HSP70; and were selectively enriched in microRNA linked to an anti-osteogenic effect and to M2 macrophage polarization. Treatment with GM or OM MVs decreased osteoblast differentiation. Osteoblasts endocytosed MVs using a mechanism that involves caveolae. These results support the hypothesis that osteoblasts produce MVs that participate in the regulation of osteogenesis.
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Affiliation(s)
- Anne M. Skelton
- Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA; (A.M.S.); (B.D.B.)
| | - D. Joshua Cohen
- Department of Biomedical Engineering, College of Engineering, Virginia Commonwealth University, Richmond, VA 23284, USA;
| | - Barbara D. Boyan
- Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA; (A.M.S.); (B.D.B.)
- Department of Biomedical Engineering, College of Engineering, Virginia Commonwealth University, Richmond, VA 23284, USA;
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA
| | - Zvi Schwartz
- Department of Biomedical Engineering, College of Engineering, Virginia Commonwealth University, Richmond, VA 23284, USA;
- Department of Periodontics, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
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Salem MA, Mohamed OG, Mosalam EM, Elberri AI, Abdel-Bar HM, Hassan M, Al-Karmalawy AA, Tripathi A, Ezzat SM, Abo Mansour HE. Investigation of the phytochemical composition, antioxidant, antibacterial, anti-osteoarthritis, and wound healing activities of selected vegetable waste. Sci Rep 2023; 13:13034. [PMID: 37563154 PMCID: PMC10415269 DOI: 10.1038/s41598-023-38591-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 07/11/2023] [Indexed: 08/12/2023] Open
Abstract
Agri-food wastes, produced following industrial food processing, are mostly discarded, leading to environmental hazards and losing the nutritional and medicinal values associated with their bioactive constituents. In this study, we performed a comprehensive analytical and biological evaluation of selected vegetable by-products (potato, onion, and garlic peels). The phytochemical analysis included UHPLC-ESI-qTOF-MS/MS in combination with molecular networking and determination of the total flavonoid and phenolic contents. Further, the antimicrobial, anti-osteoarthritis and wound healing potentials were also evaluated. In total, 47 compounds were identified, belonging to phenolic acids, flavonoids, saponins, and alkaloids as representative chemical classes. Onion peel extract (OPE) showed the higher polyphenolic contents, the promising antioxidant activity, the potential anti-osteoarthritis activity, and promising antimicrobial activity, especially against methicillin-resistant Staphylococcus aureus (MRSA). Furthermore, OPE revealed to have promising in vivo wound healing activity, restoring tissue physiology and integrity, mainly through the activation of AP-1 signaling pathway. Lastly, when OPE was loaded with nanocapsule based hydrogel, the nano-formulation revealed enhanced cellular viability. The affinities of the OPE major metabolites were evaluated against both p65 and ATF-2 targets using two different molecular docking processes revealing quercetin-3,4'-O-diglucoside, alliospiroside C, and alliospiroside D as the most promising entities with superior binding scores. These results demonstrate that vegetable by-products, particularly, those derived from onion peels can be incorporated as natural by-product for future evaluation against wounds and osteoarthritis.
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Affiliation(s)
- Mohamed A Salem
- Department of Pharmacognosy and Natural Products, Faculty of Pharmacy, Menoufia University, Gamal Abd El Nasr st., Shibīn al-Kawm, 32511, Menoufia, Egypt.
