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Watanabe M, Asawa Y, Riu D, Sakamoto T, Hoshi K, Hikita A. Identification of mesenchymal stem cell populations with high osteogenic potential using difference in cell division rate. Regen Ther 2025; 28:498-508. [PMID: 39991510 PMCID: PMC11846930 DOI: 10.1016/j.reth.2025.01.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2024] [Revised: 01/13/2025] [Accepted: 01/25/2025] [Indexed: 02/25/2025] Open
Abstract
Introduction In bone regenerative medicine, mesenchymal stem cells (MSCs) have been widely investigated for their potential in bone regeneration. However, MSCs are a heterogeneous cell population containing a variety of cell types, making it difficult to obtain a homogeneous MSC population sufficient for tissue regeneration. Our group previously reported that by selecting rapidly dividing human auricular chondrocytes, it was possible to enrich for more chondrogenic cells. In this study, we aimed to identify a highly osteogenic MSC population by using a similar approach for mouse bone marrow MSCs. Methods Mouse bone marrow MSCs were fluorescently labeled with carboxyfluorescein succinimidyl ester (CFSE) and sorted according to the fluorescence intensity using flow cytometry on day 3 after labeling. To compare the ability to produce bone matrix in vitro, osteogenic differentiation cultures were performed and mineral deposition was confirmed by alizarin red staining. Real-time qPCR was also performed to examine the differences in gene expression between the fast- and slow-dividing cell groups immediately after aliquoting and after osteogenic differentiation. Results Differences in the growth rate of the fractionated cells were maintained after culture. Results of osteogenic differentiation culture and alizarin red staining showed more extensive mineral deposition in the slow cell group than in the fast cell group. Calcium quantification also showed higher absorbance in the slow cell group compared to the fast cell group, indicating higher osteogenic differentiation potential in the slow cell group. Furthermore, real-time qPCR analysis showed that osteocalcin expression was higher in the slow cell group in cells immediately after preparative differentiation. In addition, the expression of osteocalcin and sclerostin were higher in the slow cells after osteogenic differentiation. Conclusion The slow cell population contains many highly differentiated cells that are already more deeply committed to the bone lineage, suggesting that they have higher osteogenic differentiation potential than the fast cell population. This study will contribute to the realization of better bone regenerative medicine by utilizing the high osteogenic differentiation potential of the slow cell population.
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Affiliation(s)
- Maya Watanabe
- Department of Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Yukiyo Asawa
- Division of Tissue Engineering, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Dan Riu
- Division of Tissue Engineering, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Tomoaki Sakamoto
- Division of Tissue Engineering, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Kazuto Hoshi
- Department of Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
- Division of Tissue Engineering, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
- Department of Oral-maxillofacial Surgery, Dentistry and Orthodontics, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Atsuhiko Hikita
- Division of Tissue Engineering, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
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Kaur S, Angrish N, Vasudevan M, Khare G. Global proteomics reveals pathways of mesenchymal stem cells altered by Mycobacterium tuberculosis. Sci Rep 2024; 14:30677. [PMID: 39730375 DOI: 10.1038/s41598-024-75722-5] [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: 03/28/2024] [Accepted: 10/08/2024] [Indexed: 12/29/2024] Open
Abstract
Mycobacterium tuberculosis (M. tb) has a remarkable ability to persist inside host cells. Several studies showed that M. tb infects and survives inside bone marrow mesenchymal stem cells (BM-MSCs) escaping the host immune system. Here, we have identified various cellular pathways that are modulated in human BM-MSCs upon infection with virulent M. tb and the proteomic profile of these cells varies from that of avirulent M. tb infected cells. We found that virulent M. tb infection reshapes host pathways such as stem cell differentiation, alternative splicing, cytokine production, mitochondrial function etc., which might be modulated by M. tb to persist inside this unconventional niche of human BM-MSCs. Additionally, we observed that virulent M. tb infection suppresses various cellular processes. This study uncovers the differences in the host proteomic profiles resulting from the virulent versus avirulent M. tb infection that can pave the way to identify host-directed therapeutic targets for the treatment of tuberculosis.
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Affiliation(s)
- Simran Kaur
- Department of Biochemistry, University of Delhi South Campus, New Delhi, 110021, India
- Children's Hospital of Eastern Ontario Research Institute, Ottawa, Canada
| | - Nupur Angrish
- Department of Biochemistry, University of Delhi South Campus, New Delhi, 110021, India
| | - Madavan Vasudevan
- Genomics and Data Science Unit, Theomics International Pvt. Ltd, Bangalore, 560038, India
| | - Garima Khare
- Department of Biochemistry, University of Delhi South Campus, New Delhi, 110021, India.
