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Wang D, Zhong Q, Xu Y, Fu J, Xie J, Chen R, Lei M, Tang Z, Mai H, Li H, Shi Z, Zheng S, Cheng H. Injectable visible light cross-linking aldehyde-based methacrylated hyaluronic acid hydrogels enhance cartilage repair via improved BMSC homing and chondrogenic differentiation. Int J Biol Macromol 2025; 307:141857. [PMID: 40058436 DOI: 10.1016/j.ijbiomac.2025.141857] [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] [Revised: 03/02/2025] [Accepted: 03/06/2025] [Indexed: 03/17/2025]
Abstract
Self-repair of articular cartilage defects is a significant challenge that can be addressed using drug-infused hydrogels, which improve injection convenience and provide immediate in situ adhesion. In this study, we developed a hydrogel incorporating Lipo@Kartogenin (KGN) and the cationic functional peptide SKPPGTSS (SKP) linked to aldehyde-based methacrylated hyaluronic acid (AHAMA). The innovative injectable hydrogel responded to visible light, allowing cross-linking under white light (∼30 s) and effective adhesion to cartilage tissue. The hydrogel facilitated the sustained release of KGN and SKP over approximately 28 days as it degraded, thereby promoting the homing and differentiation of endogenous bone marrow-derived mesenchymal stem cells (BMSCs). Transcriptome sequencing showed that Smad4 expression and activation of the TGF-β signaling pathway are fundamental to these processes. In vivo studies in Sprague-Dawley (SD) rats showed that this hydrogel supports optimal hyaline cartilage regeneration within 8 weeks. In conclusion, our visible light-responsive adhesive co-delivery hydrogel effectively recruited native BMSCs to cartilage lesion sites and provided an environment conducive to their differentiation into cartilage, thereby facilitating effective cartilage regeneration. This innovation represents a novel approach to the clinical repair of cartilage defects.
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Affiliation(s)
- Ding Wang
- Department of Orthopedic, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Qiang Zhong
- Department of Orthopedic, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yixin Xu
- Department of Orthopedic, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Jinlang Fu
- Department of Orthopedics, Kaiping Central Hospital, Kaiping 529300, China
| | - Jiajun Xie
- Department of Orthopedics, The Second Affiliated Hospital of Nanchang University, Jiangxi Medical College, Nanchang University, Nanchang 330006, China
| | - Rong Chen
- Department of Orthopedic, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Mingyuan Lei
- Department of Orthopedic, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Zinan Tang
- Department of Orthopedic, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Huaming Mai
- Department of Orthopedic, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Hao Li
- Department of Orthopedic, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Zhanjun Shi
- Department of Orthopedic, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
| | - Shaowei Zheng
- Department of Sports Medicine and Rehabilitation, Peking University Shenzhen Hospital, Shenzhen 518000, China; State Key Laboratory of Quality Research in Chinese Medicines, Laboratory of Drug Discovery from Natural Resources and Industrialization, School of Pharmacy, Macau University of Science and Technology, Macau 999078, China.
| | - Hao Cheng
- Department of Orthopedic, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
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Sun X, Long R, Chen Q, Feng J, Gao Y, Zhu G, Yang Z. miR-378a-3p Regulates the BMP2-Smad Pathway to Promote Chondrogenic Differentiation of Synovium-Derived Mesenchymal Stem Cells. Cell Biochem Biophys 2025; 83:1277-1288. [PMID: 39373905 DOI: 10.1007/s12013-024-01561-w] [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] [Accepted: 09/17/2024] [Indexed: 10/08/2024]
Abstract
This study aims to elucidate the role of miR-378a-3p in facilitating the proliferation and differentiation of synovium-derived mesenchymal stem cells (SMSCs) into chondrocytes. The effects of overexpressing miR-378a-3p on SMSCs were investigated through histological analysis, quantitative PCR, and western blotting. Then we identified binding sites of miR-378a-3p with BMP2 through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses and predictions from the RegRNA 2.0 database. Subsequently, BMP2 was confirmed as the target by which miR-378a-3p promotes the chondrogenic differentiation of SMSCs using a luciferase reporter gene assay and an miR-378a-3p RNA interference plasmid. Finally, by constructing a rat model with articular cartilage damage, we detected the reparative effects of miR-378a-3p overexpression on cartilage damage. Additionally, we verified the mechanism by which miR-378a-3p promotes chondrogenic differentiation in SMSCs. MiR-378a-3p enhances the proliferation and differentiation of SMSCs into chondrocytes by modulating the BMP2-Smad signaling pathway, thereby facilitating repair processes for articular cartilage injuries in rats. Notably, knockdown of BMP2 diminished the reparative efficacy of miR-378a-3p on articular cartilage damage. Upregulation of miR-378a-3p promotes chondrogenic differentiation in SMSCs through activation of the BMP2-Smad pathway, positioning it as a potential therapeutic target for osteoarthritis.
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Affiliation(s)
- Xiangyi Sun
- Department of Orthopedics, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, 311200, China
| | - Ruchao Long
- Department of Orthopedics, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, 311200, China
| | - Qiang Chen
- Department of Orthopedics, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, 311200, China
| | - Jian Feng
- Department of Orthopedics, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, 311200, China
| | - Yang Gao
- Department of Orthopedics, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, 311200, China
| | - Guangqi Zhu
- Department of Orthopedics, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, 311200, China
| | - Zhihua Yang
- Department of Orthopedics, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, 311200, China.
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Karaçoban L, Gizer M, Fidan BB, Kaplan O, Çelebier M, Korkusuz P, Turhan E, Korkusuz F. Donor tissue type alters the effects of mesenchymal stem cells on human osteoarthritic chondrocytes and their metabolomic profiles. Res Sports Med 2025:1-15. [PMID: 39971374 DOI: 10.1080/15438627.2025.2467871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Accepted: 02/11/2025] [Indexed: 02/21/2025]
Abstract
Early post-traumatic osteoarthritis due to sports injuries is not rare and cell-based therapies are currently used in the treatment. Infrapatellar fat pad (IPFP), synovium (Sy) and subcutaneous adipose (S) tissues were obtained for analysis and MSC isolation. Osteoarthritic (OACs) and normal chondrocytes were co-cultured with MSCs for days seven and 14. Tumour necrosis factor alpha (TNFα), cartilage oligomeric matrix protein (COMP) and matrix metalloproteinase-3 (MMP-3) levels were analysed in the supernatants. Untargeted metabolomic analyses were performed in the collected tissues and co-culture media of the experiment groups. TNFα concentrations were lower in IPFP-MSC and Sy-MSC had lower than OACs on day 14. Likewise, MMP-3 decreased in the same groups on day seven and day 14 (p = 0.036). Metabolomic analysis showed distinct profiles in the tissues and metabolic changes in the co-culture media. The extracellular environment of MSCs derived from the IPFP, Sy and S have distinct features and effects on OACs.
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Affiliation(s)
- Levend Karaçoban
- Department of Sports Medicine, Hacettepe University Faculty of Medicine, Ankara, Türkiye
| | - Merve Gizer
- Department of Stem Cell Sciences, Graduate School of Health Sciences, Hacettepe University, Ankara, Türkiye
- MEMS Center, Middle East Technical University, Ankara, Türkiye
| | - Bilge Başak Fidan
- Department of Analytical Chemistry, Hacettepe University Faculty of Pharmacy, Ankara, Türkiye
| | - Ozan Kaplan
- Department of Analytical Chemistry, Hacettepe University Faculty of Pharmacy, Ankara, Türkiye
| | - Mustafa Çelebier
- Department of Analytical Chemistry, Hacettepe University Faculty of Pharmacy, Ankara, Türkiye
| | - Petek Korkusuz
- MEMS Center, Middle East Technical University, Ankara, Türkiye
- Department of Histology and Embryology, Hacettepe University Faculty of Medicine, Ankara, Türkiye
| | - Egemen Turhan
- Department of Orthopaedic Surgery and Traumatology, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Feza Korkusuz
- Department of Sports Medicine, Hacettepe University Faculty of Medicine, Ankara, Türkiye
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Menssen DM, Feenstra JC, Janssen RP, Abinzano F, Ito K. Cartilage Organoids from Articular Chondroprogenitor Cells and Their Potential to Produce Neo-Hyaline Cartilage. Cartilage 2025:19476035241313179. [PMID: 39925233 PMCID: PMC11808691 DOI: 10.1177/19476035241313179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 12/13/2024] [Accepted: 12/28/2024] [Indexed: 02/11/2025] Open
Abstract
INTRODUCTION The use of autologous human primary articular chondrocytes (hPACs) for repairing damaged cartilage is the golden standard; however, their 2-dimensional (2D) expansion induces dedifferentiation, making it challenging to create hyaline cartilage. Spinner flasks are efficient for generating cartilage organoids, allowing hPACs to proliferate without dedifferentiation; however, porcine notochordal cell-derived matrix (NCM) is needed for aggregation, limiting clinical application. Human articular chondroprogenitor cells (hACPCs) can be expanded many fold while maintaining chondrogenic potential. Therefore, the scalable production of hACPC cartilage organoids without NCM in spinner flasks was investigated in this study. METHODS hPAC organoids with NCM and hACPC organoids using bone morphogenetic protein 9 (BMP-9) were produced in spinner flasks in 14 days. Thereafter, approximately 20 organoids were fused in low adhesive wells for 21 days. Organoids underwent mechanical testing, and both organoids and fused constructs were evaluated using biochemical, histological, and immunohistochemical analysis. RESULTS The hACPCs self-assembled and synthesized abundant extracellular matrix once stimulated with BMP-9. The hPAC and hACPC organoids showed similar mechanical properties, but hACPC organoids and fused constructs showed a more uniform matrix and cell distribution. CONCLUSION The hACPC organoids fused into a neo-hyaline cartilage-like tissue, demonstrating their potential for improved, scalable cartilage tissue repair.
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Affiliation(s)
- Daphne M.A. Menssen
- Orthopaedic Biomechanics, Department of Biomedical Engineering, and Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, The Netherlands
| | - Jeske C.A. Feenstra
- Orthopaedic Biomechanics, Department of Biomedical Engineering, and Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, The Netherlands
| | - Rob P.A. Janssen
- Orthopaedic Biomechanics, Department of Biomedical Engineering, and Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, The Netherlands
- Department of Orthopaedic Surgery and Trauma, Máxima Medical Center Eindhoven-Veldhoven, Eindhoven, The Netherlands
- Department of Paramedical Sciences, Fontys University of Applied Sciences, Eindhoven, The Netherlands
| | - Florencia Abinzano
- Orthopaedic Biomechanics, Department of Biomedical Engineering, and Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, The Netherlands
| | - Keita Ito
- Orthopaedic Biomechanics, Department of Biomedical Engineering, and Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, The Netherlands
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Singer J, Knezic N, Gohring G, Fite O, Christiansen J, Huard J. Synovial mesenchymal stem cells. ORTHOBIOLOGICS 2025:141-154. [DOI: 10.1016/b978-0-12-822902-6.00005-2] [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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Kovács P, Boocock DJ, Coveney C, Mobasheri A, Matta C. Aminooxy Biotin-Based Characterization of the Surfaceome of Chondrogenic Cells. Methods Mol Biol 2025; 2908:65-79. [PMID: 40304903 DOI: 10.1007/978-1-0716-4434-8_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/02/2025]
Abstract
This protocol outlines a comprehensive approach for characterizing the cell surface subproteome of chondroprogenitor cells, based on aminooxy biotinylation followed by mass spectrometry analysis. The first step involves the selective labeling of cell surface proteins with aminooxy biotin on living chondroprogenitor cells, ensuring the specific tagging of glycoproteins on the outer membrane. Subsequently, glycocapture technique is employed to enrich the glycosylated fraction of the cell surface proteins. Following multiple wash steps to reduce contamination with detergents and nonsurface proteins, shotgun mass spectrometry is applied for the quantitative and qualitative analysis of the enriched subproteome, allowing for the identification and characterization of surface proteins. The integration of these techniques offers a comprehensive and sensitive method for profiling the cell surface proteome during chondrogenesis, enabling a deeper understanding of the molecular composition of chondroprogenitor cells. This protocol holds promise for advancing our knowledge of chondrogenesis and may contribute to the identification of potential therapeutic targets for cartilage-related disorders.
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Affiliation(s)
- Patrik Kovács
- Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - David J Boocock
- John van Geest Cancer Research Centre, Nottingham Trent University, Nottingham, UK
| | - Clare Coveney
- John van Geest Cancer Research Centre, Nottingham Trent University, Nottingham, UK
| | - Ali Mobasheri
- Research Unit of Health Sciences and Technology, Faculty of Medicine, University of Oulu, Oulu, Finland
- Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania
- Department of Joint Surgery, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- World Health Organization Collaborating Centre for Public Health Aspects of Musculoskeletal Health and Aging, Université de Liège, Liège, Belgium
| | - Csaba Matta
- Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
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Roseti L, Cavallo C, Desando G, D’Alessandro M, Grigolo B. Forty Years of the Use of Cells for Cartilage Regeneration: The Research Side. Pharmaceutics 2024; 16:1622. [PMID: 39771600 PMCID: PMC11677864 DOI: 10.3390/pharmaceutics16121622] [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: 11/18/2024] [Revised: 12/13/2024] [Accepted: 12/20/2024] [Indexed: 01/11/2025] Open
Abstract
Background: The treatment of articular cartilage damage has always represented a problem of considerable practical interest for orthopedics. Over the years, many surgical techniques have been proposed to induce the growth of repairing tissue and limit degeneration. In 1994, the turning point occurred: implanted autologous cells paved the way for a new treatment option based more on regeneration than repair. Objectives: This review aims to outline biological and clinical advances, from the use of mature adult chondrocytes to cell-derived products, going through progenitor cells derived from bone marrow or adipose tissue and their concentrates for articular cartilage repair. Moreover, it highlights the relevance of gene therapy as a valuable tool for successfully implementing current regenerative treatments, and overcoming the limitations of the local delivery of growth factors. Conclusions: Finally, this review concludes with an outlook on the importance of understanding the role and mechanisms of action of the different cell compounds with a view to implementing personalized treatments.
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Affiliation(s)
| | - Carola Cavallo
- Laboratorio RAMSES, IRCCS Istituto Ortopedico Rizzoli, Via di Barbiano, 1/10, 40136 Bologna, Italy; (L.R.); (G.D.); (M.D.); (B.G.)
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Semerci Sevimli T, Inan U, Mantar D, Guler K, Ahmadova Z, Gulec K, Topal AE. In vitro Chondrogenic Induction Promotes the Expression Level of IL-10 via the TGF-β/SMAD and Canonical Wnt/β-catenin Signaling Pathways in Exosomes Secreted by Human Adipose Tissue-derived Mesenchymal Stem Cells. Cell Biochem Biophys 2024; 82:3741-3750. [PMID: 39266872 DOI: 10.1007/s12013-024-01461-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/23/2024] [Indexed: 09/14/2024]
Abstract
Current treatment approaches cannot exactly regenerate cartilage tissue. Regarding some problems encountered with cell therapy, exosomes are advantageous because of their "cell-free" nature. This study examines the relationship between IL-10 and TGF-β and Canonical Wnt/β-catenin signal pathways in human adipose tissue-derived MSCs exosomes (hAT-MSCs-Exos) after in vitro chondrogenic differentiation. Human adipose tissue-derived mesenchymal stem cells (hAT-MSCs) and, as a control group, human fetal chondroblast cells (hfCCs) were differentiated chondrogenically in vitro. Exosome isolation and characterization analyses were performed. Chondrogenic differentiation was shown by Alcian Blue and Safranin O stainings. The expression levels of IL-10, TGF-β/SMAD signaling pathway genes, and Canonical Wnt/β-catenin signaling pathway genes, which play an essential role in chondrogenesis, were analyzed by RT-qPCR. Conditioned media cytokine levels were measured by using the TGF-β and IL-10 ELISA kits. IL-10 expression was upregulated in both chondrogenic differentiated hAT-MSC-Exos (dhAT-MSC-Exos) (p < 0.0001). In the TGF-β signaling pathway, TGF-β (p < 0.0001), SMAD2 (p < 0.0001), SMAD4 (p < 0.001), ACAN (p < 0.0001), SOX9 (p < 0.05) and COL1A2 (p < 0.0001) expressions were upregulated in dhAT-MSC-Exos. SMAD3 expression was upregulated in non-differentiated hAT-MSC-Exos. In the Canonical Wnt/β-catenin signaling pathway, WNT (p < 0.0001) and CTNNB1(p < 0.0001) expressions were upregulated in dhAT-MSC-Exos. AXIN (p < 0.0001) expression was upregulated in non-differentiated hAT-MSC-Exos. TGF-β and IL-10 levels were higher in dhAT-MSCs) (p < 0.0001). Related to these results, IL-10 may induce TGF-β/SMAD and Canonical Wnt/β-catenin signaling pathways in hAT-MSC exosomes obtained after chondrogenic differentiation. Therefore, using these exosomes for cartilage regeneration can lead to the development of treatment methods.