| | - Osama G Mohamed
- Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Kasr el Aini St., Cairo, 11562, Egypt
- Natural Products Discovery Core, Life Sciences Institute, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Esraa M Mosalam
- Biochemistry Department, Faculty of Pharmacy, Menoufia University, Gamal Abd El Nasr st., Shebin El-Koum, 32511, Egypt
| | - Aya Ibrahim Elberri
- Genetic Engineering and Molecular Biology Division, Department of Zoology, Faculty of Science, Menoufia University, Shebin El-Kom, 32511, Menoufia, Egypt
| | - Hend Mohamed Abdel-Bar
- Department of Pharmaceutics, Faculty of Pharmacy, University of Sadat City, Sadat City, Egypt
| | - Mariam Hassan
- Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Kasr el Aini st., Cairo, 11562, Egypt
- Department of Microbiology and Immunology, Faculty of Pharmacy, Galala University, New Galala City, Suez, Egypt
| | - Ahmed A Al-Karmalawy
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, Giza, 12566, Egypt
| | - Ashootosh Tripathi
- Natural Products Discovery Core, Life Sciences Institute, University of Michigan, Ann Arbor, MI, 48109, USA
- Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Shahira M Ezzat
- Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Kasr el Aini St., Cairo, 11562, Egypt
- Department of Pharmacognosy, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), Giza, 12451, Egypt
| | - Hend E Abo Mansour
- Biochemistry Department, Faculty of Pharmacy, Menoufia University, Gamal Abd El Nasr st., Shebin El-Koum, 32511, Egypt
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Zhang Y, Qi G, Yan Y, Wang C, Wang Z, Jiang C, Jiang Z, Ma T, Zhang C, Yan Z. Exosomes derived from bone marrow mesenchymal stem cells pretreated with decellularized extracellular matrix enhance the alleviation of osteoarthritis through miR-3473b/phosphatase and tensin homolog axis. J Gene Med 2023; 25:e3510. [PMID: 36998238 DOI: 10.1002/jgm.3510] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Revised: 02/22/2023] [Accepted: 03/27/2023] [Indexed: 04/01/2023] Open
Abstract
BACKGROUND Osteoarthritis (OA) is a prevalent degenerative articular disease for which there is no effective treatment. Progress has been made in mesenchymal stem cell (MSC)-based therapy in OA, and the efficacy has been demonstrated to be a result of paracrine exosomes from MSCs. Decellularized extracellular matrix (dECM) provides an optimum microenvironment for the expansion of MSCs. In the present study, we aimed to investigate whether exosomes isolated from bone marrow mesenchymal stem cells (BMSCs) with dECM pretreatment (dECM-BMSC-Exos) enhance the amelioration of OA. METHODS Exosomes from BMSCs with or without dECM pretreatment were isolated. We measured and compared the effect of the BMSC-Exo and dECM-BMSC-Exo on interleukin (IL)-1β-induced chondrocytes by analyzing proliferation, anabolism and catabolism, migration and apoptosis in vitro. The in vivo experiment was performed by articular injection of exosomes into DMM mice, followed by histological evaluation of cartilage. MicroRNA sequencing of exosomes was performed on BMSC-Exo and dECM-BMSC-Exo to investigate the underlying mechanism. The function of miR-3473b was validated by rescue studies in vitro and in vivo using antagomir-3473b. RESULTS IL-1β-treated chondrocytes treated with dECM-BMSC-Exos showed enhanced proliferation, anabolism, migration and anti-apoptosis properties compared to BMSC-Exos. DMM mice injected with dECM-BMSC-Exo showed better cartilage regeneration than those injected with BMSC-Exo. Interestingly, miR-3473b was significantly elevated in dECM-BMSC-Exos and was found to mediate the protective effect in chondrocytes by targeting phosphatase and tensin homolog (PTEN), which activated the PTEN/AKT signaling pathway. CONCLUSIONS dECM-BMSC-Exo can enhance the alleviation of osteoarthritis via promoting migration, improving anabolism and inhibiting apoptosis of chondrocytes by upregulating miR-3473b, which targets PTEN.