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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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Maeda S, Matsumoto M, Segawa K, Iwamoto K, Nakamura N. Development of scaffold-free tissue-engineered constructs derived from mesenchymal stem cells with serum-free media for cartilage repair and long-term preservation. Cytotechnology 2024; 76:595-612. [PMID: 39188648 PMCID: PMC11344744 DOI: 10.1007/s10616-024-00637-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Accepted: 06/18/2024] [Indexed: 08/28/2024] Open
Abstract
Synovial mesenchymal stem cells (sMSCs) have great potential for cartilage repair, but their therapeutic design to avoid adverse effects associated with unknown factors remains a challenge. In addition, because long-term preservation is indispensable to maintain high quality levels until implantation, it is necessary to reduce their fluctuations. This study aimed to investigate the properties and feasibility of novel scaffold-free tissue-engineered constructs using serum-free media and to develop long-term preservation methods. sMSCs were cultured in serum-free media, seeded at high density in a monolayer, and finally developed as a sheet-like construct called "gMSC1". The properties of frozen gMSC1 (Fro-gMSC1) were compared with those of refrigerated gMSC1 (Ref-gMSC1) and then examined by their profile. Chondrogenic differentiation potential was analyzed by quantitative real-time polymerase chain reaction and quantification of glycosaminoglycan content. Xenografts into the cartilage defect model in rats were evaluated by histological staining. gMSC1 showed nearly similar properties independent of the preservation conditions. The animal experiment demonstrated that the defect could be filled with cartilage-like tissue with good integration to the adjacent tissue, suggesting that gMSC1 was formed and replaced the cartilage. Furthermore, several chondrogenesis-related factors were significantly secreted inside and outside gMSC1. Morphological analysis of Fro-gMSC1 revealed comparable quality levels to those of fresh gMSC1. Thus, if cryopreserved, gMSC1, with no complicated materials or processes, could have sustained cartilage repair capacity. gMSC1 is a prominent candidate in novel clinical practice for cartilage repair, allowing for large quantities to be manufactured at one time and preserved for a long term by freezing. Supplementary Information The online version contains supplementary material available at 10.1007/s10616-024-00637-y.
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Affiliation(s)
- Satoshi Maeda
- TWOCELLS Co., Ltd, 1–6-10 Deshio, Minami-ku, Hiroshima, 734–0001 Japan
| | - Masaya Matsumoto
- TWOCELLS Co., Ltd, 1–6-10 Deshio, Minami-ku, Hiroshima, 734–0001 Japan
| | - Kotaro Segawa
- TWOCELLS Co., Ltd, 1–6-10 Deshio, Minami-ku, Hiroshima, 734–0001 Japan
| | - Kaori Iwamoto
- TWOCELLS Co., Ltd, 1–6-10 Deshio, Minami-ku, Hiroshima, 734–0001 Japan
| | - Norimasa Nakamura
- Department of Orthopaedics, Osaka University Graduate School of Medicine, 2–2 Yamadaoka, Suita, Osaka, 565–0871 Japan
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D'Arrigo D, Salerno M, De Marziani L, Boffa A, Filardo G. A call for standardization for secretome and extracellular vesicles in osteoarthritis: results show disease-modifying potential, but protocols are too heterogeneous-a systematic review. Hum Cell 2024; 37:1243-1275. [PMID: 38909330 DOI: 10.1007/s13577-024-01084-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Accepted: 05/22/2024] [Indexed: 06/24/2024]
Abstract
The currently available osteoarthritis (OA) treatments offer symptoms' relief without disease-modifying effects. Increasing evidence supports the role of human mesenchymal stem cells (MSCs) to drive beneficial effects provided by their secretome and extracellular vesicles (EVs), which includes trophic and biologically active factors. Aim of this study was to evaluate the in vitro literature to understand the potential of human secretome and EVs for OA treatment and identify trends, gaps, and potential translational challenges. A systematic review was performed on PubMed, Embase, and Web-of-Science, identifying 58 studies. The effects of secretome and EVs were analysed on osteoarthritic cells regarding anabolic, anti-apoptotic/anti-inflammatory and catabolic/pro-inflammatory/degenerative activity, chondroinduction, and immunomodulation. The results showed that MSC-derived EVs elicit an increase in proliferation and migration, reduction of cell death and inflammation, downregulation of catabolic pathways, regulation of immunomodulation, and promotion of anabolic processes in arthritic cells. However, a high heterogeneity in several technical or more applicative aspects emerged. In conclusion, the use of human secretome and EVs as strategy to address OA processes has overall positive effects and disease-modifying potential. However, it is crucial to reduce protocol variability and strive toward a higher standardization, which will be essential for the translation of this promising OA treatment from the in vitro research setting to the clinical practice.
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Affiliation(s)
- Daniele D'Arrigo
- Regenerative Medicine Technologies Laboratory, EOC, Via Francesco Chiesa 5, 6500, Bellinzona, Switzerland
- Laboratoire Matière et Systèmes Complexes, Université Paris Cité, 45 Rue des Saints Pères, 75006, Paris, France
- Abbelight, Cachan, 191 Av. Aristide Briand, 94230, Cachan, France
| | - Manuela Salerno
- Applied and Translational Research center, IRCCS Istituto Ortopedico Rizzoli, Via di Barbiano 1/10, 40136, Bologna, Italy.