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Affiliation(s)
- Tugba Semerci Sevimli
- Cellular Therapy and Stem Cell Production Application and Research Center (ESTEM), Eskisehir Osmangazi University, 26040, Eskisehir, Turkey.
| | - Ulukan Inan
- Department of Orthopedics and Traumatology, Faculty of Medicine, Eskisehir Osmangazi University, 26040, Eskisehir, Turkey
| | | | - Kubra Guler
- Department of Biochemistry, School of Pharmacy, Bahcesehir University, Istanbul, Turkey
| | - Zarifa Ahmadova
- Department of Surgery, Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany
| | - Kadri Gulec
- Department of Analytical Chemistry, Faculty of Pharmacy, Anadolu University, 26470, Eskisehir, Turkey
| | - Ahmet Emin Topal
- Department of Biochemistry, School of Pharmacy, Bahcesehir University, Istanbul, Turkey
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Wu KC, Chang YH, Ding DC, Lin SZ. Mesenchymal Stromal Cells for Aging Cartilage Regeneration: A Review. Int J Mol Sci 2024; 25:12911. [PMID: 39684619 PMCID: PMC11641625 DOI: 10.3390/ijms252312911] [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: 11/06/2024] [Revised: 11/28/2024] [Accepted: 11/28/2024] [Indexed: 12/18/2024] Open
Abstract
Cartilage degeneration is a key feature of aging and osteoarthritis, characterized by the progressive deterioration of joint function, pain, and limited mobility. Current treatments focus on symptom relief, not cartilage regeneration. Mesenchymal stromal cells (MSCs) offer a promising therapeutic option due to their capability to differentiate into chondrocytes, modulate inflammation, and promote tissue regeneration. This review explores the potential of MSCs for cartilage regeneration, examining their biological properties, action mechanisms, and applications in preclinical and clinical settings. MSCs derived from bone marrow, adipose tissue, and other sources can self-renew and differentiate into multiple cell types. In aging cartilage, they aid in tissue regeneration by secreting growth factors and cytokines that enhance repair and modulate immune responses. Recent preclinical studies show that MSCs can restore cartilage integrity, reduce inflammation, and improve joint function, although clinical translation remains challenging due to limitations such as cell viability, scalability, and regulatory concerns. Advancements in MSC delivery, including scaffold-based approaches and engineered exosomes, may improve therapeutic effectiveness. Potential risks, such as tumorigenicity and immune rejection, are also discussed, emphasizing the need for optimized treatment protocols and large-scale clinical trials to develop effective, minimally invasive therapies for cartilage regeneration.
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Affiliation(s)
- Kun-Chi Wu
- Department of Orthopedics, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien 970, Taiwan;
| | - Yu-Hsun Chang
- Department of Pediatrics, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien 970, Taiwan;
| | - Dah-Ching Ding
- Department of Obstetrics and Gynecology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien 970, Taiwan
- Institute of Medical Sciences, College of Medicine, Tzu Chi University, Hualien 970, Taiwan
| | - Shinn-Zong Lin
- Department of Neurosurgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien 970, Taiwan
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Cheng R, Xie T, Ma W, Deng P, Liu C, Hong Y, Liu C, Tian J, Xu Y. Application of polydopamine-modified triphasic PLA/PCL-PLGA/Mg(OH) 2-velvet antler polypeptides scaffold loaded with fibrocartilage stem cells for the repair of osteochondral defects. Front Bioeng Biotechnol 2024; 12:1460623. [PMID: 39372430 PMCID: PMC11450761 DOI: 10.3389/fbioe.2024.1460623] [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: 07/06/2024] [Accepted: 09/06/2024] [Indexed: 10/08/2024] Open
Abstract
Articular cartilage defects often involve damage to both the cartilage and subchondral bone, requiring a scaffold that can meet the unique needs of each tissue type and establish an effective barrier between the bone and cartilage. In this study, we used 3D printing technology to fabricate a tri-phasic scaffold composed of PLA/PCL-PLGA/Mg(OH)₂, which includes a cartilage layer, an osteochondral interface, and a bone layer. The scaffold was filled with Velvet antler polypeptides (VAP), and its characterization was assessed using compression testing, XRD, FTIR, SEM, fluorescence microscopy, and EDS. In vitro investigation demonstrated that the scaffold not only supported osteogenesis but also promoted chondrogenic differentiation of fibrocartilage stem cells (FCSCs). n vivo experiments showed that the tri-phasic PLA/PCL-PLGA/Mg(OH)2-VAP scaffold together with FCSC, when transplanted to animal models, increased the recovery of osteochondral defects. Those results demonstrate the promising future of illustrated tri-phasic PLA/PCL-PLGA/Mg(OH)2-VAP scaffold loaded with FCSCs as a new bone and cartilage tissue engineering approach for osteochondral defects treatment.
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Affiliation(s)
- Renyi Cheng
- Department of Orthodontics, Affiliated Stomatology Hospital of Kunming Medical University, Kunming, Yunnan, China
- Yunnan Key Laboratory of Stomatology, Kunming, China
| | - Tao Xie
- Department of Orthodontics, Affiliated Stomatology Hospital of Kunming Medical University, Kunming, Yunnan, China
- Yunnan Key Laboratory of Stomatology, Kunming, China
| | - Wen Ma
- Yunnan Key Laboratory of Stomatology, Kunming, China
- Department of Oral and Maxillofacial Surgery, Affiliated Stomatology Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Peishen Deng
- Department of Orthodontics, Affiliated Stomatology Hospital of Kunming Medical University, Kunming, Yunnan, China
- Yunnan Key Laboratory of Stomatology, Kunming, China
| | - Chaofeng Liu
- Yunnan Key Laboratory of Stomatology, Kunming, China
- Second Clinic, Affiliated Stomatology Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Yuchen Hong
- Department of Orthodontics, Affiliated Stomatology Hospital of Kunming Medical University, Kunming, Yunnan, China
- Yunnan Key Laboratory of Stomatology, Kunming, China
| | - Changyu Liu
- Department of Orthodontics, Affiliated Stomatology Hospital of Kunming Medical University, Kunming, Yunnan, China
- Yunnan Key Laboratory of Stomatology, Kunming, China
| | - Jinjun Tian
- Department of Orthodontics, Affiliated Stomatology Hospital of Kunming Medical University, Kunming, Yunnan, China
- Yunnan Key Laboratory of Stomatology, Kunming, China
| | - Yanhua Xu
- Department of Orthodontics, Affiliated Stomatology Hospital of Kunming Medical University, Kunming, Yunnan, China
- Yunnan Key Laboratory of Stomatology, Kunming, China
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Zhidu S, Ying T, Rui J, Chao Z. Translational potential of mesenchymal stem cells in regenerative therapies for human diseases: challenges and opportunities. Stem Cell Res Ther 2024; 15:266. [PMID: 39183341 PMCID: PMC11346273 DOI: 10.1186/s13287-024-03885-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Accepted: 08/14/2024] [Indexed: 08/27/2024] Open
Abstract
Advances in stem cell technology offer new possibilities for patients with untreated diseases and disorders. Stem cell-based therapy, which includes multipotent mesenchymal stem cells (MSCs), has recently become important in regenerative therapies. MSCs are multipotent progenitor cells that possess the ability to undergo in vitro self-renewal and differentiate into various mesenchymal lineages. MSCs have demonstrated promise in several areas, such as tissue regeneration, immunological modulation, anti-inflammatory qualities, and wound healing. Additionally, the development of specific guidelines and quality control methods that ultimately result in the therapeutic application of MSCs has been made easier by recent advancements in the study of MSC biology. This review discusses the latest clinical uses of MSCs obtained from the umbilical cord (UC), bone marrow (BM), or adipose tissue (AT) in treating various human diseases such as pulmonary dysfunctions, neurological disorders, endocrine/metabolic diseases, skin burns, cardiovascular conditions, and reproductive disorders. Additionally, this review offers comprehensive information regarding the clinical application of targeted therapies utilizing MSCs. It also presents and examines the concept of MSC tissue origin and its potential impact on the function of MSCs in downstream applications. The ultimate aim of this research is to facilitate translational research into clinical applications in regenerative therapies.
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Affiliation(s)
- Song Zhidu
- Department of Ophthalmology, the Second Hospital of Jilin University, No. 218, Ziqiang Street, Nanguan District, Changchun City, Jilin Province, China
| | - Tao Ying
- Department of Anesthesiology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Jiang Rui
- Department of Orthopedics, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Zhang Chao
- Department of Ophthalmology, the Second Hospital of Jilin University, No. 218, Ziqiang Street, Nanguan District, Changchun City, Jilin Province, China.
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12
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Swain HN, Boyce PD, Bromet BA, Barozinksy K, Hance L, Shields D, Olbricht GR, Semon JA. Mesenchymal stem cells in autoimmune disease: A systematic review and meta-analysis of pre-clinical studies. Biochimie 2024; 223:54-73. [PMID: 38657832 DOI: 10.1016/j.biochi.2024.04.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 04/08/2024] [Accepted: 04/20/2024] [Indexed: 04/26/2024]
Abstract
Mesenchymal Stem Cells (MSCs) are of interest in the clinic because of their immunomodulation capabilities, capacity to act upstream of inflammation, and ability to sense metabolic environments. In standard physiologic conditions, they play a role in maintaining the homeostasis of tissues and organs; however, there is evidence that they can contribute to some autoimmune diseases. Gaining a deeper understanding of the factors that transition MSCs from their physiological function to a pathological role in their native environment, and elucidating mechanisms that reduce their therapeutic relevance in regenerative medicine, is essential. We conducted a Systematic Review and Meta-Analysis of human MSCs in preclinical studies of autoimmune disease, evaluating 60 studies that included 845 patient samples and 571 control samples. MSCs from any tissue source were included, and the study was limited to four autoimmune diseases: multiple sclerosis, rheumatoid arthritis, systemic sclerosis, and lupus. We developed a novel Risk of Bias tool to determine study quality for in vitro studies. Using the International Society for Cell & Gene Therapy's criteria to define an MSC, most studies reported no difference in morphology, adhesion, cell surface markers, or differentiation into bone, fat, or cartilage when comparing control and autoimmune MSCs. However, there were reported differences in proliferation. Additionally, 308 biomolecules were differentially expressed, and the abilities to migrate, invade, and form capillaries were decreased. The findings from this study could help to explain the pathogenic mechanisms of autoimmune disease and potentially lead to improved MSC-based therapeutic applications.
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Affiliation(s)
- Hailey N Swain
- Department of Biological Sciences, Missouri University of Science and Technology, USA
| | - Parker D Boyce
- Department of Biological Sciences, Missouri University of Science and Technology, USA
| | - Bradley A Bromet
- Department of Biological Sciences, Missouri University of Science and Technology, USA
| | - Kaiden Barozinksy
- Department of Biological Sciences, Missouri University of Science and Technology, USA
| | - Lacy Hance
- Department of Biological Sciences, Missouri University of Science and Technology, USA
| | - Dakota Shields
- Department of Mathematics and Statistics, Missouri University of Science and Technology, USA
| | - Gayla R Olbricht
- Department of Mathematics and Statistics, Missouri University of Science and Technology, USA
| | - Julie A Semon
- Department of Biological Sciences, Missouri University of Science and Technology, USA.
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13
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Pan W, Li S, Li K, Zhou P. Mesenchymal Stem Cells and Extracellular Vesicles: Therapeutic Potential in Organ Transplantation. Stem Cells Int 2024; 2024:2043550. [PMID: 38708382 PMCID: PMC11068458 DOI: 10.1155/2024/2043550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 04/01/2024] [Accepted: 04/08/2024] [Indexed: 05/07/2024] Open
Abstract
At present, organ transplantation remains the most appropriate therapy for patients with end-stage organ failure. However, the field of organ transplantation is still facing many challenges, including the shortage of organ donors, graft function damage caused by organ metastasis, and antibody-mediated immune rejection. It is therefore urgently necessary to find new and effective treatment. Stem cell therapy has been regarded as a "regenerative medicine technology." Mesenchymal stem cells (MSCs), as the most common source of cells for stem cell therapy, play an important role in regulating innate and adaptive immune responses and have been widely used in clinical trials for the treatment of autoimmune and inflammatory diseases. Increasing evidence has shown that MSCs mainly rely on paracrine pathways to exert immunomodulatory functions. In addition, mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are the main components of paracrine substances of MSCs. Herein, an overview of the application of the function of MSCs and MSC-EVs in organ transplantation will focus on the progress reported in recent experimental and clinical findings and explore their uses for graft preconditioning and recipient immune tolerance regulation. Additionally, the limitations on the use of MSC and MSC-EVs are also discussed, covering the isolation of exosomes and preservation techniques. Finally, the opportunities and challenges for translating MSCs and MSC-EVs into clinical practice of organ transplantation are also evaluated.
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Affiliation(s)
- Wennuo Pan
- Nanfang Hospital, Southern Medical University, Guangzhou 510000, China
| | - Shaohan Li
- Nanfang Hospital, Southern Medical University, Guangzhou 510000, China
| | - Kunsheng Li
- Department of Cardiothoracic Surgery, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
| | - Pengyu Zhou
- Department of Cardiovascular Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510000, China
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14
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Kiany F, Sarafraz N, Tanideh N, Bordbar H, Andisheh-Tadbir A, Zare S, Farshidfar N, Zarei M. Bone repair potential of collagen-poly(3-hydroxybutyrate)-carbon nanotubes scaffold loaded with mesenchymal stem cells for the reconstruction of critical-sized mandibular defects. JOURNAL OF STOMATOLOGY, ORAL AND MAXILLOFACIAL SURGERY 2024; 125:101670. [PMID: 37907130 DOI: 10.1016/j.jormas.2023.101670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Revised: 10/10/2023] [Accepted: 10/25/2023] [Indexed: 11/02/2023]
Abstract
The poor structural stability of collagen (COL) upon hydration poses a significant challenge in tissue engineering (TE). To overcome this limitation, the incorporation of hydrophobic polymers such as poly(3-hydroxybutyrate) (PHB), and nanomaterials such as carbon nanotubes (CNTs) has been explored. In this study, we investigated the physical, chemical, and biological characteristics of COL-based scaffolds modified with PHB and CNTs for bone tissue engineering (BTE) applications. The tensile strength analysis revealed a substantial improvement in the ultimate tensile strength with the addition of 10 % PHB and 4 % CNTs. Scanning electron microscopy (SEM) images depicted a denser and more compact structure resulting from the presence of PHB and CNTs, enhancing the scaffold's mechanical properties. Fourier-transform infrared spectroscopy (FTIR) confirmed the successful incorporation of PHB and CNTs into the composite scaffold, maintaining the chemical integrity of COL. Stereological studies also conducted in a rat model with induced critical-sized bone defects in the mandibular bone further emphasize the substantial increase in bone formation and reduction in defect volume achieved by the scaffold loaded with stem cells. These findings underscore the promising approach to enhance bone healing, using COL-based scaffolds loaded with stem cells, and the favorable results obtained in this study can contribute to the advancement of BTE strategies.