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Affiliation(s)
- Yueqi Zhang
- Department of Orthopedics, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Guobin Qi
- Department of Orthopedics, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yuheng Yan
- Department of Orthopedics, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Chenzhong Wang
- Department of Orthopedics, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhe Wang
- Department of Orthopedics, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Chang Jiang
- Department of Orthopedics, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zengxin Jiang
- Department of Orthopedics, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Orthopedics, Shanghai Sixth People's Hospital, Shanghai, China
| | - Tianle Ma
- Department of Orthopedics, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Chi Zhang
- Department of Orthopedics, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zuoqin Yan
- Department of Orthopedics, Zhongshan Hospital, Fudan University, Shanghai, China
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Yoon J, Lee SK, Park A, Lee J, Jung I, Song KB, Choi EJ, Kim S, Yu J. Exosome from IFN-γ-Primed Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells Improved Skin Inflammation and Barrier Function. Int J Mol Sci 2023; 24:11635. [PMID: 37511392 PMCID: PMC10380988 DOI: 10.3390/ijms241411635] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 07/09/2023] [Accepted: 07/15/2023] [Indexed: 07/30/2023] Open
Abstract
The pathogenesis of atopic dermatitis (AD) is multifactorial, including immune dysregulation and epidermal barrier defects, and a novel therapeutic modality that can simultaneously target multiple pathways is needed. We investigated the therapeutic effects of exosomes (IFN-γ-iExo) secreted from IFN-γ-primed induced pluripotent stem cell-derived mesenchymal stem cells (iMSC) in mice with Aspergillus fumigatus-induced AD. IFN-γ-iExo was epicutaneously administered to mice with AD-like skin lesions. The effects of IFN-γ-iExo treatment were investigated through clinical scores, transepidermal water loss (TEWL) measurements, and histopathology. To elucidate the therapeutic mechanism, we used an in vitro model of human keratinocyte HaCaT cells stimulated with IL-4 and IL-13 and performed extensive bioinformatics analysis of skin mRNA from mice. The expression of indoleamine 2,3-dioxygenase was higher in IFN-γ primed iMSCs than in iMSCs. In human keratinocyte HaCaT cells, treatment with IFN-γ-iExo led to decreases in the mRNA expression of thymic stromal lymphopoietin, IL-25, and IL-33 and increases in keratin 1, keratin 10, desmoglein 1, and ceramide synthase 3. IFN-γ-iExo treatment significantly improved clinical and histological outcomes in AD mice, including clinical scores, TEWL, inflammatory cell infiltration, and epidermal thickness. Bioinformatics analysis of skin mRNA from AD mice showed that IFN-γ-iExo treatment is predominantly involved in skin barrier function and T cell immune response. Treatment with IFN-γ-iExo improved the clinical and histological outcomes of AD mice, which were likely mediated by restoring proper skin barrier function and suppressing T cell-mediated immune response.
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Affiliation(s)
- Jin Yoon
- Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Republic of Korea; (J.Y.); (A.P.); (J.L.)
| | - Seul Ki Lee
- Brexogen Research Center, Brexogen Inc., Seoul 05855, Republic of Korea;
| | - Arum Park
- Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Republic of Korea; (J.Y.); (A.P.); (J.L.)
| | - Jiho Lee
- Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Republic of Korea; (J.Y.); (A.P.); (J.L.)
| | - Inuk Jung
- School of Computer Science and Engineering, Kyungpook National University, Daegu 41566, Republic of Korea;
| | - Kun Baek Song
- Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea; (K.B.S.); (E.J.C.)
| | - Eom Ji Choi
- Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea; (K.B.S.); (E.J.C.)
| | - Soo Kim
- Brexogen Research Center, Brexogen Inc., Seoul 05855, Republic of Korea;
| | - Jinho Yu
- Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea; (K.B.S.); (E.J.C.)