| | - Luca De Marziani
- Clinica Ortopedica e Traumatologica 2, IRCCS Istituto Ortopedico Rizzoli, Via Pupilli 1, 40136, Bologna, Italy
| | - Angelo Boffa
- Clinica Ortopedica e Traumatologica 2, IRCCS Istituto Ortopedico Rizzoli, Via Pupilli 1, 40136, Bologna, Italy
| | - Giuseppe Filardo
- Applied and Translational Research center, IRCCS Istituto Ortopedico Rizzoli, Via di Barbiano 1/10, 40136, Bologna, Italy
- Service of Orthopaedics and Traumatology, Department of Surgery, EOC, Via Tesserete 46, 6900, Lugano, Switzerland
- Università Della Svizzera Italiana, Faculty of Biomedical Sciences, Via Buffi 13, 6900, Lugano, Switzerland
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Kim H, Kim Y, Yun SY, Lee BK. Efficacy of IFN-γ-Primed Umbilical Cord-Derived Mesenchymal Stem Cells on Temporomandibular Joint Osteoarthritis. Tissue Eng Regen Med 2024; 21:473-486. [PMID: 38190096 PMCID: PMC10987468 DOI: 10.1007/s13770-023-00620-2] [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: 11/03/2023] [Revised: 11/22/2023] [Accepted: 11/30/2023] [Indexed: 01/09/2024] Open
Abstract
BACKGROUND Temporomandibular joint osteoarthritis (TMJOA) is a degenerative disease affecting the cartilage and subchondral bone, leading to temporomandibular joint pain and dysfunction. The complex nature of TMJOA warrants effective alternative treatments, and mesenchymal stem cells (MSCs) have shown promise in regenerative therapies. The aim of this study is twofold: firstly, to ascertain the optimal interferon-gamma (IFN-γ)-primed MSC cell line for TMJOA treatment, and secondly, to comprehensively evaluate the therapeutic efficacy of IFN-γ-primed mesenchymal stem cells derived from the human umbilical cord matrix in a rat model of TMJOA. METHODS We analyzed changes in the expression of several key genes associated with OA protection in MSC-secreted compounds. Following this, we performed co-culture experiments using a transwell system to predict gene expression changes in primed MSCs in the TMJOA environment. Subsequently, we investigated the efficacy of the selected IFN-γ-primed human umbilical cord matrix-derived MSCs (hUCM-MSCs) for TMJOA treatment in a rat model. RESULTS IFN-γ-primed MSCs exhibited enhanced expression of IDO, TSG-6, and FGF-2. Moreover, co-culturing with rat OA chondrocytes induced a decrease in pro-inflammatory and extracellular matrix degradation factors. In the rat TMJOA model, IFN-γ-primed MSCs with elevated IDO1, TSG-6, and FGF2 expression exhibited robust anti-inflammatory and therapeutic capacities, promoting the improvement of the inflammatory environment and cartilage regeneration. CONCLUSION These findings underscore the importance of prioritizing the mitigation of the inflammatory milieu in TMJOA treatment and highlight IFN-γ-primed MSCs secreting these three factors as a promising, comprehensive therapeutic strategy.
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Affiliation(s)
- Hyunjeong Kim
- Biomedical Engineering Research Center, Asan Medical Center, Asan Institute for Life Sciences, Seoul, Korea
| | - Yerin Kim
- Asan Medical Center, AMIST, College of Medicine, University of Ulsan, Seoul, Korea
| | - So-Yeon Yun
- Asan Medical Center, AMIST, College of Medicine, University of Ulsan, Seoul, Korea
| | - Bu-Kyu Lee
- Biomedical Engineering Research Center, Asan Medical Center, Asan Institute for Life Sciences, Seoul, Korea.
- Asan Medical Center, AMIST, College of Medicine, University of Ulsan, Seoul, Korea.
- Department of Oral and Maxillofacial Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
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Jeyaraman M, Nallakumarasamy A, Jeyaraman N, Ramasubramanian S. Tissue engineering in chondral defect. COMPUTATIONAL BIOLOGY FOR STEM CELL RESEARCH 2024:361-378. [DOI: 10.1016/b978-0-443-13222-3.00033-2] [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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Razak HRBA, Corona K, Totlis T, Chan LYT, Salreta JF, Sleiman O, Vasso M, Baums MH. Mesenchymal stem cell implantation provides short-term clinical improvement and satisfactory cartilage restoration in patients with knee osteoarthritis but the evidence is limited: a systematic review performed by the early-osteoarthritis group of ESSKA-European knee associates section. Knee Surg Sports Traumatol Arthrosc 2023; 31:5306-5318. [PMID: 37737920 PMCID: PMC10719133 DOI: 10.1007/s00167-023-07575-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 09/05/2023] [Indexed: 09/23/2023]
Abstract
PURPOSE Implantation of mesenchymal stem cells (MSCs) is a potential cell-based modality for cartilage repair. Currently, its clinical use largely surrounds focal cartilage defect repair and intra-articular injections in knee osteoarthritis. The MSCs' implantation efficacy as a treatment option for osteoarthritis remains contentious. This systematic review aims to evaluate studies that focused on MSCs implantation in patients with knee OA to provide a summary of this treatment option outcomes. METHODS A systematic search was performed in PubMed (Medline), Scopus, Cinahl, and the Cochrane Library. Original studies investigating outcomes of MSCs implantations in patients with knee OA were included. Data on clinical outcomes using subjective scores, radiological outcomes, and second-look arthroscopy gradings were extracted. RESULTS Nine studies were included in this review. In all included studies, clinical outcome scores revealed significantly improved functionality and better postoperative pain scores at 2-3 years follow-up. Improved cartilage volume and quality at the lesion site was observed in five studies that included a postoperative magnetic resonance imaging assessment and studies that performed second-look arthroscopy. No major complications or tumorigenesis occurred. Outcomes were consistent in both single MSCs implantation and concurrent HTO with MSCs implantation in cases with excessive varus deformity. CONCLUSION According to the available literature, MSCs implantation in patients with mild to moderate knee osteoarthritis is safe and provides short-term clinical improvement and satisfactory cartilage restoration, either as a standalone procedure or combined with HTO in cases with axial deformity. However, the evidence is limited due to the high heterogeneity among studies and the insufficient number of studies including a control group and mid-term outcomes. LEVEL OF EVIDENCE IV.