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Affiliation(s)
- Farin Kiany
- Department of Periodontics, Oral and Dental Disease Research Center, School of Dentistry, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Najmeh Sarafraz
- Department of Periodontology, School of Dentistry, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
| | - Nader Tanideh
- Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hossein Bordbar
- Histomorphometry and Stereology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Azadeh Andisheh-Tadbir
- Department of Oral and Maxillofacial Pathology, School of Dentistry, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Shahrokh Zare
- Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Nima Farshidfar
- Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Moein Zarei
- Department of Polymer and Biomaterials Science, West Pomeranian University of Technology, Szczecin, Poland.
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15
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Casado-Losada I, Acosta M, Schädl B, Priglinger E, Wolbank S, Nürnberger S. Unlocking Potential: Low Bovine Serum Albumin Enhances the Chondrogenicity of Human Adipose-Derived Stromal Cells in Pellet Cultures. Biomolecules 2024; 14:413. [PMID: 38672430 PMCID: PMC11048491 DOI: 10.3390/biom14040413] [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: 02/21/2024] [Revised: 03/23/2024] [Accepted: 03/26/2024] [Indexed: 04/28/2024] Open
Abstract
Bovine serum albumin (BSA) plays a crucial role in cell culture media, influencing cellular processes such as proliferation and differentiation. Although it is commonly included in chondrogenic differentiation media, its specific function remains unclear. This study explores the effect of different BSA concentrations on the chondrogenic differentiation of human adipose-derived stromal/stem cells (hASCs). hASC pellets from six donors were cultured under chondrogenic conditions with three BSA concentrations. Surprisingly, a lower BSA concentration led to enhanced chondrogenesis. The degree of this effect was donor-dependent, classifying them into two groups: (1) high responders, forming at least 35% larger, differentiated pellets with low BSA in comparison to high BSA; (2) low responders, which benefitted only slightly from low BSA doses with a decrease in pellet size and marginal differentiation, indicative of low intrinsic differentiation potential. In all cases, increased chondrogenesis was accompanied by hypertrophy under low BSA concentrations. To the best of our knowledge, this is the first study showing improved chondrogenicity and the tendency for hypertrophy with low BSA concentration compared to standard levels. Once the tendency for hypertrophy is understood, the determination of BSA concentration might be used to tune hASC chondrogenic or osteogenic differentiation.
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Affiliation(s)
- Isabel Casado-Losada
- Department of Orthopedics and Trauma-Surgery, Division of Trauma-Surgery, Medical University of Vienna, 1090 Vienna, Austria; (I.C.-L.); (M.A.)
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, 1200 Vienna, Austria (E.P.); (S.W.)
- Austrian Cluster for Tissue Regeneration, 1200 Vienna, Austria
| | - Melanie Acosta
- Department of Orthopedics and Trauma-Surgery, Division of Trauma-Surgery, Medical University of Vienna, 1090 Vienna, Austria; (I.C.-L.); (M.A.)
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, 1200 Vienna, Austria (E.P.); (S.W.)
| | - Barbara Schädl
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, 1200 Vienna, Austria (E.P.); (S.W.)
- Austrian Cluster for Tissue Regeneration, 1200 Vienna, Austria
- University Clinic of Dentistry, Medical University of Vienna, 1090 Vienna, Austria
| | - Eleni Priglinger
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, 1200 Vienna, Austria (E.P.); (S.W.)
- Austrian Cluster for Tissue Regeneration, 1200 Vienna, Austria
- Department for Orthopedics and Traumatology, Kepler University Hospital GmbH, Johannes Kepler University Linz, 4020 Linz, Austria
| | - Susanne Wolbank
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, 1200 Vienna, Austria (E.P.); (S.W.)
- Austrian Cluster for Tissue Regeneration, 1200 Vienna, Austria
| | - Sylvia Nürnberger
- Department of Orthopedics and Trauma-Surgery, Division of Trauma-Surgery, Medical University of Vienna, 1090 Vienna, Austria; (I.C.-L.); (M.A.)
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, 1200 Vienna, Austria (E.P.); (S.W.)
- Austrian Cluster for Tissue Regeneration, 1200 Vienna, Austria
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16
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Tjandra KC, Novriansyah R, Sudiasa INS, Ar A, Rahmawati NAD, Dilogo IH. Modified Mesenchymal stem cell, platelet-rich plasma, and hyaluronic acid intervention in early stage osteoarthritis: A systematic review, meta-analysis, and meta-regression of arthroscopic-guided intra-articular approaches. PLoS One 2024; 19:e0295876. [PMID: 38457479 PMCID: PMC10923406 DOI: 10.1371/journal.pone.0295876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 01/25/2024] [Indexed: 03/10/2024] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) hold promise for osteoarthritis (OA) treatment, potentially enhanced by combining them with platelet-rich plasma (PRP) and hyaluronic acid (HA). This study aimed to assess the synergy of MSCs, PRP, and varying HA doses, and determine optimal MSC sources to treat early-stage OA in the perspective of Lysholm score, VAS Score, KSS score, and WOMAC score. METHOD Original articles from 2013 to 2023 were screened from four databases, focusing on clinical trials and randomized controlled trials. The Risk of Bias in Non-randomized Studies-of Interventions (ROB-2) tool evaluated bias, and a PICOS criteria table guided result construction. Revman 5.4 analyzed outcomes such as Lysholm score, VAS score, KSS, WOMAC score, cartilage volume, and defect size using MRI. This systematic review adhered to PRISMA guidelines. RESULT Nine studies met the final inclusion criteria. Meta-analysis revealed a significant improvement in Lysholm score (MD: 17.89; 95% CI: 16.01, 19.77; I2 = 0%, P = 0.56), a notable reduction in VAS score (MD: -2.62; 95% CI: -2.83, -2.41; I2 = 99%, P < 0.00001), elevated KSS (MD: 29.59; 95% CI: 27.66, 31.52; I2 = 95%, P < 0.0001), and reduced WOMAC score (MD: -12.38; 95% CI: -13.75, -11.01; I2 = 99%, P < 0.0001). CONCLUSIONS Arthroscopic guided high-dose subchondral application of primary cultured synovial MSCs in popliteal PRP media with HA effectively regenerates cartilage defects and improves clinical outcomes in early-stage osteoarthritis. Clarification of MSC sources and quantities enhances the understanding of this promising treatment modality.
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Affiliation(s)
- Kevin Christian Tjandra
- Department of Medicine, Faculty of Medicine, Universitas Diponegoro, Semarang, Indonesia
- Kariadi General Hospital, Semarang, Indonesia
| | - Robin Novriansyah
- Kariadi General Hospital, Semarang, Indonesia
- Department of Surgery, Faculty of Medicine, Universitas Diopnegoro, Semarang, Indonesia
| | - I. Nyoman Sebastian Sudiasa
- Department of Medicine, Faculty of Medicine, Universitas Diponegoro, Semarang, Indonesia
- Kariadi General Hospital, Semarang, Indonesia
| | - Ardiyana Ar
- Department of Medicine, Faculty of Medicine, Universitas Diponegoro, Semarang, Indonesia
- Kariadi General Hospital, Semarang, Indonesia
| | - Nurul Azizah Dian Rahmawati
- Department of Medicine, Faculty of Medicine, Universitas Diponegoro, Semarang, Indonesia
- Kariadi General Hospital, Semarang, Indonesia
| | - Ismail Hadisoebroto Dilogo
- Stem Cell Medical Technology Integrated Service Unit, Cipto Mangunkusumo Central Hospital, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia
- Stem Cell and Tissue Engineering Research Cluster Indonesian Medical Education and Research Institute (IMERI) Universitas Indonesia, Jakarta, Indonesia
- Department of Orthopaedic and Traumatology, Cipto Mangunkusumo General Hospital, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia
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17
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Chen Y, Luo X, Kang R, Cui K, Ou J, Zhang X, Liang P. Current therapies for osteoarthritis and prospects of CRISPR-based genome, epigenome, and RNA editing in osteoarthritis treatment. J Genet Genomics 2024; 51:159-183. [PMID: 37516348 DOI: 10.1016/j.jgg.2023.07.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 07/13/2023] [Accepted: 07/15/2023] [Indexed: 07/31/2023]
Abstract
Osteoarthritis (OA) is one of the most common degenerative joint diseases worldwide, causing pain, disability, and decreased quality of life. The balance between regeneration and inflammation-induced degradation results in multiple etiologies and complex pathogenesis of OA. Currently, there is a lack of effective therapeutic strategies for OA treatment. With the development of CRISPR-based genome, epigenome, and RNA editing tools, OA treatment has been improved by targeting genetic risk factors, activating chondrogenic elements, and modulating inflammatory regulators. Supported by cell therapy and in vivo delivery vectors, genome, epigenome, and RNA editing tools may provide a promising approach for personalized OA therapy. This review summarizes CRISPR-based genome, epigenome, and RNA editing tools that can be applied to the treatment of OA and provides insights into the development of CRISPR-based therapeutics for OA treatment. Moreover, in-depth evaluations of the efficacy and safety of these tools in human OA treatment are needed.
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Affiliation(s)
- Yuxi Chen
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510275, China
| | - Xiao Luo
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510275, China
| | - Rui Kang
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510275, China
| | - Kaixin Cui
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510275, China
| | - Jianping Ou
- Center for Reproductive Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, Guangdong 510630, China
| | - Xiya Zhang
- Center for Reproductive Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, Guangdong 510630, China.
| | - Puping Liang
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510275, China.
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18
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Goshima A, Etani Y, Hirao M, Yamakawa S, Okamura G, Miyama A, Takami K, Miura T, Fukuda Y, Kurihara T, Ochiai N, Oyama S, Otani S, Tamaki M, Ishibashi T, Tomita T, Kanamoto T, Nakata K, Okada S, Ebina K. Basic fibroblast growth factor promotes meniscus regeneration through the cultivation of synovial mesenchymal stem cells via the CXCL6-CXCR2 pathway. Osteoarthritis Cartilage 2023; 31:1581-1593. [PMID: 37562758 DOI: 10.1016/j.joca.2023.07.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 06/21/2023] [Accepted: 07/20/2023] [Indexed: 08/12/2023]
Abstract
OBJECTIVE To investigate the efficacy of basic fibroblast growth factor (bFGF) in promoting meniscus regeneration by cultivating synovial mesenchymal stem cells (SMSCs) and to validate the underlying mechanisms. METHODS Human SMSCs were collected from patients with osteoarthritis. Eight-week-old nude rats underwent hemi-meniscectomy, and SMSCs in pellet form, either with or without bFGF (1.0 × 106 cells per pellet), were implanted at the site of meniscus defects. Rats were divided into the control (no transplantation), FGF (-) (pellet without bFGF), and FGF (+) (pellet with bFGF) groups. Different examinations, including assessment of the regenerated meniscus area, histological scoring of the regenerated meniscus and cartilage, meniscus indentation test, and immunohistochemistry analysis, were performed at 4 and 8 weeks after surgery. RESULTS Transplanted SMSCs adhered to the regenerative meniscus. Compared with the control group, the FGF (+) group had larger regenerated meniscus areas, superior histological scores of the meniscus and cartilage, and better meniscus mechanical properties. RNA sequencing of SMSCs revealed that the gene expression of chemokines that bind to CXCR2 was upregulated by bFGF. Furthermore, conditioned medium derived from SMSCs cultivated with bFGF exhibited enhanced cell migration, proliferation, and chondrogenic differentiation, which were specifically inhibited by CXCR2 or CXCL6 inhibitors. CONCLUSION SMSCs cultured with bFGF promoted the expression of CXCL6. This mechanism may enhance cell migration, proliferation, and chondrogenic differentiation, thereby resulting in superior meniscus regeneration and cartilage preservation.
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Affiliation(s)
- Atsushi Goshima
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
| | - Yuki Etani
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
| | - Makoto Hirao
- Department of Orthopaedic Surgery, National Hospital Organization, Osaka Minami Medical Center, 2-1 Kidohigashi-machi, Kawachinagano, Osaka 586-8521, Japan
| | - Satoshi Yamakawa
- Department of Sports Medical Biomechanics, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
| | - Gensuke Okamura
- Department of Orthopaedic Surgery, Osaka Rosai Hospital, 1179-3 Nagasone-cho, Kita-ku, Sakai 591-8025, Japan
| | - Akira Miyama
- Department of Orthopaedic Surgery, Osaka Toneyama Medical Center, 5-1-1 Toneyama, Toyonaka, Osaka 560-8552, Japan
| | - Kenji Takami
- Department of Orthopedic Surgery, Nippon Life Hospital, 2-1-54 Enokojima, Nishi-ku, Osaka 550-0006, Japan
| | - Taihei Miura
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
| | - Yuji Fukuda
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
| | - Takuya Kurihara
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
| | - Nagahiro Ochiai
- Department of Musculoskeletal Regenerative Medicine, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
| | - Shohei Oyama
- Department of Musculoskeletal Regenerative Medicine, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
| | - Shunya Otani
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
| | - Masashi Tamaki
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
| | - Teruya Ishibashi
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
| | - Tetsuya Tomita
- Graduate School of Health Sciences, Morinomiya University of Medical Sciences, 1-26-16, Nankou-kita, Suminoe, Osaka, Japan
| | - Takashi Kanamoto
- Department of Health and Sport Sciences, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
| | - Ken Nakata
- Department of Health and Sport Sciences, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
| | - Seiji Okada
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
| | - Kosuke Ebina
- Department of Musculoskeletal Regenerative Medicine, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
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19
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Zhang Q, Zhou W, Yang F, Shi J. Sericin nano-gel agglomerates mimicking the pericellular matrix induce the condensation of mesenchymal stem cells and trigger cartilage micro-tissue formation without exogenous stimulation of growth factors in vitro. Biomater Sci 2023; 11:6480-6491. [PMID: 37671745 DOI: 10.1039/d3bm00501a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/07/2023]
Abstract
Mesenchymal stem cells (MSCs) are excellent seed cells for cartilage tissue engineering and regenerative medicine. Though the condensation of MSCs is the first step of their differentiation into chondrocytes in skeletal development, the process is a challenge in cartilage repairing by MSCs. The pericellular matrix (PCM), a distinct region surrounding the chondrocytes, acts as an extracellular linker among cells and forms the microenvironment of chondrocytes. Inspired by this, sericin nano-gel soft-agglomerates were prepared and used as linkers to induce MSCs to assemble into micro-spheres and differentiate into cartilage-like micro-tissues without exogenous stimulation of growth factors. These sericin nano-gel soft-agglomerates are composed of sericin nano-gels prepared by the chelation of metal ions and sericin protein. The MSCs cultured on 2D culture plates self-assembled into cell-microspheres centered by sericin nano-gel agglomerates. The self-assembly progress of MSCs is superior to the traditional centrifugation to achieve MSC condensation due to its facility, friendliness to MSCs and avoidance of the side-effects of growth factors. The analysis of transcriptomic results suggested that sericin nano-gel agglomerates offered a soft mechanical stimulation to MSCs similar to that of the PCM to chondrocytes and triggered some signaling pathways as associated with MSC chondrogenesis. The strategy of utilizing biomaterials to mimic the PCM as a linker and as a mechanical micro-environment and to induce cell aggregation and trigger the differentiation of MSCs can be employed to drive 3D cellular organization and micro-tissue fabrication in vitro. These cartilage micro-masses reported in this study can be potential candidates for cartilage repairing, cellular building blocks for 3D bio-printing and a model for cartilage development and drug screening.
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Affiliation(s)
- Qing Zhang
- College of Sericulture, Textile and Biomass Sciences, State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, 400715, China.