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Peng W, Yang Y, Chen J, Xu Z, Lou Y, Li Q, Zhao N, Qian K, Liu F. Small Extracellular Vesicles Secreted by iPSC-Derived MSCs Ameliorate Pulmonary Inflammation and Lung Injury Induced by Sepsis through Delivery of miR-125b-5p. J Immunol Res 2023; 2023:8987049. [PMID: 37425491 PMCID: PMC10329558 DOI: 10.1155/2023/8987049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 12/07/2022] [Accepted: 05/18/2023] [Indexed: 07/11/2023] Open
Abstract
Background Sepsis-induced acute lung injury is a common critical illness in intensive care units with no effective treatment is currently available. Small extracellular vesicles, secreted by mesenchymal stem cells (MSCs), derived from human-induced pluripotent stem cells (iMSC-sEV), possess striking advantages when incorporated MSCs and iPSCs, which are considered extremely promising cell-free therapeutic agents. However, no studies have yet been conducted to systemically examine the effects and underlying mechanisms of iMSC-sEV application on attenuated lung injury under sepsis conditions. Method iMSC-sEV were intraperitoneally administered in a rat septic lung injury model induced by cecal ligation and puncture (CLP). The efficacy of iMSC-sEV was assessed by histology, immunohistochemistry, and pro-inflammatory cytokines of bronchoalveolar lavage fluid. We also evaluated the in vitro effects of iMSC-sEV on the activation of the inflammatory response in alveolar macrophages (AMs). Small RNA sequencing was utilized to detect changes in the miRNA expression profile in lipopolysaccharide (LPS)-treated AMs after iMSC-sEV administration. The effects of miR-125b-5p on the function of AMs were studied. Results iMSC-sEV were able to attenuate pulmonary inflammation and lung injury following CLP-induced lung injury. iMSC-sEV were internalized by AMs and alleviated the release of inflammatory factors by inactivating the NF-κB signaling pathway. Moreover, miR-125b-5p showed a fold-change in LPS-treated AMs after iMSC-sEV administration and was enriched in iMSC-sEV. Mechanistically, iMSC-sEV transmitted miR-125b-5p into LPS-treated AMs to target TRAF6. Conclusion Our findings demonstrated that iMSC-sEV treatment protects against septic lung injury and exerts anti-inflammatory effects on AMs at least partially through miR-125b-5p, suggesting that iMSC-sEV may provide a novel cell-free strategy for the treatment of septic lung injury.
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Affiliation(s)
- Wei Peng
- Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- Medical Innovation Center, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Yun Yang
- Department of Critical Care Medicine, The People's Hospital of Fengcheng City, Yichun, Jiangxi, China
| | - Jiaquan Chen
- Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- Medical Innovation Center, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Zeyao Xu
- Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- Medical Innovation Center, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Yuanlei Lou
- Institute of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Qi Li
- Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- Medical Innovation Center, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Ning Zhao
- Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- Medical Innovation Center, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Kejian Qian
- Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- Medical Innovation Center, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Fen Liu
- Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- Medical Innovation Center, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
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Zhou JQ, Wan HY, Wang ZX, Jiang N. Stimulating factors for regulation of osteogenic and chondrogenic differentiation of mesenchymal stem cells. World J Stem Cells 2023; 15:369-384. [PMID: 37342227 PMCID: PMC10277964 DOI: 10.4252/wjsc.v15.i5.369] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Revised: 02/21/2023] [Accepted: 03/29/2023] [Indexed: 05/26/2023] Open
Abstract
Mesenchymal stem cells (MSCs), distributed in many tissues in the human body, are multipotent cells capable of differentiating in specific directions. It is usually considered that the differentiation process of MSCs depends on specialized external stimulating factors, including cell signaling pathways, cytokines, and other physical stimuli. Recent findings have revealed other underrated roles in the differentiation process of MSCs, such as material morphology and exosomes. Although relevant achievements have substantially advanced the applicability of MSCs, some of these regulatory mechanisms still need to be better understood. Moreover, limitations such as long-term survival in vivo hinder the clinical application of MSCs therapy. This review article summarizes current knowledge regarding the differentiation patterns of MSCs under specific stimulating factors.
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Affiliation(s)
- Jia-Qi Zhou
- Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Hao-Yang Wan
- Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Zi-Xuan Wang
- Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Nan Jiang
- Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
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Liu N, Dong J, Li L, Liu F. Osteoimmune Interactions and Therapeutic Potential of Macrophage-Derived Small Extracellular Vesicles in Bone-Related Diseases. Int J Nanomedicine 2023; 18:2163-2180. [PMID: 37131544 PMCID: PMC10149074 DOI: 10.2147/ijn.s403192] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 04/19/2023] [Indexed: 05/04/2023] Open
Abstract
Due to the aging of the global population, the burden of bone-related diseases has increased sharply. Macrophage, as indispensable components of both innate immune responses and adaptive immunity, plays a considerable role in maintaining bone homeostasis and promoting bone establishment. Small extracellular vesicles (sEVs) have attracted increasing attention because they participate in cell cross-talk in pathological environments and can serve as drug delivery systems. In recent years, an increasing number of studies have expanded our knowledge about the effects of macrophage-derived sEVs (M-sEVs) in bone diseases via different forms of polarization and their biological functions. In this review, we comprehensively describe on the application and mechanisms of M-sEVs in various bone diseases and drug delivery, which may provide new perspectives for treating and diagnosing human bone disorders, especially osteoporosis, arthritis, osteolysis, and bone defects.