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Affiliation(s)
| | - Katia Corona
- Orthopedics and Traumatology, Fondazione Policlinico Universitario A. Gemelli IRCCS-Sacred Heart Catholic University, Rome, Italy
| | - Trifon Totlis
- Thessaloniki Minimally Invasive Surgery (The-MIS) Orthopaedic Centre, St. Luke's Hospital, Thessaloniki, Greece.
- Department of Anatomy and Surgical Anatomy, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece.
| | - Li Yi Tammy Chan
- Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Drive, Singapore, 117597, Singapore
| | - Jose Filipe Salreta
- Orthopaedic and Traumatology Department, Hospital Garcia de Orta, Almada, Portugal
| | - Obeida Sleiman
- Department of Orthopedics, Trauma Surgery and Sports Traumatology, Catholic Clinical Center Ruhr North (KKRN), Dorsten, Germany
| | - Michele Vasso
- Department of Medicine and Health Sciences, University of Molise, Via Francesco De Sanctis, 86100, Campobasso, Italy
| | - Mike H Baums
- Department of Orthopedics, Trauma Surgery and Sports Traumatology, Catholic Clinical Center Ruhr North (KKRN), Dorsten, Germany
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Hamilton M, Wang J, Dhar P, Stehno-Bittel L. Controlled-Release Hydrogel Microspheres to Deliver Multipotent Stem Cells for Treatment of Knee Osteoarthritis. Bioengineering (Basel) 2023; 10:1315. [PMID: 38002439 PMCID: PMC10669156 DOI: 10.3390/bioengineering10111315] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 11/03/2023] [Accepted: 11/12/2023] [Indexed: 11/26/2023] Open
Abstract
Osteoarthritis (OA) is the most common form of joint disease affecting articular cartilage and peri-articular tissues. Traditional treatments are insufficient, as they are aimed at mitigating symptoms. Multipotent Stromal Cell (MSC) therapy has been proposed as a treatment capable of both preventing cartilage destruction and treating symptoms. While many studies have investigated MSCs for treating OA, therapeutic success is often inconsistent due to low MSC viability and retention in the joint. To address this, biomaterial-assisted delivery is of interest, particularly hydrogel microspheres, which can be easily injected into the joint. Microspheres composed of hyaluronic acid (HA) were created as MSC delivery vehicles. Microrheology measurements indicated that the microspheres had structural integrity alongside sufficient permeability. Additionally, encapsulated MSC viability was found to be above 70% over one week in culture. Gene expression analysis of MSC-identifying markers showed no change in CD29 levels, increased expression of CD44, and decreased expression of CD90 after one week of encapsulation. Analysis of chondrogenic markers showed increased expressions of aggrecan (ACAN) and SRY-box transcription factor 9 (SOX9), and decreased expression of osteogenic markers, runt-related transcription factor 2 (RUNX2), and alkaline phosphatase (ALPL). In vivo analysis revealed that HA microspheres remained in the joint for up to 6 weeks. Rats that had undergone destabilization of the medial meniscus and had overt OA were treated with empty HA microspheres, MSC-laden microspheres, MSCs alone, or a control vehicle. Pain measurements taken before and after the treatment illustrated temporarily decreased pain in groups treated with encapsulated cells. Finally, the histopathological scoring of each group illustrated significantly less OA damage in those treated with encapsulated cells compared to controls. Overall, these studies demonstrate the potential of using HA-based hydrogel microspheres to enhance the therapeutic efficacy of MSCs in treating OA.
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Affiliation(s)
- Megan Hamilton
- Bioengineering Program, School of Engineering, University of Kansas, Lawrence, KS 66045, USA;
- Likarda, Kansas City, MO 64137, USA;
| | - Jinxi Wang
- Department of Orthopedic Surgery and Sport Medicine, School of Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA;
| | - Prajnaparamita Dhar
- Bioengineering Program, School of Engineering, University of Kansas, Lawrence, KS 66045, USA;
| | - Lisa Stehno-Bittel
- Likarda, Kansas City, MO 64137, USA;
- Department of Orthopedic Surgery and Sport Medicine, School of Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA;
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Moreno IY, Parsaie A, Gesteira TF, Coulson-Thomas VJ. Characterization of the Limbal Epithelial Stem Cell Niche. Invest Ophthalmol Vis Sci 2023; 64:48. [PMID: 37906057 PMCID: PMC10619699 DOI: 10.1167/iovs.64.13.48] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 10/09/2023] [Indexed: 11/02/2023] Open
Abstract
Purpose Limbal epithelial stem cells (LESCs) reside within a LSC niche (LSCN). We recently identified that hyaluronan (HA) is a major constituent of the LSCN, and that HA is necessary for maintaining LESCs in the "stem cell" state, both in vitro and in vivo. Herein, we characterized the LSCN to identify key components of the HA-specific LSCN. Methods The cornea and limbal rim were dissected from mouse corneas, subjected to mRNA extraction, and sequenced using a NextSeq 500 (Illumina) and data processed using CLC Genomics Workbench 20 (Qiagen) and the STRING database to identify key components of the LSCN. Their expression was confirmed by real-time PCR, Western blotting, and immunohistochemistry. Furthermore, the differential expression of key compounds in different corneal cell types were determined with single-cell RNA sequencing. Results We identified that the hyaladherins inter-alpha-inhibitor (IαI), TSG-6 and versican are highly expressed in the limbus. Specifically, HA/HC complexes are present in the LSCN, in the stroma underlying the limbal epithelium, and surrounding the limbal vasculature. For IαI, heavy chains 5 and 2 (HC5 and HC2) were found to be the most highly expressed HCs in the mouse and human limbus and were associate with HA-forming HA/HC-specific matrices. Conclusions The LSCN contains HA/HC complexes, which have been previously correlated with stem cell niches. The identification of HA/HC complexes in the LSCN could serve as a new therapeutic avenue for treating corneal pathology. Additionally, HA/HC complexes could be used as a substrate for culturing LESCs before LESC transplantation.