- School of Materials Science and Engineering, Zhejiang University, Hangzhou 310027, China
| | - Wei Zhou
- College of Sericulture, Textile and Biomass Sciences, State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, 400715, China.
| | - Futing Yang
- College of Sericulture, Textile and Biomass Sciences, State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, 400715, China.
| | - Jifeng Shi
- College of Sericulture, Textile and Biomass Sciences, State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, 400715, China.
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20
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Αnatolitou A, Μavrogenis AF, Sideri KI, Psalla D, Krystalli AA, Prassinos NN. Comparison of allogeneic mesenchymal stem cells therapeutic potentials in rabbits' cartilage defects: Μacroscopic and histological outcomes. Res Vet Sci 2023; 162:104948. [PMID: 37478792 DOI: 10.1016/j.rvsc.2023.104948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 06/12/2023] [Accepted: 07/01/2023] [Indexed: 07/23/2023]
Abstract
Mesenchymal stem cells are safe and effective for treating joint injuries. However, the most suitable cell source remains controversial. This randomized controlled, double-blind study aimed to evaluate the potentials of rabbit allogeneic bone marrow- (BMSCs), adipose- (ASCs) and synovial membrane- (SDSCs) derived stem cells encapsulated in fibrin glue (FG) in vivo. The therapeutic properties of fibrin glue in critical-sized osteochondral defects (ODs) were also investigated. A 3 × 3 mm-sized OD was created in the femoral patellar groove on both knees of New Zealand rabbits, except from the left knees of the control group in which the OD was 2 × 3mm. The rabbits were randomly divided into four groups (right/left knee): 3 × 3 mm / 2 × 3 mm-sized OD control group, FG/FG with ASCs group, FG/FG with BMSCs group, FG/FG with SDSCs group. The International Cartilage Repair Society (ICRS) and the O'Driscoll scales were used to evaluate tissue characteristics after 12 weeks. FG promoted the production of reparative tissue with superior macroscopic features. Allogeneic MSCs combined with FG improved the macroscopic and histological scores more than the FG groups. The tissue in the SDSCs group was macroscopically and histologically better than the ASCs and BMSCs groups. The ICRS score differed among the SDSCs and the ASCs groups, while the empty critical-sized ODs were filled with inferior tissue compared to smaller ones. The preclinical feasibility of stem cells for OD regeneration in rabbits and the osteochondrogenic superiority of SDSCs was demonstrated. Additional tests and extended studies are required to reassure the long-term safety of these findings.
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Affiliation(s)
- A Αnatolitou
- Surgery & Obstetrics Unit, Companion Animal Clinic, School of Veterinary Medicine, Faculty of Health Sciences, Aristotle University, Thessaloniki, Greece.
| | - A F Μavrogenis
- National and Kapodistrian University of Athens, First Department of Orthopaedics, School of Medicine, Athens, Greece
| | - K I Sideri
- Surgery Clinic, School of Veterinary Medicine, University of Thessaly, Karditsa, Greece
| | - D Psalla
- Laboratory of Pathology, School of Veterinary Medicine, Faculty of Health Sciences, Aristotle University, Thessaloniki, Greece
| | - A A Krystalli
- Surgery & Obstetrics Unit, Companion Animal Clinic, School of Veterinary Medicine, Faculty of Health Sciences, Aristotle University, Thessaloniki, Greece
| | - N N Prassinos
- Surgery & Obstetrics Unit, Companion Animal Clinic, School of Veterinary Medicine, Faculty of Health Sciences, Aristotle University, Thessaloniki, Greece
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21
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Cunha NSC, Malvea A, Sadat S, Ibrahim GM, Fehlings MG. Pediatric Spinal Cord Injury: A Review. CHILDREN (BASEL, SWITZERLAND) 2023; 10:1456. [PMID: 37761417 PMCID: PMC10530251 DOI: 10.3390/children10091456] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Revised: 08/14/2023] [Accepted: 08/23/2023] [Indexed: 09/29/2023]
Abstract
A spinal cord injury (SCI) can be a devastating condition in children, with profound implications for their overall health and quality of life. In this review, we aim to provide a concise overview of the key aspects associated with SCIs in the pediatric population. Firstly, we discuss the etiology and epidemiology of SCIs in children, highlighting the diverse range of causes. We explore the unique anatomical and physiological characteristics of the developing spinal cord that contribute to the specific challenges faced by pediatric patients. Next, we delve into the clinical presentation and diagnostic methods, emphasizing the importance of prompt and accurate diagnosis to facilitate appropriate interventions. Furthermore, we approach the multidisciplinary management of pediatric SCIs, encompassing acute medical care, surgical interventions, and ongoing supportive therapies. Finally, we explore emerging research as well as innovative therapies in the field, and we emphasize the need for continued advancements in understanding and treating SCIs in children to improve their functional independence and overall quality of life.
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Affiliation(s)
| | - Anahita Malvea
- Division of Neurosurgery, Krembil Neuroscience Centre, University Health Network, Toronto, ON M5T 2S8, Canada;
| | - Sarah Sadat
- Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A1, Canada;
| | - George M. Ibrahim
- Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON M5G 1E8, Canada;
- Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON M5S 1A1, Canada
| | - Michael G. Fehlings
- Division of Neurosurgery, Krembil Neuroscience Centre, University Health Network, Toronto, ON M5T 2S8, Canada;
- Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON M5S 1A1, Canada
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22
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Volova LT, Kotelnikov GP, Shishkovsky I, Volov DB, Ossina N, Ryabov NA, Komyagin AV, Kim YH, Alekseev DG. 3D Bioprinting of Hyaline Articular Cartilage: Biopolymers, Hydrogels, and Bioinks. Polymers (Basel) 2023; 15:2695. [PMID: 37376340 DOI: 10.3390/polym15122695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 05/29/2023] [Accepted: 05/30/2023] [Indexed: 06/29/2023] Open
Abstract
The musculoskeletal system, consisting of bones and cartilage of various types, muscles, ligaments, and tendons, is the basis of the human body. However, many pathological conditions caused by aging, lifestyle, disease, or trauma can damage its elements and lead to severe disfunction and significant worsening in the quality of life. Due to its structure and function, articular (hyaline) cartilage is the most susceptible to damage. Articular cartilage is a non-vascular tissue with constrained self-regeneration capabilities. Additionally, treatment methods, which have proven efficacy in stopping its degradation and promoting regeneration, still do not exist. Conservative treatment and physical therapy only relieve the symptoms associated with cartilage destruction, and traditional surgical interventions to repair defects or endoprosthetics are not without serious drawbacks. Thus, articular cartilage damage remains an urgent and actual problem requiring the development of new treatment approaches. The emergence of biofabrication technologies, including three-dimensional (3D) bioprinting, at the end of the 20th century, allowed reconstructive interventions to get a second wind. Three-dimensional bioprinting creates volume constraints that mimic the structure and function of natural tissue due to the combinations of biomaterials, living cells, and signal molecules to create. In our case-hyaline cartilage. Several approaches to articular cartilage biofabrication have been developed to date, including the promising technology of 3D bioprinting. This review represents the main achievements of such research direction and describes the technological processes and the necessary biomaterials, cell cultures, and signal molecules. Special attention is given to the basic materials for 3D bioprinting-hydrogels and bioinks, as well as the biopolymers underlying the indicated products.
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Affiliation(s)
- Larisa T Volova
- Research and Development Institute of Biotechnologies, Samara State Medical University, Chapayevskaya St. 89, 443099 Samara, Russia
| | - Gennadiy P Kotelnikov
- Research and Development Institute of Biotechnologies, Samara State Medical University, Chapayevskaya St. 89, 443099 Samara, Russia
| | - Igor Shishkovsky
- Skolkovo Institute of Science and Technology, Moscow 121205, Russia
| | - Dmitriy B Volov
- Research and Development Institute of Biotechnologies, Samara State Medical University, Chapayevskaya St. 89, 443099 Samara, Russia
| | - Natalya Ossina
- Research and Development Institute of Biotechnologies, Samara State Medical University, Chapayevskaya St. 89, 443099 Samara, Russia
| | - Nikolay A Ryabov
- Research and Development Institute of Biotechnologies, Samara State Medical University, Chapayevskaya St. 89, 443099 Samara, Russia
| | - Aleksey V Komyagin
- Research and Development Institute of Biotechnologies, Samara State Medical University, Chapayevskaya St. 89, 443099 Samara, Russia
| | - Yeon Ho Kim
- RokitHealth Care Ltd., 9, Digital-ro 10-gil, Geumcheon-gu, Seoul 08514, Republic of Korea
| | - Denis G Alekseev
- Research and Development Institute of Biotechnologies, Samara State Medical University, Chapayevskaya St. 89, 443099 Samara, Russia
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23
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Ravi S, Chokkakula LPP, Giri PS, Korra G, Dey SR, Rath SN. 3D Bioprintable Hypoxia-Mimicking PEG-Based Nano Bioink for Cartilage Tissue Engineering. ACS APPLIED MATERIALS & INTERFACES 2023; 15:19921-19936. [PMID: 37058130 DOI: 10.1021/acsami.3c00389] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/03/2023]
Abstract
As hypoxia plays a significant role in the formation and maintenance of cartilage tissue, aiming to develop native hypoxia-mimicking tissue engineering scaffolds is an efficient method to treat articular cartilage (AC) defects. Cobalt (Co) is documented for its hypoxic-inducing effects in vitro by stabilizing the hypoxia-inducible factor-1α (HIF-1α), a chief regulator of stem cell fate. Considering this, we developed a novel three-dimensional (3D) bioprintable hypoxia-mimicking nano bioink wherein cobalt nanowires (Co NWs) were incorporated into the poly(ethylene glycol) diacrylate (PEGDA) hydrogel system as a hypoxia-inducing agent and encapsulated with umbilical cord-derived mesenchymal stem cells (UMSCs). In the current study, we investigated the impact of Co NWs on the chondrogenic differentiation of UMSCs in the PEGDA hydrogel system. Herein, the hypoxia-mimicking nano bioink (PEGDA+Co NW) was rheologically optimized to bioprint geometrically stable cartilaginous constructs. The bioprinted 3D constructs were evaluated for their physicochemical characterization, swelling-degradation behavior, mechanical properties, cell proliferation, and the expression of chondrogenic markers by histological, immunofluorescence, and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) methods. The results disclosed that, compared to the control (PEGDA) group, the hypoxia-mimicking nano bioink (PEGDA+Co NW) group outperformed in print fidelity and mechanical properties. Furthermore, live/dead staining, double-stranded DNA (dsDNA) content, and glycosaminoglycans (GAGs) content demonstrated that adding low amounts of Co NWs (<20 ppm) into PEGDA hydrogel system supported UMSC adhesion, proliferation, and differentiation. Histological and immunofluorescence staining of the PEGDA+Co NW bioprinted structures revealed the production of type 2 collagen (COL2) and sulfated GAGs, rendering it a feasible option for cartilage repair. It was further corroborated by a significant upregulation of the hypoxia-mediated chondrogenic and downregulation of the hypertrophic/osteogenic marker expression. In conclusion, the hypoxia-mimicking hydrogel system, including PEGDA and Co2+ ions, synergistically directs the UMSCs toward the chondrocyte lineage without using expensive growth factors and provides an alternative strategy for translational applications in the cartilage tissue engineering field.
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Affiliation(s)
- Subhashini Ravi
- Regenerative Medicine and Stem cell Laboratory (RMS), Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Kandi 502284, Telangana, India
| | - L P Pavithra Chokkakula
- Department of Materials Science and Metallurgical Engineering, Indian Institute of Technology Hyderabad, Kandi 502284, Telangana, India
| | - Pravin Shankar Giri
- Regenerative Medicine and Stem cell Laboratory (RMS), Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Kandi 502284, Telangana, India
| | - Gayathri Korra
- Department of Obstetrics and Gynecology, Sri Manjeera Super Specialty Hospital, Sangareddy 502001, Medak, Telangana, India
| | - Suhash Ranjan Dey
- Department of Materials Science and Metallurgical Engineering, Indian Institute of Technology Hyderabad, Kandi 502284, Telangana, India
| | - Subha Narayan Rath
- Regenerative Medicine and Stem cell Laboratory (RMS), Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Kandi 502284, Telangana, India
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24
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Takács R, Kovács P, Ebeid RA, Almássy J, Fodor J, Ducza L, Barrett-Jolley R, Lewis R, Matta C. Ca2+-Activated K+ Channels in Progenitor Cells of Musculoskeletal Tissues: A Narrative Review. Int J Mol Sci 2023; 24:ijms24076796. [PMID: 37047767 PMCID: PMC10095002 DOI: 10.3390/ijms24076796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 04/01/2023] [Accepted: 04/04/2023] [Indexed: 04/08/2023] Open
Abstract
Musculoskeletal disorders represent one of the main causes of disability worldwide, and their prevalence is predicted to increase in the coming decades. Stem cell therapy may be a promising option for the treatment of some of the musculoskeletal diseases. Although significant progress has been made in musculoskeletal stem cell research, osteoarthritis, the most-common musculoskeletal disorder, still lacks curative treatment. To fine-tune stem-cell-based therapy, it is necessary to focus on the underlying biological mechanisms. Ion channels and the bioelectric signals they generate control the proliferation, differentiation, and migration of musculoskeletal progenitor cells. Calcium- and voltage-activated potassium (KCa) channels are key players in cell physiology in cells of the musculoskeletal system. This review article focused on the big conductance (BK) KCa channels. The regulatory function of BK channels requires interactions with diverse sets of proteins that have different functions in tissue-resident stem cells. In this narrative review article, we discuss the main ion channels of musculoskeletal stem cells, with a focus on calcium-dependent potassium channels, especially on the large conductance BK channel. We review their expression and function in progenitor cell proliferation, differentiation, and migration and highlight gaps in current knowledge on their involvement in musculoskeletal diseases.
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Affiliation(s)
- Roland Takács
- Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary
| | - Patrik Kovács
- Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary
| | - Rana Abdelsattar Ebeid
- Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary
| | - János Almássy
- Department of Physiology, Faculty of Medicine, Semmelweis University, H-1428 Budapest, Hungary
| | - János Fodor
- Department of Physiology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary
| | - László Ducza
- Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary
| | - Richard Barrett-Jolley
- Department of Musculoskeletal Biology, Faculty of Health and Life Sciences, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool L69 3GA, UK
| | - Rebecca Lewis
- Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, UK
| | - Csaba Matta
- Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary
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25
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Goh D, Yang Y, Lee EH, Hui JHP, Yang Z. Managing the Heterogeneity of Mesenchymal Stem Cells for Cartilage Regenerative Therapy: A Review. Bioengineering (Basel) 2023; 10:bioengineering10030355. [PMID: 36978745 PMCID: PMC10045936 DOI: 10.3390/bioengineering10030355] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Revised: 03/12/2023] [Accepted: 03/12/2023] [Indexed: 03/18/2023] Open
Abstract
Articular cartilage defects commonly result from trauma and are associated with significant morbidity. Since cartilage is an avascular, aneural, and alymphatic tissue with a poor intrinsic healing ability, the regeneration of functional hyaline cartilage remains a difficult clinical problem. Mesenchymal stem cells (MSCs) are multipotent cells with multilineage differentiation potential, including the ability to differentiate into chondrocytes. Due to their availability and ease of ex vivo expansion, clinicians are increasingly applying MSCs in the treatment of cartilage lesions. However, despite encouraging pre-clinical and clinical data, inconsistencies in MSC proliferative and chondrogenic potential depending on donor, tissue source, cell subset, culture conditions, and handling techniques remain a key barrier to widespread clinical application of MSC therapy in cartilage regeneration. In this review, we highlight the strategies to manage the heterogeneity of MSCs ex vivo for more effective cartilage repair, including reducing the MSC culture expansion period, and selecting MSCs with higher chondrogenic potential through specific genetic markers, surface markers, and biophysical attributes. The accomplishment of a less heterogeneous population of culture-expanded MSCs may improve the scalability, reproducibility, and standardisation of MSC therapy for clinical application in cartilage regeneration.