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Affiliation(s)
- Nan Liu
- Department of Orthopedics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of China
| | - Jinlei Dong
- Department of Orthopedics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of China
| | - Lianxin Li
- Department of Orthopedics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of China
| | - Fanxiao Liu
- Department of Orthopedics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of China
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Sunartvanichkul T, Arayapisit T, Sangkhamanee SS, Chaweewannakorn C, Iwasaki K, Klaihmon P, Sritanaudomchai H. Stem cell-derived exosomes from human exfoliated deciduous teeth promote angiogenesis in hyperglycemic-induced human umbilical vein endothelial cells. J Appl Oral Sci 2023; 31:e20220427. [PMID: 37042872 PMCID: PMC10118382 DOI: 10.1590/1678-7757-2022-0427] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 01/12/2023] [Accepted: 02/07/2023] [Indexed: 04/13/2023] Open
Abstract
OBJECTIVE To investigate the angiogenesis in human umbilical vein endothelial cells (HUVEC) under high glucose concentration, treated with exosomes derived from stem cells from human exfoliated deciduous teeth (SHED). METHODOLOGY SHED-derived exosomes were isolated by differential centrifugation and were characterized by nanoparticle tracking analysis, transmission electron microscopy, and flow cytometric assays. We conducted in vitro experiments to examine the angiogenesis in HUVEC under high glucose concentration. Cell Counting Kit-8, migration assay, tube formation assay, quantitative real-time PCR, and immunostaining were performed to study the role of SHED-derived exosomes in cell proliferation, migration, and angiogenic activities. RESULTS The characterization confirmed SHED-derived exosomes: size ranged from 60-150 nm with a mode of 134 nm, cup-shaped morphology, and stained positively for CD9, CD63, and CD81. SHED-exosome significantly enhanced the proliferation and migration of high glucose-treated HUVEC. A significant reduction was observed in tube formation and a weak CD31 staining compared to the untreated-hyperglycemic-induced group. Interestingly, exosome treatment improved tube formation qualitatively and demonstrated a significant increase in tube formation in the covered area, total branching points, total tube length, and total loop parameters. Moreover, SHED-exosome upregulates angiogenesis-related factors, including the GATA2 gene and CD31 protein. CONCLUSIONS Our data suggest that the use of SHED-derived exosomes potentially increases angiogenesis in HUVEC under hyperglycemic conditions, which includes increased cell proliferation, migration, tubular structures formation, GATA2 gene, and CD31 protein expression. SHED-exosome usage may provide a new treatment strategy for periodontal patients with diabetes mellitus.
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Affiliation(s)
| | - Tawepong Arayapisit
- Mahidol University, Faculty of Dentistry, Department of Anatomy, Bangkok, Thailand
| | | | | | - Kengo Iwasaki
- Osaka Dental University, Advanced Medical Research Center, Translational Research Institute for Medical Innovation, Osaka, Japan
| | - Phatchanat Klaihmon
- Mahidol University, Faculty of Medicine Siriraj Hospital, Siriraj Center of Excellence for Stem Cell Research, Bangkok, Thailand
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Aldoghachi AF, Loh JK, Wang ML, Yang YP, Chien CS, Teh HX, Omar AH, Cheong SK, Yeap SK, Ho WY, Ong AHK. Current developments and therapeutic potentials of exosomes from induced pluripotent stem cells-derived mesenchymal stem cells. J Chin Med Assoc 2023; 86:356-365. [PMID: 36762931 DOI: 10.1097/jcma.0000000000000899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/11/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent cells derived from adult human tissues that have the ability to proliferate in vitro and maintain their multipotency, making them attractive cell sources for regenerative medicine. However, MSCs reportedly show limited proliferative capacity with inconsistent therapeutic outcomes due to their heterogeneous nature. On the other hand, induced pluripotent stem cells (iPSC) have emerged as an alternative source for the production of various specialized cell types via their ability to differentiate from all three primary germ layers, leading to applications in regenerative medicine, disease modeling, and drug therapy. Notably, iPSCs can differentiate into MSCs in monolayer, commonly referred to as induced mesenchymal stem cells (iMSCs). These cells show superior therapeutic qualities compared with adult MSCs as the applications of the latter are restricted by passage number and autoimmune rejection when applied in tissue regeneration trials. Furthermore, increasing evidence shows that the therapeutic properties of stem cells are a consequence of the paracrine effects mediated by their secretome such as from exosomes, a type of extracellular vesicle secreted by most cell types. Several studies that investigated the potential of exosomes in regenerative medicine and therapy have revealed promising results. Therefore, this review focuses on the recent findings of exosomes secreted from iMSCs as a potential noncell-based therapy.