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Affiliation(s)
- Isabel Y. Moreno
- College of Optometry, University of Houston, Houston, Texas, United States
| | - Arian Parsaie
- College of Optometry, University of Houston, Houston, Texas, United States
- College of Natural Science and Mathematics, University of Houston, Houston, Texas, United States
| | - Tarsis F. Gesteira
- College of Optometry, University of Houston, Houston, Texas, United States
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11
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Zhang P, Dong B, Yuan P, Li X. Human umbilical cord mesenchymal stem cells promoting knee joint chondrogenesis for the treatment of knee osteoarthritis: a systematic review. J Orthop Surg Res 2023; 18:639. [PMID: 37644595 PMCID: PMC10466768 DOI: 10.1186/s13018-023-04131-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 08/23/2023] [Indexed: 08/31/2023] Open
Abstract
PURPOSE The onset of OA is affected by a variety of factors, which eventually lead to the loss of cartilage in the joints, the formation of osteophytes, the loss of normal knee mobility, and pain and discomfort, which seriously affects the quality of life. HUC-MSCs can promote cartilage production and have been widely used in research in the past decade. This article systematically summarizes that it is well used in basic research and clinical studies to promote inflammatory chondrogenesis in the treatment of OA. Provide a theoretical basis for clinical treatment. PATIENTS AND METHODS This study collected CNKI, Wanfang, PubMed, and articles related to the treatment of OA with HUC-MSCs since their publication, excluding non-basic and clinical studies such as reviews and meta-analysis. A total of 31 basic experimental studies and 12 clinical studies were included. Systematically analyze the effects of HUC-MSCs on inhibiting inflammatory factors, promoting chondrocyte production, and current clinical treatment. RESULTS HUC-MSCs can reduce inflammatory factors such as MMP-13, ADAMTS-5, IL-1β, IL-1, IL-6, TNF-α, induced conversion from M1 to M2 in OA to protect cartilage damage and reduce OA inflammation. Synthesize ColII, SOX9, and aggrecan at the same time to promote cartilage synthesis. CONCLUSION HUC-MSCs not only have typical stem cell biological characteristics, but also have rich sources and convenient material extraction. Compared with stem cells from other sources, HUC-MSCs have stronger proliferation, differentiation, and immune regulation abilities. Furthermore, there are no ethical issues associated with their use. SAFETY Primarily attributed to pain, the majority of individuals experience recovery within 24 h following injection. HUC-MSCs possess the ability to alleviate pain, enhance knee joint function, and potentially postpone the need for surgical intervention in both non-surgical and other cases, making them highly deserving of clinical promotion and application.
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Affiliation(s)
| | - Bo Dong
- Xi'an Hong Hui Hospital, Xi'an, Shaanxi, China.
| | - Puwei Yuan
- Xi'an Hong Hui Hospital, Xi'an, Shaanxi, China
| | - Xun Li
- Xi'an Hong Hui Hospital, Xi'an, Shaanxi, China
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12
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Lee TJ, Jeong CD, Lee TH. Dry Arthroscopic Cartilage Repair of the Knee Joint Using Umbilical Cord Mesenchymal Stem Cells: Kelly Clamp Technique. Arthrosc Tech 2023; 12:e1355-e1359. [PMID: 37654868 PMCID: PMC10466224 DOI: 10.1016/j.eats.2023.04.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 04/11/2023] [Indexed: 09/02/2023] Open
Abstract
Among various cartilage regeneration treatments, methods using mesenchymal stem cells, whose safety and effectiveness have been verified, are emerging. Mesenchymal stem cell can be implanted through open arthrotomy or arthroscopy. Although arthroscopic surgery has the advantage of earlier recovery and less scar formation compared to open arthrotomy, dry arthroscopy is not technically easy, which is necessary for successful implantation and prevention of washout. This Technical Note will introduce an easier and more effective method of dry arthroscopic mesenchymal stem cell implantation.