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Affiliation(s)
- Doreen Goh
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, NUHS Tower block Level 11, Singapore 119288, Singapore
- NUS Tissue Engineering Program, Life Sciences Institute, National University of Singapore, 27 Medical Drive, DSO (Kent Ridge) Building, Level 4, Singapore 11751, Singapore
| | - Yanmeng Yang
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, NUHS Tower block Level 11, Singapore 119288, Singapore
- NUS Tissue Engineering Program, Life Sciences Institute, National University of Singapore, 27 Medical Drive, DSO (Kent Ridge) Building, Level 4, Singapore 11751, Singapore
- Critical Analytics for Manufacturing Personalised-Medicine, Singapore-MIT Alliance for Research and Technology, Singapore 138602, Singapore
| | - Eng Hin Lee
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, NUHS Tower block Level 11, Singapore 119288, Singapore
- NUS Tissue Engineering Program, Life Sciences Institute, National University of Singapore, 27 Medical Drive, DSO (Kent Ridge) Building, Level 4, Singapore 11751, Singapore
- Critical Analytics for Manufacturing Personalised-Medicine, Singapore-MIT Alliance for Research and Technology, Singapore 138602, Singapore
| | - James Hoi Po Hui
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, NUHS Tower block Level 11, Singapore 119288, Singapore
- NUS Tissue Engineering Program, Life Sciences Institute, National University of Singapore, 27 Medical Drive, DSO (Kent Ridge) Building, Level 4, Singapore 11751, Singapore
| | - Zheng Yang
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, NUHS Tower block Level 11, Singapore 119288, Singapore
- NUS Tissue Engineering Program, Life Sciences Institute, National University of Singapore, 27 Medical Drive, DSO (Kent Ridge) Building, Level 4, Singapore 11751, Singapore
- Critical Analytics for Manufacturing Personalised-Medicine, Singapore-MIT Alliance for Research and Technology, Singapore 138602, Singapore
- Correspondence: ; Tel.: +65-6516-5398
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26
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Protocols and Techniques for Orthobiologic Procedures. Phys Med Rehabil Clin N Am 2023; 34:105-115. [DOI: 10.1016/j.pmr.2022.08.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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27
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Gregory DA, Fricker ATR, Mitrev P, Ray M, Asare E, Sim D, Larpnimitchai S, Zhang Z, Ma J, Tetali SSV, Roy I. Additive Manufacturing of Polyhydroxyalkanoate-Based Blends Using Fused Deposition Modelling for the Development of Biomedical Devices. J Funct Biomater 2023; 14:jfb14010040. [PMID: 36662087 PMCID: PMC9865795 DOI: 10.3390/jfb14010040] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/26/2022] [Accepted: 12/30/2022] [Indexed: 01/12/2023] Open
Abstract
In the last few decades Additive Manufacturing has advanced and is becoming important for biomedical applications. In this study we look at a variety of biomedical devices including, bone implants, tooth implants, osteochondral tissue repair patches, general tissue repair patches, nerve guidance conduits (NGCs) and coronary artery stents to which fused deposition modelling (FDM) can be applied. We have proposed CAD designs for these devices and employed a cost-effective 3D printer to fabricate proof-of-concept prototypes. We highlight issues with current CAD design and slicing and suggest optimisations of more complex designs targeted towards biomedical applications. We demonstrate the ability to print patient specific implants from real CT scans and reconstruct missing structures by means of mirroring and mesh mixing. A blend of Polyhydroxyalkanoates (PHAs), a family of biocompatible and bioresorbable natural polymers and Poly(L-lactic acid) (PLLA), a known bioresorbable medical polymer is used. Our characterisation of the PLA/PHA filament suggest that its tensile properties might be useful to applications such as stents, NGCs, and bone scaffolds. In addition to this, the proof-of-concept work for other applications shows that FDM is very useful for a large variety of other soft tissue applications, however other more elastomeric MCL-PHAs need to be used.
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28
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Lin W, Yang Z, Shi L, Wang H, Pan Q, Zhang X, Zhang P, Lin S, Li G. Alleviation of osteoarthritis by intra-articular transplantation of circulating mesenchymal stem cells. Biochem Biophys Res Commun 2022; 636:25-32. [PMID: 36332479 DOI: 10.1016/j.bbrc.2022.10.064] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 09/20/2022] [Accepted: 10/18/2022] [Indexed: 11/19/2022]
Abstract
This study aimed to evaluate the efficacy of intra-articular delivery of peripheral blood derived mesenchymal stromal cells (PB-MSCs) on the progression of trauma-induced osteoarthritis (OA) in mice. Adult male C57BL/6J mice subjected to destabilization of the medial meniscus surgeries (DMM) were randomly divided into four groups: sham surgery group; vehicle control group (treated with saline), PBMSC-treated group, or adipose tissue derived MSCs (AD-MSC)-treated group (n = 4 per group). PB-MSCs and AD-MSCs were harvested and cultured following previously established protocols, and pre-labeled with BrdU for 48 h before transplantation. PB-MSCs or AD-MSCs (5 × 105 cells/mouse; passage 3-5) were intra-articular injected into the right knee joints thrice post-surgery. The mice were euthanized at 8 weeks post-surgery and knee joint samples were collected for micro-CT and histological examinations. PB-MSCs administration significantly reduced subchondral bone volume comparing to the vehicle control group. Safranin O staining showed that PB-MSCs treatment ameliorated degeneration of articular cartilage, which was comparable to AD-MSCs treatment. The expression of catabolic marker MMP13 was significantly reduced in articular cartilage of the PB-MSCs treated group comparing to that of the vehicle control group. Co-expression of BrdU and Sox9 indicated that injected PB-MSCs differentiated in chondrocytes in situ, along with reduced levels of IL-6 within peripheral sera of PB-MSCs- and AD-MSCs-treated mice. Therefore, administration of PB-MSCs or AD-MSCs attenuated trauma-induced OA progression through inhibiting cartilage degradation and inflammation. PB-MSCs are ideal cell source for treating cartilage-associated diseases.
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Affiliation(s)
- Weiping Lin
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, PR China; Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, PR China
| | - Zhengmeng Yang
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, PR China; Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, PR China
| | - Liu Shi
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, PR China; Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, PR China
| | - Haixing Wang
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, PR China; Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, PR China
| | - Qi Pan
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, PR China; Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, PR China
| | - Xiaoting Zhang
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, PR China; Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, PR China
| | - Peng Zhang
- Institute of Translational and Medical Research and Development Center, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, PR China
| | - Sien Lin
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, PR China; Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, PR China; Orthopaedic Center, Affiliated Hospital of Guangdong Medical University, Guangdong Medical University, Zhanjiang, 524002, PR China.
| | - Gang Li
- Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, PR China; Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, PR China; Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, 518057, PR China.
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29
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Miguel F, Barbosa F, Ferreira FC, Silva JC. Electrically Conductive Hydrogels for Articular Cartilage Tissue Engineering. Gels 2022; 8:710. [PMID: 36354618 PMCID: PMC9689960 DOI: 10.3390/gels8110710] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 10/30/2022] [Accepted: 11/01/2022] [Indexed: 09/10/2023] Open
Abstract
Articular cartilage is a highly specialized tissue found in diarthrodial joints, which is crucial for healthy articular motion. Despite its importance, articular cartilage has limited regenerative capacities, and the degeneration of this tissue is a leading cause of disability worldwide, with hundreds of millions of people affected. As current treatment options for cartilage degeneration remain ineffective, tissue engineering has emerged as an exciting approach to create cartilage substitutes. In particular, hydrogels seem to be suitable candidates for this purpose due to their biocompatibility and high customizability, being able to be tailored to fit the biophysical properties of native cartilage. Furthermore, these hydrogel matrices can be combined with conductive materials in order to simulate the natural electrochemical properties of articular cartilage. In this review, we highlight the most common conductive materials combined with hydrogels and their diverse applications, and then present the current state of research on the development of electrically conductive hydrogels for cartilage tissue engineering. Finally, the main challenges and future perspectives for the application of electrically conductive hydrogels on articular cartilage repair strategies are also discussed.
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Affiliation(s)
- Filipe Miguel
- iBB—Institute for Bioengineering and Biosciences and Department of Bioengineering, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
- Associate Laboratory i4HB—Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
| | - Frederico Barbosa
- iBB—Institute for Bioengineering and Biosciences and Department of Bioengineering, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
- Associate Laboratory i4HB—Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
| | - Frederico Castelo Ferreira
- iBB—Institute for Bioengineering and Biosciences and Department of Bioengineering, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
- Associate Laboratory i4HB—Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
| | - João Carlos Silva
- iBB—Institute for Bioengineering and Biosciences and Department of Bioengineering, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
- Associate Laboratory i4HB—Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
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30
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Zhao J, Meng H, Liao S, Su Y, Guo L, Wang A, Xu W, Zhou H, Peng J. Therapeutic effect of human umbilical cord mesenchymal stem cells in early traumatic osteonecrosis of the femoral head. J Orthop Translat 2022; 37:126-142. [PMID: 36313533 PMCID: PMC9582590 DOI: 10.1016/j.jot.2022.09.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Revised: 09/10/2022] [Accepted: 09/13/2022] [Indexed: 11/23/2022] Open
Abstract
Background Osteonecrosis of the femoral head (ONFH) is a refractory disease due to its unclear pathomechanism. Therapies during the early stage of ONFH have not achieved satisfactory results. Therefore, this study aims to explore the available evidence for the therapeutic effect of human umbilical cord mesenchymal stem cells (HUCMSCs) on early-stage traumatic ONFH. Methods Early-stage traumatic ONFH was established. The femoral heads of rats were then locally administered HUCMSCs. Four weeks and eight weeks after surgery, bone repair of the necrotic area in the femoral head was analyzed to evaluate the therapeutic effect of HUCMSCs using micro-CT, histopathological staining, immunofluorescence staining, Luminex. Results HUCMSCs were still present in the femoral head four weeks later, and the morphological, micro-CT and histopathological outcomes in the 4-week HUCMSC-treated group were better than those in the model, NS and 8-week HUCMSC-treated groups. Local transplantation of HUCMSCs promoted bone repair and prevented bone loss in the necrotic area of the femoral head. Conclusions HUCMSCs can survive and positively affect the femoral head through local transplantation in early-stage traumatic ONFH. The conclusions of this study can provide a treatment option for patients who have ONFH and can serve as basic research on the advanced development of this disease. The Translational potential of this article The study indicated that the positive effect of exogenous HUCMSCs in the treatment of early-stage traumatic ONFH provides the solid basis and guidance for the clinical application of HUCMSCs.
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Affiliation(s)
- Jun Zhao
- Institute of Orthopedics, Chinese PLA General Hospital, Beijing Key Laboratory (No BZ0128), Beijing Key Lab of Regenerative Medicine in Orthopedics Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Beijing, 100853, China
| | - Haoye Meng
- Institute of Orthopedics, Chinese PLA General Hospital, Beijing Key Laboratory (No BZ0128), Beijing Key Lab of Regenerative Medicine in Orthopedics Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Beijing, 100853, China
| | - Sida Liao
- Institute of Orthopedics, Chinese PLA General Hospital, Beijing Key Laboratory (No BZ0128), Beijing Key Lab of Regenerative Medicine in Orthopedics Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Beijing, 100853, China
| | - Yaoyu Su
- Institute of Orthopedics, Chinese PLA General Hospital, Beijing Key Laboratory (No BZ0128), Beijing Key Lab of Regenerative Medicine in Orthopedics Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Beijing, 100853, China
| | - Li Guo
- The Eight Medical Center of PLA General Hospital, China
| | - Aiyuan Wang
- Institute of Orthopedics, Chinese PLA General Hospital, Beijing Key Laboratory (No BZ0128), Beijing Key Lab of Regenerative Medicine in Orthopedics Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Beijing, 100853, China
| | - Wenjing Xu
- Institute of Orthopedics, Chinese PLA General Hospital, Beijing Key Laboratory (No BZ0128), Beijing Key Lab of Regenerative Medicine in Orthopedics Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Beijing, 100853, China
| | - Hao Zhou
- Institute of Orthopedics, Chinese PLA General Hospital, Beijing Key Laboratory (No BZ0128), Beijing Key Lab of Regenerative Medicine in Orthopedics Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Beijing, 100853, China
| | - Jiang Peng
- Institute of Orthopedics, Chinese PLA General Hospital, Beijing Key Laboratory (No BZ0128), Beijing Key Lab of Regenerative Medicine in Orthopedics Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Beijing, 100853, China,Corresponding author.
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Liu T, Zhu W, Zhang X, He C, Liu X, Xin Q, Chen K, Wang H. Recent Advances in Cell and Functional Biomaterial Treatment for Spinal Cord Injury. BIOMED RESEARCH INTERNATIONAL 2022; 2022:5079153. [PMID: 35978649 PMCID: PMC9377911 DOI: 10.1155/2022/5079153] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 07/17/2022] [Accepted: 07/25/2022] [Indexed: 12/17/2022]
Abstract
Spinal cord injury (SCI) is a devastating central nervous system disease caused by accidental events, resulting in loss of sensory and motor function. Considering the multiple effects of primary and secondary injuries after spinal cord injury, including oxidative stress, tissue apoptosis, inflammatory response, and neuronal autophagy, it is crucial to understand the underlying pathophysiological mechanisms, local microenvironment changes, and neural tissue functional recovery for preparing novel treatment strategies. Treatment based on cell transplantation has become the forefront of spinal cord injury therapy. The transplanted cells provide physical and nutritional support for the damaged tissue. At the same time, the implantation of biomaterials with specific biological functions at the site of the SCI has also been proved to improve the local inhibitory microenvironment and promote axonal regeneration, etc. The combined transplantation of cells and functional biomaterials for SCI treatment can result in greater neuroprotective and regenerative effects by regulating cell differentiation, enhancing cell survival, and providing physical and directional support for axon regeneration and neural circuit remodeling. This article reviews the pathophysiology of the spinal cord, changes in the microenvironment after injury, and the mechanisms and strategies for spinal cord regeneration and repair. The article will focus on summarizing and discussing the latest intervention models based on cell and functional biomaterial transplantation and the latest progress in combinational therapies in SCI repair. Finally, we propose the future prospects and challenges of current treatment regimens for SCI repair, to provide references for scientists and clinicians to seek better SCI repair strategies in the future.
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Affiliation(s)
- Tianyi Liu
- Department of Neurosurgery, First Hospital of Jilin University, Changchun 130021, China
| | - Wenhao Zhu
- Department of Neurosurgery, First Hospital of Jilin University, Changchun 130021, China
| | - Xiaoyu Zhang
- Department of Neurosurgery, First Hospital of Jilin University, Changchun 130021, China
| | - Chuan He
- Department of Neurosurgery, First Hospital of Jilin University, Changchun 130021, China
| | - Xiaolong Liu
- Department of Neurosurgery, First Hospital of Jilin University, Changchun 130021, China
| | - Qiang Xin
- Department of Neurosurgery, First Hospital of Jilin University, Changchun 130021, China
| | - Kexin Chen
- Institute of Translational Medicine, First Hospital of Jilin University, Changchun 130021, China
| | - Haifeng Wang
- Department of Neurosurgery, First Hospital of Jilin University, Changchun 130021, China
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Zhang X, Sun W, Wu W, Chen M, Ji T, Xu H, Wang Y. Pin1-mediated regulation of articular cartilage stem/progenitor cell aging. Tissue Cell 2022; 76:101765. [PMID: 35227974 DOI: 10.1016/j.tice.2022.101765] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 02/21/2022] [Accepted: 02/21/2022] [Indexed: 12/28/2022]
Abstract
Cartilage stem/progenitor cells (CSPCs) was recently isolated and identified from the cartilage tissue. CSPCs is essential for repair and regeneration of cartilage in osteoarthritis (OA). Aging is a primary risk factor for cartilage damage and joint OA. Although studies have confirmed the link between cell aging and OA, the underlying molecular mechanisms regulating CSPCs aging are not fully understood. In this study, we investigated the role of Pin1 in the aging of rat knee joint CSPCs. We isolated CSPCs from rat knee joints and demonstrated that, in long-term in vitro culture, Pin1 protein levels are significantly reduced. At the same time, expression of the senescence-related β-galactosidase and the senescence marker p16INK4A were markedly elevated. In addition, Pin1 overexpression reversed the progression of cellular senescence, as evidenced by the down-regulation of senescence-related β-galactosidase, increased EdU positive cells and diminished levels of p16INK4A. In contrast, Pin1 siRNA incorporation promoted CSPCs senescence. In addition, we also observed the distribution of cell cycles through flow cytometry and revealed that Pin1 deficiency results in cell cycle arrest in the G1 phase, suggesting severe lack of proliferation ability, a sign of cellular senescence. Collectively, these results validated that Pin1 is an essential regulator of CSPCs aging.