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Affiliation(s)
- Ahmed Faris Aldoghachi
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras, Malaysia
| | - Jit-Kai Loh
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras, Malaysia
- Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Mong-Lien Wang
- Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Yi-Ping Yang
- Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Chian-Shiu Chien
- Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Hui Xin Teh
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras, Malaysia
| | - Alfaqih Hussain Omar
- Biomedicine Programme, School of Health Sciences, Universiti Sains Malaysia, Malaysia
| | - Soon-Keng Cheong
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras, Malaysia
- National Cancer Council (MAKNA), Kuala Lumpur, Malaysia
| | - Swee Keong Yeap
- Marine Biotechnology, China-ASEAN College of Marine Sciences, Xiamen University Malaysia Campus, Jalan Sunsuria, Bandar Sunsuria, Sepang, Selangor, Malaysia
| | - Wan Yong Ho
- Faculty of Sciences and Engineering, University of Nottingham Malaysia, Semenyih, Malaysia
| | - Alan Han-Kiat Ong
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras, Malaysia
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Thakur A. Shedding Lights on the Extracellular Vesicles as Functional Mediator and Therapeutic Decoy for COVID-19. Life (Basel) 2023; 13:life13030840. [PMID: 36983995 PMCID: PMC10052528 DOI: 10.3390/life13030840] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 03/08/2023] [Accepted: 03/15/2023] [Indexed: 03/30/2023] Open
Abstract
COVID-19 is an infectious disease caused by the novel coronavirus (SARS-CoV-2) that first appeared in late 2019 and has since spread across the world. It is characterized by symptoms such as fever, cough, and shortness of breath and can lead to death in severe cases. To help contain the virus, measures such as social distancing, handwashing, and other public health measures have been implemented. Vaccine and drug candidates, such as those developed by Pfizer/BioNTech, AstraZeneca, Moderna, Novavax, and Johnson & Johnson, have been developed and are being distributed worldwide. Clinical trials for drug treatments such as remdesivir, dexamethasone, and monoclonal antibodies are underway and have shown promising results. Recently, exosomes have gained attention as a possible mediator of the COVID-19 infection. Exosomes, small vesicles with a size of around 30-200 nm, released from cells, contain viral particles and other molecules that can activate the immune system and/or facilitate viral entry into target cells. Apparently, the role of exosomes in eliciting various immune responses and causing tissue injury in COVID-19 pathogenesis has been discussed. In addition, the potential of exosomes as theranostic and therapeutic agents for the treatment of COVID-19 has been elaborated.
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Affiliation(s)
- Abhimanyu Thakur
- Ben May Department for Cancer Research, Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, USA
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Ren Y, Zhang H. Emerging role of exosomes in vascular diseases. Front Cardiovasc Med 2023; 10:1090909. [PMID: 36937921 PMCID: PMC10017462 DOI: 10.3389/fcvm.2023.1090909] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 01/11/2023] [Indexed: 03/06/2023] Open
Abstract
Exosomes are biological small spherical lipid bilayer vesicles secreted by most cells in the body. Their contents include nucleic acids, proteins, and lipids. Exosomes can transfer material molecules between cells and consequently have a variety of biological functions, participating in disease development while exhibiting potential value as biomarkers and therapeutics. Growing evidence suggests that exosomes are vital mediators of vascular remodeling. Endothelial cells (ECs), vascular smooth muscle cells (VSMCs), inflammatory cells, and adventitial fibroblasts (AFs) can communicate through exosomes; such communication is associated with inflammatory responses, cell migration and proliferation, and cell metabolism, leading to changes in vascular function and structure. Essential hypertension (EH), atherosclerosis (AS), and pulmonary arterial hypertension (PAH) are the most common vascular diseases and are associated with significant vascular remodeling. This paper reviews the latest research progress on the involvement of exosomes in vascular remodeling through intercellular information exchange and provides new ideas for understanding related diseases.