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Affiliation(s)
- Tae Jin Lee
- Department of Orthopedic Surgery, 9988 Joint & Spine Hospital, Seoul, Republic of Korea
| | - Chan Dong Jeong
- Department of Orthopedic Surgery, 9988 Joint & Spine Hospital, Seoul, Republic of Korea
| | - Tae Hoon Lee
- Department of Orthopedic Surgery, 9988 Joint & Spine Hospital, Seoul, Republic of Korea
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13
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Yu L, Cavelier S, Hannon B, Wei M. Recent development in multizonal scaffolds for osteochondral regeneration. Bioact Mater 2023; 25:122-159. [PMID: 36817819 PMCID: PMC9931622 DOI: 10.1016/j.bioactmat.2023.01.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 12/30/2022] [Accepted: 01/14/2023] [Indexed: 02/05/2023] Open
Abstract
Osteochondral (OC) repair is an extremely challenging topic due to the complex biphasic structure and poor intrinsic regenerative capability of natural osteochondral tissue. In contrast to the current surgical approaches which yield only short-term relief of symptoms, tissue engineering strategy has been shown more promising outcomes in treating OC defects since its emergence in the 1990s. In particular, the use of multizonal scaffolds (MZSs) that mimic the gradient transitions, from cartilage surface to the subchondral bone with either continuous or discontinuous compositions, structures, and properties of natural OC tissue, has been gaining momentum in recent years. Scrutinizing the latest developments in the field, this review offers a comprehensive summary of recent advances, current hurdles, and future perspectives of OC repair, particularly the use of MZSs including bilayered, trilayered, multilayered, and gradient scaffolds, by bringing together onerous demands of architecture designs, material selections, manufacturing techniques as well as the choices of growth factors and cells, each of which possesses its unique challenges and opportunities.
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Affiliation(s)
- Le Yu
- Department of Chemical and Biomolecular Engineering, Ohio University, Athens, OH, 45701, USA
| | - Sacha Cavelier
- Department of Chemical and Biomolecular Engineering, Ohio University, Athens, OH, 45701, USA
| | - Brett Hannon
- Biomedical Engineering Program, Ohio University, Athens, OH, 45701, USA
| | - Mei Wei
- Biomedical Engineering Program, Ohio University, Athens, OH, 45701, USA
- Department of Mechanical Engineering, Ohio University, Athens, OH, 45701, USA
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14
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Gupta PK, Maheshwari S, Cherian JJ, Goni V, Sharma AK, Tripathy SK, Talari K, Pandey V, Sancheti PK, Singh S, Bandyopadhyay S, Shetty N, Kamath SU, Prahaldbhai PS, Abraham J, Kannan S, Bhat S, Parshuram S, Shahavi V, Sharma A, Verma NN, Kumar U. Efficacy and Safety of Stempeucel in Osteoarthritis of the Knee: A Phase 3 Randomized, Double-Blind, Multicenter, Placebo-Controlled Study. Am J Sports Med 2023; 51:2254-2266. [PMID: 37366164 DOI: 10.1177/03635465231180323] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/28/2023]
Abstract
BACKGROUND Osteoarthritis is a chronic, progressive, and degenerative condition with limited therapy options. Recently, biologic therapies have been an evolving option for the management of osteoarthritis. PURPOSE To assess whether allogenic mesenchymal stromal cells (MSCs) have the potential to improve functional parameters and induce cartilage regeneration in patients with osteoarthritis. STUDY DESIGN Randomized controlled trial; Level of evidence, 1. METHODS A total of 146 patients with grade 2 and 3 osteoarthritis were randomized to either an MSC group or placebo group with a ratio of 1:1. There were 73 patients per group who received either a single intra-articular injection of bone marrow-derived MSCs (BMMSCs; 25 million cells) or placebo, followed by 20 mg per 2 mL of hyaluronic acid under ultrasound guidance. The primary endpoint was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score. The secondary endpoints were WOMAC subscores for pain, stiffness, and physical function; the visual analog scale score for pain; and magnetic resonance imaging findings using T2 mapping and cartilage volume. RESULTS Overall, 65 patients from the BMMSC group and 68 patients from the placebo group completed 12-month follow-up. The BMMSC group showed significant improvements in the WOMAC total score compared with the placebo group at 6 and 12 months (percentage change: -23.64% [95% CI, -32.88 to -14.40] at 6 months and -45.60% [95% CI, -55.97 to -35.23] at 12 months P < .001; percentage change, -44.3%). BMMSCs significantly improved WOMAC pain, stiffness, and physical function subscores as well as visual analog scale scores at 6 and 12 months (P < .001). T2 mapping showed that there was no worsening of deep cartilage in the medial femorotibial compartment of the knee in the BMMSC group at 12-month follow-up, whereas in the placebo group, there was significant and gradual worsening of cartilage (P < .001). Cartilage volume did not change significantly in the BMMSC group. There were 5 adverse events that were possibly/probably related to the study drug and consisted of injection-site swelling and pain, which improved within a few days. CONCLUSION In this small randomized trial, BMMSCs proved to be safe and effective for the treatment of grade 2 and 3 osteoarthritis. The intervention was simple and easy to administer, provided sustained relief of pain and stiffness, improved physical function, and prevented worsening of cartilage quality for ≥12 months. REGISTRATION CTRI/2018/09/015785 (National Institutes of Health and Clinical Trials Registry-India).