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Affiliation(s)
- Xiao Zhang
- Department of Orthopaedics, Affiliated Hospital of Nantong University, Nantong University, Nantong, Jiangsu, 226001, China; Medical College, Nantong University, Nantong, Jiangsu, 226001, China
| | - Weiwei Sun
- Department of Orthopaedics, Affiliated Hospital of Nantong University, Nantong University, Nantong, Jiangsu, 226001, China; Medical College, Nantong University, Nantong, Jiangsu, 226001, China
| | - Weijie Wu
- Department of Orthopaedics, The Sixth People's Hospital of Nantong, Nantong, Jiangsu, 226001, China
| | - Minhao Chen
- Department of Orthopaedics, Affiliated Hospital of Nantong University, Nantong University, Nantong, Jiangsu, 226001, China
| | - Tianyi Ji
- Department of Orthopaedics, Affiliated Hospital of Nantong University, Nantong University, Nantong, Jiangsu, 226001, China; Medical College, Nantong University, Nantong, Jiangsu, 226001, China
| | - Hua Xu
- Department of Orthopaedics, Affiliated Hospital of Nantong University, Nantong University, Nantong, Jiangsu, 226001, China.
| | - Youhua Wang
- Department of Orthopaedics, Affiliated Hospital of Nantong University, Nantong University, Nantong, Jiangsu, 226001, China.
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Synovial mesenchymal progenitor derived aggrecan regulates cartilage homeostasis and endogenous repair capacity. Cell Death Dis 2022; 13:470. [PMID: 35585042 PMCID: PMC9117284 DOI: 10.1038/s41419-022-04919-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 05/03/2022] [Accepted: 05/05/2022] [Indexed: 12/14/2022]
Abstract
Aggrecan is a critical component of the extracellular matrix of all cartilages. One of the early hallmarks of osteoarthritis (OA) is the loss of aggrecan from articular cartilage followed by degeneration of the tissue. Mesenchymal progenitor cell (MPC) populations in joints, including those in the synovium, have been hypothesized to play a role in the maintenance and/or repair of cartilage, however, the mechanism by which this may occur is unknown. In the current study, we have uncovered that aggrecan is secreted by synovial MPCs from healthy joints yet accumulates inside synovial MPCs within OA joints. Using human synovial biopsies and a rat model of OA, we established that this observation in aggrecan metabolism also occurs in vivo. Moreover, the loss of the "anti-proteinase" molecule alpha-2 macroglobulin (A2M) inhibits aggrecan secretion in OA synovial MPCs, whereas overexpressing A2M rescues the normal secretion of aggrecan. Using mice models of OA and cartilage repair, we have demonstrated that intra-articular injection of aggrecan into OA joints inhibits cartilage degeneration and stimulates cartilage repair respectively. Furthermore, when synovial MPCs overexpressing aggrecan were transplanted into injured joints, increased cartilage regeneration was observed vs. wild-type MPCs or MPCs with diminished aggrecan expression. Overall, these results suggest that aggrecan secreted from joint-associated MPCs may play a role in tissue homeostasis and repair of synovial joints.
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Ma J, Sun Y, Zhou H, Li X, Bai Y, Liang C, Jia X, Zhang P, Yang L. Animal Models of Femur Head Necrosis for Tissue Engineering and Biomaterials Research. Tissue Eng Part C Methods 2022; 28:214-227. [PMID: 35442092 DOI: 10.1089/ten.tec.2022.0043] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Femur head necrosis, also known as osteonecrosis of the femoral head (ONFH), is a widespread disabling pathology mostly affecting young and middle-aged population and one of the major causes of total hip arthroplasty in the elderly. Currently, there are limited number of different clinical or medication options for the treatment or the reversal of progressive ONFH, but their clinical outcomes are neither satisfactory nor consistent. In pursuit of more reliable therapeutic strategies for ONFH, including recently emerged tissue engineering and biomaterials approaches, in vivo animal models are extremely important for therapeutic efficacy evaluation and mechanistic exploration. Based on the better understanding of pathogenesis of ONFH, animal modeling method has evolved into three major routes, including steroid-, alcohol-, and injury/trauma-induced osteonecrosis, respectively. There is no consensus yet on a standardized ONFH animal model for tissue engineering and biomaterial research; therefore, appropriate animal modeling method should be carefully selected depending on research purposes and scientific hypotheses. In this work, mainstream types of ONFH animal model and their modeling techniques are summarized, showing both merits and demerits for each. In addition, current studies and experimental techniques of evaluating therapeutic efficacy on the treatment of ONFH using animal models are also summarized, along with discussions on future directions related to tissue engineering and biomaterial research. Impact statement Exploration of tissue engineering and biomaterial-based therapeutic strategy for the treatment of femur head necrosis is important since there are limited options available with satisfactory clinical outcomes. To promote the translation of these technologies from benchwork to bedside, animal model should be carefully selected to provide reliable results and clinical outcome prediction. Therefore, osteonecrosis of the femoral head animal modeling methods as well as associated tissue engineering and biomaterial research are overviewed and discussed in this work, as an attempt to provide guidance for model selection and optimization in tissue engineering and biomaterial translational studies.
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Affiliation(s)
- Jiali Ma
- School of Materials Science and Engineering, Hebei University of Technology, Tianjin, People's Republic of China
| | - Yuting Sun
- Department of Anatomy and Histology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, People's Republic of China
| | - Huan Zhou
- School of Materials Science and Engineering, Hebei University of Technology, Tianjin, People's Republic of China.,Center for Health Sciences and Engineering, School of Health Sciences and Biomedical Engineering, Hebei University of Technology, Tianjin, People's Republic of China
| | - Xinle Li
- Department of Anatomy and Histology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, People's Republic of China
| | - Yanjie Bai
- School of Chemical Engineering, Hebei University of Technology, Tianjin, People's Republic of China
| | - Chunyong Liang
- School of Materials Science and Engineering, Hebei University of Technology, Tianjin, People's Republic of China.,Changzhou Blon Minimally Invasive Medical Device Technology Co. Ltd., Jiangsu, People's Republic of China
| | - Xiaowei Jia
- School of Materials Science and Engineering, Hebei University of Technology, Tianjin, People's Republic of China
| | - Ping Zhang
- Department of Anatomy and Histology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, People's Republic of China
| | - Lei Yang
- School of Materials Science and Engineering, Hebei University of Technology, Tianjin, People's Republic of China.,Center for Health Sciences and Engineering, School of Health Sciences and Biomedical Engineering, Hebei University of Technology, Tianjin, People's Republic of China
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Liu Y, Schwam J, Chen Q. Senescence-Associated Cell Transition and Interaction (SACTAI): A Proposed Mechanism for Tissue Aging, Repair, and Degeneration. Cells 2022; 11:1089. [PMID: 35406653 PMCID: PMC8997723 DOI: 10.3390/cells11071089] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/21/2022] [Accepted: 03/22/2022] [Indexed: 02/01/2023] Open
Abstract
Aging is a broad process that occurs as a time-dependent functional decline and tissue degeneration in living organisms. On a smaller scale, aging also exists within organs, tissues, and cells. As the smallest functional unit in living organisms, cells "age" by reaching senescence where proliferation stops. Such cellular senescence is achieved through replicative stress, telomere erosion and stem cell exhaustion. It has been shown that cellular senescence is key to tissue degradation and cell death in aging-related diseases (ARD). However, senescent cells constitute only a small percentage of total cells in the body, and they are resistant to death during aging. This suggests that ARD may involve interaction of senescent cells with non-senescent cells, resulting in senescence-triggered death of non-senescent somatic cells and tissue degeneration in aging organs. Here, based on recent research evidence from our laboratory and others, we propose a mechanism-Senescence-Associated Cell Transition and Interaction (SACTAI)-to explain how cell heterogeneity arises during aging and how the interaction between somatic cells and senescent cells, some of which are derived from aging somatic cells, results in cell death and tissue degeneration.
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Affiliation(s)
| | | | - Qian Chen
- Laboratory of Molecular Biology and Nanomedicine, Department of Orthopaedics, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI 02903, USA; (Y.L.); (J.S.)
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Liu X, Liu Y, He H, Xiang W, He C. Human adipose and synovial mesenchymal stem cells improve osteoarthritis in rats by reducing chondrocyte reactive oxygen species and inhibiting inflammatory response. J Clin Lab Anal 2022; 36:e24353. [PMID: 35312120 PMCID: PMC9102617 DOI: 10.1002/jcla.24353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 03/02/2022] [Accepted: 03/08/2022] [Indexed: 12/01/2022] Open
Abstract
Background We explored the therapeutic effects of Adipose‐derived mesenchymal stem cells (ADMSCs) and Synovial‐derived mesenchymal stem cells (SDMSCs) on osteoarthritis (OA). Methods SDMSCs and ADMSCs were co‐cultured with chondrocytes and stimulated with interleukin (IL)‐1β. An OA model was established on rats by intra‐articular injection with ADMSCs and SDMSCs. After 8 weeks, the joint diameter difference was detected, and histological staining was used to observe the pathological changes in cartilage tissue. Enzyme‐linked immunosorbent assay (ELISA) was used to detect the expressions of IL‐6, tumor necrosis factor (TNF)‐α and IL‐1β in joint fluid. The expressions of COL2A1, Aggrecan, Matrix metalloproteinase (MMP)‐13, SOX9, IL‐6, TNF‐α and IL‐1β were detected by qRT‐PCR and Western blotting in cartilage tissue. Reactive oxygen species (ROS) content in cells and cartilage tissues was detected by ROS kit. Results SDMSCs and ADMSCs co‐cultured with chondrocytes could reduce MMP‐13 expression, increase the expressions of COL2A1, Aggrecan and SOX9, as well as reverse the effects of IL‐1β on promoting ROS content and inflammatory factors levels. After the OA model was established, the injection of ADMSCs and SDMSCs reduced the differences in joint diameter and tissue lesions in OA rats. The OA model led to increased levels of IL‐6, TNF‐α and IL‐1β in joint fluid and cartilage tissue, while the injection of ADMSCs and SDMSCs inhibited the inflammatory factor levels in OA rats, and increased the expressions of COL2A1, Aggrecan and SOX9 in OA rats. Conclusion ADMSCs and SDMSCs improve osteoarthritis in rats by reducing chondrocyte ROS and inhibiting inflammatory response.
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Affiliation(s)
- Xunzhi Liu
- Orthopedics Department First Affiliated Hospital of Gannan Medical University Ganzhou City China
| | - Yaqing Liu
- Pediatric Department First Affiliated Hospital of Gannan Medical University Ganzhou City China
| | - Huabin He
- Orthopedics Department First Affiliated Hospital of Gannan Medical University Ganzhou City China
| | - Weiwei Xiang
- Orthopedics Department First Affiliated Hospital of Gannan Medical University Ganzhou City China
| | - Cheng He
- Orthopedics Department First Affiliated Hospital of Gannan Medical University Ganzhou City China
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Velarde F, Ezquerra S, Delbruyere X, Caicedo A, Hidalgo Y, Khoury M. Mesenchymal stem cell-mediated transfer of mitochondria: mechanisms and functional impact. Cell Mol Life Sci 2022; 79:177. [PMID: 35247083 PMCID: PMC11073024 DOI: 10.1007/s00018-022-04207-3] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Revised: 01/27/2022] [Accepted: 02/11/2022] [Indexed: 12/13/2022]
Abstract
There is a steadily growing interest in the use of mitochondria as therapeutic agents. The use of mitochondria derived from mesenchymal stem/stromal cells (MSCs) for therapeutic purposes represents an innovative approach to treat many diseases (immune deregulation, inflammation-related disorders, wound healing, ischemic events, and aging) with an increasing amount of promising evidence, ranging from preclinical to clinical research. Furthermore, the eventual reversal, induced by the intercellular mitochondrial transfer, of the metabolic and pro-inflammatory profile, opens new avenues to the understanding of diseases' etiology, their relation to both systemic and local risk factors, and also leads to new therapeutic tools for the control of inflammatory and degenerative diseases. To this end, we illustrate in this review, the triggers and mechanisms behind the transfer of mitochondria employed by MSCs and the underlying benefits as well as the possible adverse effects of MSCs mitochondrial exchange. We relay the rationale and opportunities for the use of these organelles in the clinic as cell-based product.
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Affiliation(s)
- Francesca Velarde
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
- Laboratory of Nano-Regenerative Medicine, Faculty of Medicine, Universidad de los Andes, Santiago, Chile
- Cells for Cells and REGENERO, The Chilean Consortium for Regenerative Medicine, Santiago, Chile
- Faculty of Medicine, Universidad de los Andes, Santiago, Chile
| | - Sarah Ezquerra
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
- Laboratory of Nano-Regenerative Medicine, Faculty of Medicine, Universidad de los Andes, Santiago, Chile
- Cells for Cells and REGENERO, The Chilean Consortium for Regenerative Medicine, Santiago, Chile
| | - Xavier Delbruyere
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
- Laboratory of Nano-Regenerative Medicine, Faculty of Medicine, Universidad de los Andes, Santiago, Chile
- Cells for Cells and REGENERO, The Chilean Consortium for Regenerative Medicine, Santiago, Chile
| | - Andres Caicedo
- Universidad San Francisco de Quito USFQ, Colegio de Ciencias de la Salud, Escuela de Medicina, Quito, Ecuador
- Universidad San Francisco de Quito USFQ, Instituto de Investigaciones en Biomedicina iBioMed, Quito, Ecuador
- Mito-Act Research Consortium, Quito, Ecuador
- Sistemas Médicos SIME, Universidad San Francisco de Quito USFQ, Quito, Ecuador
| | - Yessia Hidalgo
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile.
- Laboratory of Nano-Regenerative Medicine, Faculty of Medicine, Universidad de los Andes, Santiago, Chile.
- Cells for Cells and REGENERO, The Chilean Consortium for Regenerative Medicine, Santiago, Chile.
| | - Maroun Khoury
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile.
- Laboratory of Nano-Regenerative Medicine, Faculty of Medicine, Universidad de los Andes, Santiago, Chile.
- Cells for Cells and REGENERO, The Chilean Consortium for Regenerative Medicine, Santiago, Chile.
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Mesenchymal Stem Cells Based Treatment in Dental Medicine: A Narrative Review. Int J Mol Sci 2022; 23:ijms23031662. [PMID: 35163584 PMCID: PMC8836082 DOI: 10.3390/ijms23031662] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 01/29/2022] [Accepted: 01/29/2022] [Indexed: 02/01/2023] Open
Abstract
Application of mesenchymal stem cells (MSC) in regenerative therapeutic procedures is becoming an increasingly important topic in medicine. Since the first isolation of dental tissue-derived MSC, there has been an intense investigation on the characteristics and potentials of these cells in regenerative dentistry. Their multidifferentiation potential, self-renewal capacity, and easy accessibility give them a key role in stem cell-based therapy. So far, several different dental stem cell types have been discovered and their potential usage is found in most of the major dental medicine branches. These cells are also researched in multiple fields of medicine for the treatment of degenerative and inflammatory diseases. In this review, we summarized dental MSC sources and analyzed their treatment modalities with particular emphasis on temporomandibular joint osteoarthritis (TMJ OA).