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Affiliation(s)
- Yi Ren
- Institute of Microcirculation, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Graduate School, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Honggang Zhang
- Institute of Microcirculation, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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Pastore S, Troisi A, Romani R, Bellezza I, Gargaro M, Di Michele A, Orlandi R, Guerrera G, Bazzano M, Polisca A. Isolation of extracellular vesicles from bitch's amnion-derived cells culture and their CD59 expression: Preliminary results. Theriogenology 2023; 198:164-171. [PMID: 36587540 DOI: 10.1016/j.theriogenology.2022.12.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 12/07/2022] [Accepted: 12/07/2022] [Indexed: 12/13/2022]
Abstract
Extracellular vesicles (EVs) are small spherical particles surrounded by a membrane with an unusual lipid composition and a striking cholesterol/phospholipidic ratio. About 2000 lipid and 3500 protein species were identified in EVs secreted by different cell sources. EVs mediate cell to cell communication in proximity to or distant from the cell of origin. In particular, it was suggested that they represent modulators of multiple processes during pregnancy. The aim of this study was to identify the presence of EVs in canine amnion-derived cells (ASCs) culture and the expression of CD 59 on their surface. Amniotic membrane was collected in PBS with antibiotics added from 2 bitches during elective caesarean section. Cells culture was prepared and EVs were isolated. EVs were used to evaluate CD59 expression by flow cytofluorimetry. We found that the majority of EVs expressed CD59. Our results could increase the knowledge about the complex mechanisms that regulate the pregnancy in the bitch.
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Affiliation(s)
- S Pastore
- Department of Veterinary Medicine, University of Perugia, Via San Costanzo 4, 06126, Perugia, Italy.
| | - A Troisi
- School of Biosciences and Veterinary Medicine, University of Camerino, Via Circonvallazione 93/95, 62024, Macerata, Italy
| | - R Romani
- Department of Medicine and Surgery, University of Perugia, Piazzale Gambuli, 1, 06129, Perugia, Italy
| | - I Bellezza
- Department of Medicine and Surgery, University of Perugia, Piazzale Gambuli, 1, 06129, Perugia, Italy
| | - M Gargaro
- Department of Medicine and Surgery, University of Perugia, Piazzale Gambuli, 1, 06129, Perugia, Italy
| | - A Di Michele
- Department of Physic and Geology, University of Perugia, Via Pascoli, 06123, Perugia, Italy
| | - R Orlandi
- Anicura Tyrus Clinica Veterinaria, Via Bartocci 1G, 05100, Terni, Italy
| | - G Guerrera
- Veterinarian Freelance, Campobasso, Italy
| | - M Bazzano
- School of Biosciences and Veterinary Medicine, University of Camerino, Via Circonvallazione 93/95, 62024, Macerata, Italy
| | - A Polisca
- Department of Veterinary Medicine, University of Perugia, Via San Costanzo 4, 06126, Perugia, Italy
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Mahdavi-Jouibari F, Parseh B, Kazeminejad E, Khosravi A. Hopes and opportunities of stem cells from human exfoliated deciduous teeth (SHED) in cartilage tissue regeneration. Front Bioeng Biotechnol 2023; 11:1021024. [PMID: 36860887 PMCID: PMC9968979 DOI: 10.3389/fbioe.2023.1021024] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 01/30/2023] [Indexed: 02/17/2023] Open
Abstract
Cartilage lesions are common conditions, affecting elderly and non-athletic populations. Despite recent advances, cartilage regeneration remains a major challenge today. The absence of an inflammatory response following damage and the inability of stem cells to penetrate into the healing site due to the absence of blood and lymph vessels are assumed to hinder joint repair. Stem cell-based regeneration and tissue engineering have opened new horizons for treatment. With advances in biological sciences, especially stem cell research, the function of various growth factors in the regulation of cell proliferation and differentiation has been established. Mesenchymal stem cells (MSCs) isolated from different tissues have been shown to increase into therapeutically relevant cell numbers and differentiate into mature chondrocytes. As MSCs can differentiate and become engrafted inside the host, they are considered suitable candidates for cartilage regeneration. Stem cells from human exfoliated deciduous teeth (SHED) provide a novel and non-invasive source of MSCs. Due to their simple isolation, chondrogenic differentiation potential, and minimal immunogenicity, they can be an interesting option for cartilage regeneration. Recent studies have reported that SHED-derived secretome contains biomolecules and compounds that efficiently promote regeneration in damaged tissues, including cartilage. Overall, this review highlighted the advances and challenges of cartilage regeneration using stem cell-based therapies by focusing on SHED.