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Affiliation(s)
- Pawan Kumar Gupta
- Stempeutics Research, Bangalore, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Sunil Maheshwari
- Medilink Hospital and Research Centre, Ahmedabad, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Joe Joseph Cherian
- St John's Medical College, Bangalore, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Vijay Goni
- Postgraduate Institute of Medical Education and Research, Chandigarh, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Arun Kumar Sharma
- Sawai Man Singh Hospital & Medical College, Jaipur, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Sujith Kumar Tripathy
- All India Institutes of Medical Sciences, Bhubaneswar, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Keerthi Talari
- Yashoda Hospital, Hyderabad, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Vivek Pandey
- Kasturba Medical College, Manipal, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Parag Kantilal Sancheti
- Sancheti Institute for Orthopaedics and Rehabilitation, Pune, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Saurabh Singh
- Banaras Hindu University, Varanasi, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Syamasis Bandyopadhyay
- Apollo Gleneagles Hospital, Kolkata, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Naresh Shetty
- Ramaiah Medical College, Bangalore, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Surendra Umesh Kamath
- Kasturba Medical College Hospital, Mangalore, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Purohit Sharad Prahaldbhai
- Sanjivani Super Specialty Hospital, Ahmedabad, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Jijy Abraham
- Stempeutics Research, Bangalore, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Suresh Kannan
- Stempeutics Research, Bangalore, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Samatha Bhat
- Stempeutics Research, Bangalore, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Shivashankar Parshuram
- Stempeutics Research, Bangalore, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Vinayaka Shahavi
- Alkem Laboratories, Mumbai, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Akhilesh Sharma
- Alkem Laboratories, Mumbai, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Nikhil N Verma
- Rush University Medical Center, Chicago, Illinois, USA
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
| | - Uday Kumar
- Stempeutics Research, Bangalore, India
- Investigation performed at Post Graduate Institute of Medical Education & Research, Chandigarh and St. John's Medical College Hospital, Bengaluru, India
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15
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Lubis AMT, Aprianto P, Pawitan JA, Priosoeryanto BP, Dewi TIT, Kamal AF. Intra-articular injection of secretome, derived from umbilical cord mesenchymal stem cell, enhances the regeneration process of cartilage in early-stage osteo-arthritis: an animal study. Acta Orthop 2023; 94:300-306. [PMID: 37377012 DOI: 10.2340/17453674.2023.12359] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Indexed: 06/29/2023] Open
Abstract
BACKGROUND AND PURPOSE Mesenchymal stem cells (MSCs), both endogenous and exogenous, enhance chondrocyte proliferation by stimulating collagen type II. Secretome, an MSC derivate, has shown to also provide this mechanism through a paracrine effect. We aimed to evaluate the use of secretome and MSC in the management of early osteoarthritis (OA). ANIMALS AND METHODS 19 (1 control) male sheep (Ovies aries), which were operated on with total lateral meniscectomy to induce knee OA, were divided into 3 groups: the secretome group, hyaluronic acid group, and MSC group. Each group was injected with the respective substances and was evaluated macroscopically and microscopically. The Osteoarthritis Research Society International (OARSI) score was calculated for all subjects and a descriptive and comparative statistical analysis was undertaken. RESULTS The macroscopic analysis of the treated groups revealed better OARSI score in the secretome group compared with the other 2 groups. The secretome group showed a significantly better microscopic score compared with the hyaluronic acid group (mean difference [MD] 6.0, 95% confidence interval [CI] 0.15-12), but no significant difference compared with the MSC group (MD 1.0, CI -4.8 to 6.8). CONCLUSION Intra-articular injection of secretome is effective in managing early-stage osteoarthritis in the animal model compared with hyaluronic acid and has similar efficacy to MSC injection.
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Affiliation(s)
- Andri Maruli Tua Lubis
- Department of Orthopaedics and Traumatology, Cipto Mangunkusumo General Hospital, Jakarta; Department of Orthopaedics and Traumatology, Faculty of Medicine Universitas Indonesia, Jakarta
| | - Petrus Aprianto
- Department of Orthopaedics and Traumatology, Cipto Mangunkusumo General Hospital, Jakarta; Department of Orthopaedics and Traumatology, Faculty of Medicine Universitas Indonesia, Jakarta
| | - Jeanne Adiwinata Pawitan
- Department of Histology, Cipto Mangunkusumo General Hospital - Faculty of Medicine Universitas Indonesia, Jakarta
| | | | - Tri Isyani Tungga Dewi
- Department of Veterinary Pathology, Faculty of Agriculture, IBP University, Bogor, Indonesia
| | - Achmad Fauzi Kamal
- Department of Orthopaedics and Traumatology, Cipto Mangunkusumo General Hospital, Jakarta; Department of Orthopaedics and Traumatology, Faculty of Medicine Universitas Indonesia, Jakarta.
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16
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Niu J, Liu Y, Wang J, Wang H, Zhao Y, Zhang M. Thrombospondin-2 acts as a critical regulator of cartilage regeneration: A review. Medicine (Baltimore) 2023; 102:e33651. [PMID: 37115081 PMCID: PMC10145989 DOI: 10.1097/md.0000000000033651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Revised: 03/15/2023] [Accepted: 04/10/2023] [Indexed: 04/29/2023] Open
Abstract
The degeneration of articular cartilage tissue is the most common cause of articular cartilage diseases such as osteoarthritis. There are limitations in chondrocyte self-renewal and conventional treatments. During cartilage regeneration and repair, growth factors are typically used to induce cartilage differentiation in stem cells. The role of thrombospondin-2 in cartilage formation has received much attention in recent years. This paper reviews the role of thrombospondin-2 in cartilage regeneration and the important role it plays in protecting cartilage from damage caused by inflammation or trauma and in the regenerative repair of cartilage by binding to different receptors and activating different intracellular signaling pathways. These studies provide new ideas for cartilage repair in clinical settings.