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Sharma S, Jeyaraman M, Muthu S. Role of stem cell therapy in neurosciences. ESSENTIALS OF EVIDENCE-BASED PRACTICE OF NEUROANESTHESIA AND NEUROCRITICAL CARE 2022:163-179. [DOI: 10.1016/b978-0-12-821776-4.00012-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
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Labusca L, Herea DD, Emanuela Minuti A, Stavila C, Danceanu C, Plamadeala P, Chiriac H, Lupu N. Magnetic Nanoparticles and Magnetic Field Exposure Enhances Chondrogenesis of Human Adipose Derived Mesenchymal Stem Cells But Not of Wharton Jelly Mesenchymal Stem Cells. Front Bioeng Biotechnol 2021; 9:737132. [PMID: 34733830 PMCID: PMC8558412 DOI: 10.3389/fbioe.2021.737132] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 09/10/2021] [Indexed: 02/05/2023] Open
Abstract
Purpose: Iron oxide based magnetic nanoparticles (MNP) are versatile tools in biology and medicine. Adipose derived mesenchymal stem cells (ADSC) and Wharton Jelly mesenchymal stem cells (WJMSC) are currently tested in different strategies for regenerative regenerative medicine (RM) purposes. Their superiority compared to other mesenchymal stem cell consists in larger availability, and superior proliferative and differentiation potential. Magnetic field (MF) exposure of MNP-loaded ADSC has been proposed as a method to deliver mechanical stimulation for increasing conversion to musculoskeletal lineages. In this study, we investigated comparatively chondrogenic conversion of ADSC-MNP and WJMSC with or without MF exposure in order to identify the most appropriate cell source and differentiation protocol for future cartilage engineering strategies. Methods: Human primary ADSC and WJMSC from various donors were loaded with proprietary uncoated MNP. The in vitro effect on proliferation and cellular senescence (beta galactosidase assay) in long term culture was assessed. In vitro chondrogenic differentiation in pellet culture system, with or without MF exposure, was assessed using pellet histology (Safranin O staining) as well as quantitative evaluation of glycosaminoglycan (GAG) deposition per cell. Results: ADSC-MNP complexes displayed superior proliferative capability and decreased senescence after long term (28 days) culture in vitro compared to non-loaded ADSC and to WJMSC-MNP. Significant increase in chondrogenesis conversion in terms of GAG/cell ratio could be observed in ADSC-MNP. MF exposure increased glycosaminoglycan deposition in MNP-loaded ADSC, but not in WJMSC. Conclusion: ADSC-MNP display decreased cellular senescence and superior chondrogenic capability in vitro compared to non-loaded cells as well as to WJMSC-MNP. MF exposure further increases ADSC-MNP chondrogenesis in ADSC, but not in WJMSC. Loading ADSC with MNP can derive a successful procedure for obtaining improved chondrogenesis in ADSC. Further in vivo studies are needed to confirm the utility of ADSC-MNP complexes for cartilage engineering.
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Affiliation(s)
- Luminita Labusca
- National Institute of Research and Development for Technical Physics, Iasi, Romania
- Orthopedics and Traumatology Clinic County Emergency Hospital Saint Spiridon, Iasi, Romania
| | - Dumitru-Daniel Herea
- National Institute of Research and Development for Technical Physics, Iasi, Romania
| | - Anca Emanuela Minuti
- National Institute of Research and Development for Technical Physics, Iasi, Romania
- Faculty of Physics, Alexandru Ioan Cuza University, Iasi, Romania
| | - Cristina Stavila
- National Institute of Research and Development for Technical Physics, Iasi, Romania
- Faculty of Physics, Alexandru Ioan Cuza University, Iasi, Romania
| | - Camelia Danceanu
- National Institute of Research and Development for Technical Physics, Iasi, Romania
- Faculty of Physics, Alexandru Ioan Cuza University, Iasi, Romania
| | - Petru Plamadeala
- Pathology Department County Children Emergency Hospital Saint Mary, Iasi, Romania
| | - Horia Chiriac
- National Institute of Research and Development for Technical Physics, Iasi, Romania
| | - Nicoleta Lupu
- National Institute of Research and Development for Technical Physics, Iasi, Romania
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Di Piazza E, Pandolfi E, Cacciotti I, Del Fattore A, Tozzi AE, Secinaro A, Borro L. Bioprinting Technology in Skin, Heart, Pancreas and Cartilage Tissues: Progress and Challenges in Clinical Practice. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:ijerph182010806. [PMID: 34682564 PMCID: PMC8535210 DOI: 10.3390/ijerph182010806] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 09/29/2021] [Accepted: 10/08/2021] [Indexed: 12/16/2022]
Abstract
Bioprinting is an emerging additive manufacturing technique which shows an outstanding potential for shaping customized functional substitutes for tissue engineering. Its introduction into the clinical space in order to replace injured organs could ideally overcome the limitations faced with allografts. Presently, even though there have been years of prolific research in the field, there is a wide gap to bridge in order to bring bioprinting from "bench to bedside". This is due to the fact that bioprinted designs have not yet reached the complexity required for clinical use, nor have clear GMP (good manufacturing practices) rules or precise regulatory guidelines been established. This review provides an overview of some of the most recent and remarkable achievements for skin, heart, pancreas and cartilage bioprinting breakthroughs while highlighting the critical shortcomings for each tissue type which is keeping this technique from becoming widespread reality.
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Affiliation(s)
- Eleonora Di Piazza
- Multifactorial and Complex Disease Research Area, Preventive and Predictive Medicine Unit, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy; (E.D.P.); (A.E.T.)
| | - Elisabetta Pandolfi
- Multifactorial and Complex Disease Research Area, Preventive and Predictive Medicine Unit, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy; (E.D.P.); (A.E.T.)
- Correspondence:
| | - Ilaria Cacciotti
- Engineering Department, Niccolò Cusano University of Rome, INSTM RU, 00166 Rome, Italy;
| | - Andrea Del Fattore
- Genetics and Rare Diseases Research Area, Bone Physiopathology Research Unit, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy;
| | - Alberto Eugenio Tozzi
- Multifactorial and Complex Disease Research Area, Preventive and Predictive Medicine Unit, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy; (E.D.P.); (A.E.T.)
| | - Aurelio Secinaro
- Clinical Management and Technological Innovations Area, Department of Imaging, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy; (A.S.); (L.B.)
| | - Luca Borro
- Clinical Management and Technological Innovations Area, Department of Imaging, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy; (A.S.); (L.B.)
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Stem Cells in Autologous Microfragmented Adipose Tissue: Current Perspectives in Osteoarthritis Disease. Int J Mol Sci 2021; 22:ijms221910197. [PMID: 34638538 PMCID: PMC8508703 DOI: 10.3390/ijms221910197] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Revised: 09/09/2021] [Accepted: 09/14/2021] [Indexed: 12/13/2022] Open
Abstract
Osteoarthritis (OA) is a chronic debilitating disorder causing pain and gradual degeneration of weight-bearing joints with detrimental effects on cartilage volume as well as cartilage damage, generating inflammation in the joint structure. The etiology of OA is multifactorial. Currently, therapies are mainly addressing the physical and occupational aspects of osteoarthritis using pharmacologic pain treatment and/or surgery to manage the symptomatology of the disease with no specific regard to disease progression or prevention. Herein, we highlight alternative therapeutics for OA specifically considering innovative and encouraging translational methods with the use of adipose mesenchymal stem cells.
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Liu Z, Tamaddon M, Chen SM, Wang H, San Cheong V, Gang F, Sun X, Liu C. Determination of an Initial Stage of the Bone Tissue Ingrowth Into Titanium Matrix by Cell Adhesion Model. Front Bioeng Biotechnol 2021; 9:736063. [PMID: 34589474 PMCID: PMC8473621 DOI: 10.3389/fbioe.2021.736063] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Accepted: 07/21/2021] [Indexed: 11/30/2022] Open
Abstract
For achieving early intervention treatment to help patients delay or avoid joint replacement surgery, a personalized scaffold should be designed coupling the effects of mechanical, fluid mechanical, chemical, and biological factors on tissue regeneration, which results in time- and cost-consuming trial-and-error analyses to investigate the in vivo test and related experimental tests. To optimize the fluid mechanical and material properties to predict osteogenesis and cartilage regeneration for the in vivo and clinical trial, a simulation approach is developed for scaffold design, which is composed of a volume of a fluid model for simulating the bone marrow filling process of the bone marrow and air, as well as a discrete phase model and a cell impingement model for tracking cell movement during bone marrow fillings. The bone marrow is treated as a non-Newtonian fluid, rather than a Newtonian fluid, because of its viscoelastic property. The simulation results indicated that the biofunctional bionic scaffold with a dense layer to prevent the bone marrow flow to the cartilage layer and synovia to flow into the trabecular bone area guarantee good osteogenesis and cartilage regeneration, which leads to high-accuracy in vivo tests in sheep . This approach not only predicts the final bioperformance of the scaffold but also could optimize the scaffold structure and materials by their biochemical, biological, and biomechanical properties.
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Affiliation(s)
- Ziyu Liu
- Division of Surgery & Interventional Science, University College London, Royal National Orthopaedic Hospital, London, United Kingdom
- School of Engineering Medicine, Beihang University, Beijing, China
- Key Laboratory of Advanced Materials of Ministry of Education of China, School of Materials Science and Engineering, Tsinghua University, Beijing, China
| | - Maryam Tamaddon
- Division of Surgery & Interventional Science, University College London, Royal National Orthopaedic Hospital, London, United Kingdom
| | - Shen-Mao Chen
- Division of Surgery & Interventional Science, University College London, Royal National Orthopaedic Hospital, London, United Kingdom
| | - Haoyu Wang
- Division of Surgery & Interventional Science, University College London, Royal National Orthopaedic Hospital, London, United Kingdom
| | - Vee San Cheong
- Insigno Institute of in Silico Medicine and Department of Automatic Control and Systems Engineering, University of Sheffield, Sheffield, United Kingdom
| | - Fangli Gang
- School of Engineering Medicine, Beihang University, Beijing, China
- Key Laboratory of Advanced Materials of Ministry of Education of China, School of Materials Science and Engineering, Tsinghua University, Beijing, China
| | - Xiaodan Sun
- Key Laboratory of Advanced Materials of Ministry of Education of China, School of Materials Science and Engineering, Tsinghua University, Beijing, China
| | - Chaozong Liu
- Division of Surgery & Interventional Science, University College London, Royal National Orthopaedic Hospital, London, United Kingdom
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Shin DI, Kim M, Park DY, Min BH, Yun HW, Chung JY, Min KJ. Motorized Shaver Harvest Results in Similar Cell Yield and Characteristics Compared With Rongeur Biopsy During Arthroscopic Synovium-Derived Mesenchymal Stem Cell Harvest. Arthroscopy 2021; 37:2873-2882. [PMID: 33798652 DOI: 10.1016/j.arthro.2021.03.042] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 03/14/2021] [Accepted: 03/15/2021] [Indexed: 02/02/2023]
Abstract
PURPOSE To compare cell yield and character of synovium-derived mesenchymal stem cell (SDMSC) harvested by 2 different techniques using rongeur and motorized shaver during knee arthroscopy. METHODS This study was performed in 15 patients undergoing partial meniscectomy. Two different techniques were used to harvest SDMSCs in each patient from the synovial membrane at 2 different locations overlying the anterior fat pad, each within 1 minute of harvest time. Cell yield and proliferation rates were evaluated. Cell surface marker analysis was done after passage 2 (P2). Trilineage differentiation potential was evaluated by real-time quantitative polymerase chain reaction and histology. Statistical analysis between the 2 methods was done using the Mann-Whitney U test. RESULTS Wet weight of total harvested tissue was 69.93 (± 20.02) mg versus 378.91 (± 168.87) mg for the rongeur and shaver group, respectively (P < .0001). Mononucleated cell yield was 3.32 (± 0.89) versus 3.18 (± 0.97) × 103 cells/mg, respectively (P = .67). Fluorescence-activated cell sorting analysis revealed similar SDMSC-related cell surface marker expression levels in both groups, with positive expression for CD44, CD73, CD90, and CD105 and decreased expression for CD34 and CD45. Both groups showed similar trilineage differentiation potential in histology. Chondrogenic (SOX9, ACAN, COL2), adipogenic (LPL, PLIN1, PPAR-γ), and osteogenic (OCN, OSX, RUNX2) gene marker expression levels also were similar between both groups. CONCLUSIONS No difference was observed between rongeur biopsy and motorized shaver harvest methods regarding SDMSC yield and cell characteristics. CLINICAL RELEVANCE The current study shows that both rongeur and motorized shaver harvest are safe and effective methods for obtaining SDMSCs. Motorized shaver harvest results in higher volume of tissue acquisition per time, thereby leading to higher number of SDMSCs which may be useful during clinical application.
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Affiliation(s)
- Dong Il Shin
- Cell Therapy Center, Ajou University School of Medicine, Suwon, Republic of Korea; Department of Molecular Science and Technology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Mijin Kim
- Cell Therapy Center, Ajou University School of Medicine, Suwon, Republic of Korea; Department of Molecular Science and Technology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Do Young Park
- Cell Therapy Center, Ajou University School of Medicine, Suwon, Republic of Korea; Department of Orthopedic Surgery, Ajou University School of Medicine, Suwon, Republic of Korea; Department of Biomedical Sciences, Ajou University School of Medicine, Suwon, Republic of Korea.
| | - Byoung-Hyun Min
- Cell Therapy Center, Ajou University School of Medicine, Suwon, Republic of Korea; Department of Molecular Science and Technology, Ajou University School of Medicine, Suwon, Republic of Korea; Department of Orthopedic Surgery, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Hee-Woong Yun
- Cell Therapy Center, Ajou University School of Medicine, Suwon, Republic of Korea; Department of Molecular Science and Technology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Jun Young Chung
- Department of Orthopedic Surgery, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Kyung Jun Min
- Department of Orthopedic Surgery, Ajou University School of Medicine, Suwon, Republic of Korea
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Rahman S, Szojka ARA, Liang Y, Kunze M, Goncalves V, Mulet-Sierra A, Jomha NM, Adesida AB. Inability of Low Oxygen Tension to Induce Chondrogenesis in Human Infrapatellar Fat Pad Mesenchymal Stem Cells. Front Cell Dev Biol 2021; 9:703038. [PMID: 34381784 PMCID: PMC8350173 DOI: 10.3389/fcell.2021.703038] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 06/14/2021] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVE Articular cartilage of the knee joint is avascular, exists under a low oxygen tension microenvironment, and does not self-heal when injured. Human infrapatellar fat pad-sourced mesenchymal stem cells (IFP-MSC) are an arthroscopically accessible source of mesenchymal stem cells (MSC) for the repair of articular cartilage defects. Human IFP-MSC exists physiologically under a low oxygen tension (i.e., 1-5%) microenvironment. Human bone marrow mesenchymal stem cells (BM-MSC) exist physiologically within a similar range of oxygen tension. A low oxygen tension of 2% spontaneously induced chondrogenesis in micromass pellets of human BM-MSC. However, this is yet to be demonstrated in human IFP-MSC or other adipose tissue-sourced MSC. In this study, we explored the potential of low oxygen tension at 2% to drive the in vitro chondrogenesis of IFP-MSC. We hypothesized that 2% O2 will induce stable chondrogenesis in human IFP-MSC without the risk of undergoing endochondral ossification at ectopic sites of implantation. METHODS Micromass pellets of human IFP-MSC were cultured under 2% O2 or 21% O2 (normal atmosphere O2) in the presence or absence of chondrogenic medium with transforming growth factor-β3 (TGFβ3) for 3 weeks. Following in vitro chondrogenesis, the resulting pellets were implanted in immunodeficient athymic nude mice for 3 weeks. RESULTS A low oxygen tension of 2% was unable to induce chondrogenesis in human IFP-MSC. In contrast, chondrogenic medium with TGFβ3 induced in vitro chondrogenesis. All pellets were devoid of any evidence of undergoing endochondral ossification after subcutaneous implantation in athymic mice.