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Affiliation(s)
- Forough Mahdavi-Jouibari
- Department of Medical Biotechnology, Faculty of Advanced Medical Technologies, Golestan University of Medical Sciences, Gorgan, Iran
| | - Benyamin Parseh
- Stem Cell Research Center, Golestan University of Medical Sciences, Gorgan, Iran,Faculty of Advanced Medical Technologies, Golestan University of Medical Sciences, Gorgan, Iran
| | - Ezatolah Kazeminejad
- Stem Cell Research Center, Golestan University of Medical Sciences, Gorgan, Iran,Dental Research Center, Golestan University of Medical Sciences, Gorgan, Iran,*Correspondence: Ezatolah Kazeminejad, Dr. ; Ayyoob Khosravi,
| | - Ayyoob Khosravi
- Stem Cell Research Center, Golestan University of Medical Sciences, Gorgan, Iran,Department of Molecular Medicine, Faculty of Advanced Medical Technologies, Golestan University of Medical Sciences, Gorgan, Iran,*Correspondence: Ezatolah Kazeminejad, Dr. ; Ayyoob Khosravi,
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Lyu K, Liu X, Liu T, Lu J, Jiang L, Chen Y, Long L, Wang X, Shi H, Wang F, Li S. miRNAs contributing to the repair of tendon injury. Cell Tissue Res 2023; 393:201-215. [PMID: 37249708 PMCID: PMC10406718 DOI: 10.1007/s00441-023-03780-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 05/02/2023] [Indexed: 05/31/2023]
Abstract
Tendon injury is one of the most common disorders of the musculoskeletal system, with a higher likelihood of occurrence in elderly individuals and athletes. In posthealing tendons, two undesirable consequences, tissue fibrosis and a reduction in mechanical properties, usually occur, resulting in an increased probability of rerupture or reinjury; thus, it is necessary to propose an appropriate treatment. Currently, most methods do not sufficiently modulate the tendon healing process and restore the function and structure of the injured tendon to those of a normal tendon, since there is still inadequate information about the effects of multiple cellular and other relevant signaling pathways on tendon healing and how the expression of their components is regulated. microRNAs are vital targets for promoting tendon repair and can modulate the expression of biological components in signaling pathways involved in various physiological and pathological responses. miRNAs are a type of noncoding ribonucleic acid essential for regulating processes such as cell proliferation, differentiation, migration and apoptosis; inflammatory responses; vascularization; fibrosis; and tissue repair. This article focuses on the biogenesis response of miRNAs while presenting their mechanisms in tendon healing with perspectives and suggestions.
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Affiliation(s)
- Kexin Lyu
- School of Physical Education, Southwest Medical University, Luzhou, China
| | - Xinyue Liu
- School of Physical Education, Southwest Medical University, Luzhou, China
| | - Tianzhu Liu
- Neurology Department, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Jingwei Lu
- School of Physical Education, Southwest Medical University, Luzhou, China
| | - Li Jiang
- School of Physical Education, Southwest Medical University, Luzhou, China
| | - Yixuan Chen
- School of Physical Education, Southwest Medical University, Luzhou, China
| | - Longhai Long
- Spinal Surgery Department, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Xiaoqiang Wang
- Spinal Surgery Department, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Houyin Shi
- Traumatology and Orthopedics Department, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Fan Wang
- The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Sen Li
- Spinal Surgery Department, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
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