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Affiliation(s)
- Samia Rahman
- Laboratory of Stem Cell Biology and Orthopedic Tissue Engineering, Division of Orthopedic Surgery and Surgical Research, Department of Surgery, University of Alberta, Edmonton, AB, Canada
| | - Alexander R. A. Szojka
- Laboratory of Stem Cell Biology and Orthopedic Tissue Engineering, Division of Orthopedic Surgery and Surgical Research, Department of Surgery, University of Alberta, Edmonton, AB, Canada
| | - Yan Liang
- Laboratory of Stem Cell Biology and Orthopedic Tissue Engineering, Division of Orthopedic Surgery and Surgical Research, Department of Surgery, University of Alberta, Edmonton, AB, Canada
| | - Melanie Kunze
- Laboratory of Stem Cell Biology and Orthopedic Tissue Engineering, Division of Orthopedic Surgery and Surgical Research, Department of Surgery, University of Alberta, Edmonton, AB, Canada
| | - Victoria Goncalves
- Laboratory of Stem Cell Biology and Orthopedic Tissue Engineering, Division of Orthopedic Surgery and Surgical Research, Department of Surgery, University of Alberta, Edmonton, AB, Canada
| | - Aillette Mulet-Sierra
- Laboratory of Stem Cell Biology and Orthopedic Tissue Engineering, Division of Orthopedic Surgery and Surgical Research, Department of Surgery, University of Alberta, Edmonton, AB, Canada
| | - Nadr M. Jomha
- Laboratory of Stem Cell Biology and Orthopedic Tissue Engineering, Division of Orthopedic Surgery and Surgical Research, Department of Surgery, University of Alberta, Edmonton, AB, Canada
| | - Adetola B. Adesida
- Laboratory of Stem Cell Biology and Orthopedic Tissue Engineering, Division of Orthopedic Surgery and Surgical Research, Department of Surgery, University of Alberta, Edmonton, AB, Canada
- Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of Alberta Hospital, Edmonton, AB, Canada
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Chijimatsu R, Miwa S, Okamura G, Miyahara J, Tachibana N, Ishikura H, Higuchi J, Maenohara Y, Tsuji S, Sameshima S, Takagi K, Nakazato K, Kawaguchi K, Yamagami R, Inui H, Taketomi S, Tanaka S, Saito T. Divergence in chondrogenic potential between in vitro and in vivo of adipose- and synovial-stem cells from mouse and human. Stem Cell Res Ther 2021; 12:405. [PMID: 34266496 PMCID: PMC8281654 DOI: 10.1186/s13287-021-02485-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 06/23/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Somatic stem cell transplantation has been performed for cartilage injury, but the reparative mechanisms are still conflicting. The chondrogenic potential of stem cells are thought as promising features for cartilage therapy; however, the correlation between their potential for chondrogenesis in vitro and in vivo remains undefined. The purpose of this study was to investigate the intrinsic chondrogenic condition depends on cell types and explore an indicator to select useful stem cells for cartilage regeneration. METHODS The chondrogenic potential of two different stem cell types derived from adipose tissue (ASCs) and synovium (SSCs) of mice and humans was assessed using bone morphogenic protein-2 (BMP2) and transforming growth factor-β1 (TGFβ1). Their in vivo chondrogenic potential was validated through transplantation into a mouse osteochondral defect model. RESULTS All cell types showed apparent chondrogenesis under the combination of BMP2 and TGFβ1 in vitro, as assessed by the formation of proteoglycan- and type 2 collagen (COL2)-rich tissues. However, our results vastly differed with those observed following single stimulation among species and cell types; apparent chondrogenesis of mouse SSCs was observed with supplementation of BMP2 or TGFβ1, whereas chondrogenesis of mouse ASCs and human SSCs was observed with supplementation of BMP2 not TGFβ1. Human ASCs showed no obvious chondrogenesis following single stimulation. Mouse SSCs showed the formation of hyaline-like cartilage which had less fibrous components (COL1/3) with supplementation of TGFβ1. However, human cells developed COL1/3+ tissues with all treatments. Transcriptomic analysis for TGFβ receptors and ligands of cells prior to chondrogenic induction did not indicate their distinct reactivity to the TGFβ1 or BMP2. In the transplanted site in vivo, mouse SSCs formed hyaline-like cartilage (proteoglycan+/COL2+/COL1-/COL3-) but other cell types mainly formed COL1/3-positive fibrous tissues in line with in vitro reactivity to TGFβ1. CONCLUSION Optimal chondrogenic factors driving chondrogenesis from somatic stem cells are intrinsically distinct among cell types and species. Among them, the response to TGFβ1 may possibly represent the fate of stem cells when locally transplanted into cartilage defects.
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Affiliation(s)
- Ryota Chijimatsu
- Bone and Cartilage Regenerative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Satoshi Miwa
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | | | - Junya Miyahara
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Naohiro Tachibana
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hisatoshi Ishikura
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Junya Higuchi
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yuji Maenohara
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | | | - Shin Sameshima
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kentaro Takagi
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Keiu Nakazato
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kohei Kawaguchi
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Ryota Yamagami
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hiroshi Inui
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Shuji Taketomi
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Sakae Tanaka
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Taku Saito
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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Cartilage from human-induced pluripotent stem cells: comparison with neo-cartilage from chondrocytes and bone marrow mesenchymal stromal cells. Cell Tissue Res 2021; 386:309-320. [PMID: 34241697 PMCID: PMC8557148 DOI: 10.1007/s00441-021-03498-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 06/23/2021] [Indexed: 11/01/2022]
Abstract
Cartilage has little intrinsic capacity for repair, so transplantation of exogenous cartilage cells is considered a realistic option for cartilage regeneration. We explored whether human-induced pluripotent stem cells (hiPSCs) could represent such unlimited cell sources for neo-cartilage comparable to human primary articular chondrocytes (hPACs) or human bone marrow-derived mesenchymal stromal cells (hBMSCs). For this, chondroprogenitor cells (hiCPCs) and hiPSC-derived mesenchymal stromal cells (hiMSCs) were generated from two independent hiPSC lines and characterized by morphology, flow cytometry, and differentiation potential. Chondrogenesis was compared to hBMSCs and hPACs by histology, immunohistochemistry, and RT-qPCR, while similarities were estimated based on Pearson correlations using a panel of 20 relevant genes. Our data show successful differentiations of hiPSC into hiMSCs and hiCPCs. Characteristic hBMSC markers were shared between hBMSCs and hiMSCs, with the exception of CD146 and CD45. However, neo-cartilage generated from hiMSCs showed low resemblances when compared to hBMSCs (53%) and hPACs (39%) characterized by lower collagen type 2 and higher collagen type 1 expression. Contrarily, hiCPC neo-cartilage generated neo-cartilage more similar to hPACs (65%), with stronger expression of matrix deposition markers. Our study shows that taking a stepwise approach to generate neo-cartilage from hiPSCs via chondroprogenitor cells results in strong similarities to neo-cartilage of hPACs within 3 weeks following chondrogenesis, making them a potential candidate for regenerative therapies. Contrarily, neo-cartilage deposited by hiMSCs seems more prone to hypertrophic characteristics compared to hPACs. We therefore compared chondrocytes derived from hiMSCs and hiCPCs with hPACs and hBMSCs to outline similarities and differences between their neo-cartilage and establish their potential suitability for regenerative medicine and disease modelling.
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Wu SC, Chang CH, Chang LH, Wu CW, Chen JW, Chen CH, Lin YS, Chang JK, Ho ML. Simvastatin Enhances the Chondrogenesis But Not the Osteogenesis of Adipose-Derived Stem Cells in a Hyaluronan Microenvironment. Biomedicines 2021; 9:biomedicines9050559. [PMID: 34067739 PMCID: PMC8156330 DOI: 10.3390/biomedicines9050559] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 05/11/2021] [Accepted: 05/14/2021] [Indexed: 11/16/2022] Open
Abstract
Directing adipose-derived stem cells (ADSCs) toward chondrogenesis is critical for ADSC-based articular cartilage regeneration. Simvastatin (SIM) was reported to promote both chondrogenic and osteogenic differentiation of ADSCs by upregulating bone morphogenetic protein-2 (BMP-2). We previously found that ADSC chondrogenesis is initiated and promoted in a hyaluronan (HA) microenvironment (HAM). Here, we further hypothesized that SIM augments HAM-induced chondrogenesis but not osteogenesis of ADSCs. ADSCs were treated with SIM in a HAM (SIM plus HAM) by HA-coated wells or HA-enriched fibrin (HA/Fibrin) hydrogel, and chondrogenic differentiation of ADSCs was evaluated. SIM plus HAM increased chondrogenesis more than HAM or SIM alone, including cell aggregation, chondrogenic gene expression (collagen type II and aggrecan) and cartilaginous tissue formation (collagen type II and sulfated glycosaminoglycan). In contrast, SIM-induced osteogenesis in ADSCs was reduced in SIM plus HAM, including mRNA expression of osteogenic genes, osteocalcin and alkaline phosphatase (ALP), ALP activity and mineralization. SIM plus HAM also showed the most effective increases in the mRNA expression of BMP-2 and transcription factors of SOX-9 and RUNX-2 in ADSCs, while these effects were reversed by CD44 blockade. HAM suppressed the levels of JNK, p-JNK, P38 and p-P38 in ADSCs, and SIM plus HAM also decreased SIM-induced phosphorylated JNK and p38 levels. In addition, SIM enhanced articular cartilage regeneration, as demonstrated by implantation of an ADSCs/HA/Fibrin construct in an ex vivo porcine articular chondral defect model. The results from this study indicate that SIM may be an enhancer of HAM-initiated MSC-based chondrogenesis and avoid osteogenesis.
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Affiliation(s)
- Shun-Cheng Wu
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan; (S.-C.W.); (L.-H.C.); (C.-W.W.); (J.-W.C.); (C.-H.C.); (Y.-S.L.)
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan;
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80701, Taiwan
- Post-Baccalaureate Program in Nursing, Asia University, Taichung 41354, Taiwan
| | - Chih-Hsiang Chang
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan;
| | - Ling-Hua Chang
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan; (S.-C.W.); (L.-H.C.); (C.-W.W.); (J.-W.C.); (C.-H.C.); (Y.-S.L.)
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan;
| | - Che-Wei Wu
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan; (S.-C.W.); (L.-H.C.); (C.-W.W.); (J.-W.C.); (C.-H.C.); (Y.-S.L.)
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan;
| | - Jhen-Wei Chen
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan; (S.-C.W.); (L.-H.C.); (C.-W.W.); (J.-W.C.); (C.-H.C.); (Y.-S.L.)
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan;
| | - Chung-Hwan Chen
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan; (S.-C.W.); (L.-H.C.); (C.-W.W.); (J.-W.C.); (C.-H.C.); (Y.-S.L.)
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan;
- Department of Orthopaedics, College of Medicine, Kaohsiung Medical University, Kaohsiung 80701, Taiwan
- Division of Adult Reconstruction Surgery, Department of Orthopedics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80701, Taiwan
- Department of Orthopedics, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung 80701, Taiwan
| | - Yi-Shan Lin
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan; (S.-C.W.); (L.-H.C.); (C.-W.W.); (J.-W.C.); (C.-H.C.); (Y.-S.L.)
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan;
| | - Je-Ken Chang
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan; (S.-C.W.); (L.-H.C.); (C.-W.W.); (J.-W.C.); (C.-H.C.); (Y.-S.L.)
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan;
- Department of Orthopaedics, College of Medicine, Kaohsiung Medical University, Kaohsiung 80701, Taiwan
- Correspondence: (J.-K.C.); (M.-L.H.)
| | - Mei-Ling Ho
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan; (S.-C.W.); (L.-H.C.); (C.-W.W.); (J.-W.C.); (C.-H.C.); (Y.-S.L.)
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung 80701, Taiwan;
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80701, Taiwan
- Department of Physiology, College of Medicine, Kaohsiung Medical University, Kaohsiung 80701, Taiwan
- Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 80424, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80701, Taiwan
- Correspondence: (J.-K.C.); (M.-L.H.)
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Comparison of the Donor Age-Dependent and In Vitro Culture-Dependent Mesenchymal Stem Cell Aging in Rat Model. Stem Cells Int 2021; 2021:6665358. [PMID: 34093710 PMCID: PMC8140846 DOI: 10.1155/2021/6665358] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 01/12/2021] [Accepted: 04/27/2021] [Indexed: 12/14/2022] Open
Abstract
Clinical experiments suggest that mesenchymal stem cells (MSCs) may be useful for tissue repair therapies or treatment of the autoimmune disorders. There is still lack of consensus concerning the age limit of MSC donors, majority of researchers suggest the autologous MSC therapies of patients not exceeding age limit of 55-60 yrs. The purpose of our study was to compare the selected parameters of MSCs from adipose tissue (adipose stem cell, ASC) collected from young and old rats of ages corresponding to patient's ages 25 yrs. and 80 yrs., respectively. The differences of parameters of ASCs from young and old animals were compared with the differences between ASCs from short-term (3 passage) and long-term (30 passage) in vitro culture. Cell morphology, surface marker expression, growth potential, metabolic activity, β-galactosidase activity, clonogenic potential, angiogenic potential, and differentiation ability of ASCs from young and aged animals and from in vitro cultures at 3rd and 30th passages were compared and analyzed. It may be concluded that ASCs may be applied for autologous transplantations in aged patients. Comparison of ASC aging dynamics depending on host aging or in vitro culture duration suggests that long-term in vitro culture may affect ASCs more than natural aging process of their host. We suggest that ASCs expanded in vitro prior to their clinical use must be carefully screened for the possible aging effects resulting not only from donor age, but from the duration of their in vitro culture.
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Comparison of Osteogenic Differentiation Potential of Human Dental-Derived Stem Cells Isolated from Dental Pulp, Periodontal Ligament, Dental Follicle, and Alveolar Bone. Stem Cells Int 2021; 2021:6631905. [PMID: 33927769 PMCID: PMC8049831 DOI: 10.1155/2021/6631905] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 03/10/2021] [Accepted: 03/24/2021] [Indexed: 01/09/2023] Open
Abstract
Background Mesenchymal stem cells (MSCs) have become promising candidates for regeneration medicine due to their multidifferentiation potential and immunomodulatory ability. Compared with classic MSCs derived from the bone marrow and fat, dental-derived MSCs show high plasticity, accessibility, and applicability. Therefore, they are considered alternative sources for regeneration medicine. Methods Four types of MSCs were isolated from the dental pulp, periodontal ligament, dental follicle, and alveolar bone of the same donor, and there were five different individuals. We analyzed their morphology, immunophenotype, proliferation rate, apoptosis, trilineage differentiation potential, and the gene expression during osteogenic differentiation. Results Our research demonstrated that DPSCs, PDLSCs, DFPCs and ABMMSCs exhibited similar morphology and immunophenotype. DFPCs showed a higher rate of proliferation and apoptosis. When cultured in the trilineage differentiation medium, all types of MSCs presented the differentiation potential of osteogenesis, adipogenesis, and chondrogenesis. Through staining and genetic analysis during osteogenic induction, ABMMSCs and PDLSCs showed the highest osteogenic ability, followed by DPSCs, and DFPCs were the lowest. Conclusions Overall, our results indicated that different dental-derived stem cells possessed different biological characteristics. For bone tissue engineering, ABMMSCs and PDLSCs can be used as optimal candidates of seed cells.
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