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Affiliation(s)
- Jing Niu
- The College of Life Sciences and Medicine, Northwest University, Xi’an, P. R. China
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Disease, Department of General Dentistry and Emergency, School of Stomatology, Fourth Military Medical University, Xi’an, P. R. China
| | - Yanli Liu
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Disease, Department of General Dentistry and Emergency, School of Stomatology, Fourth Military Medical University, Xi’an, P. R. China
| | - Junjun Wang
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Disease, Department of General Dentistry and Emergency, School of Stomatology, Fourth Military Medical University, Xi’an, P. R. China
| | - Hui Wang
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Disease, Department of General Dentistry and Emergency, School of Stomatology, Fourth Military Medical University, Xi’an, P. R. China
| | - Ying Zhao
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Disease, Department of General Dentistry and Emergency, School of Stomatology, Fourth Military Medical University, Xi’an, P. R. China
- Department of Anesthesiology and Perioperative Medicine, Xi’an People’s Hospital (Xi’an Fourth Hospital), Northwest University, Xi’an, P. R. China
| | - Min Zhang
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Disease, Department of General Dentistry and Emergency, School of Stomatology, Fourth Military Medical University, Xi’an, P. R. China
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Thanaskody K, Jusop AS, Tye GJ, Wan Kamarul Zaman WS, Dass SA, Nordin F. MSCs vs. iPSCs: Potential in therapeutic applications. Front Cell Dev Biol 2022; 10:1005926. [PMID: 36407112 PMCID: PMC9666898 DOI: 10.3389/fcell.2022.1005926] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 10/21/2022] [Indexed: 01/24/2023] Open
Abstract
Over the past 2 decades, mesenchymal stem cells (MSCs) have attracted a lot of interest as a unique therapeutic approach for a variety of diseases. MSCs are capable of self-renewal and multilineage differentiation capacity, immunomodulatory, and anti-inflammatory properties allowing it to play a role in regenerative medicine. Furthermore, MSCs are low in tumorigenicity and immune privileged, which permits the use of allogeneic MSCs for therapies that eliminate the need to collect MSCs directly from patients. Induced pluripotent stem cells (iPSCs) can be generated from adult cells through gene reprogramming with ectopic expression of specific pluripotency factors. Advancement in iPS technology avoids the destruction of embryos to make pluripotent cells, making it free of ethical concerns. iPSCs can self-renew and develop into a plethora of specialized cells making it a useful resource for regenerative medicine as they may be created from any human source. MSCs have also been used to treat individuals infected with the SARS-CoV-2 virus. MSCs have undergone more clinical trials than iPSCs due to high tumorigenicity, which can trigger oncogenic transformation. In this review, we discussed the overview of mesenchymal stem cells and induced pluripotent stem cells. We briefly present therapeutic approaches and COVID-19-related diseases using MSCs and iPSCs.
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Affiliation(s)
- Kalaiselvaan Thanaskody
- Centre for Tissue Engineering and Regenerative Medicine (CTERM), Faculty of Medicine, University Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Amirah Syamimi Jusop
- Centre for Tissue Engineering and Regenerative Medicine (CTERM), Faculty of Medicine, University Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Gee Jun Tye
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Gelugor, Malaysia
| | - Wan Safwani Wan Kamarul Zaman
- Department of Biomedical Engineering, Faculty of Engineering, Universiti Malaya, Kuala Lumpur, Malaysia,Centre for Innovation in Medical Engineering (CIME), Department of Biomedical Engineering, Faculty of Engineering, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Sylvia Annabel Dass
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Gelugor, Malaysia
| | - Fazlina Nordin
- Centre for Tissue Engineering and Regenerative Medicine (CTERM), Faculty of Medicine, University Kebangsaan Malaysia, Kuala Lumpur, Malaysia,*Correspondence: Fazlina Nordin,
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18
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Tu Z, Karnoub AE. Mesenchymal stem/stromal cells in breast cancer development and management. Semin Cancer Biol 2022; 86:81-92. [PMID: 36087857 DOI: 10.1016/j.semcancer.2022.09.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 09/02/2022] [Accepted: 09/03/2022] [Indexed: 11/17/2022]
Abstract
Mesenchymal stem/stromal cells (MSCs) encompass a heterogeneous population of fibroblastic progenitor cells that reside in multiple tissues around the body. They are endowed with capacities to differentiate into multiple connective tissue lineages, including chondrocytes, adipocytes, and osteoblasts, and are thought to function as trophic cells recruited to sites of injury and inflammation where they contribute to tissue regeneration. In keeping with these roles, MSCs also to home to sites of breast tumorigenesis, akin to their migration to wounds, and participate in tumor stroma formation. Mounting evidence over the past two decades has described the critical regulatory roles for tumor-associated MSCs in various aspects of breast tumor pathogenesis, be it tumor initiation, growth, angiogenesis, tumor microenvironment formation, immune evasion, cancer cell migration, invasion, survival, therapeutic resistance, dissemination, and metastatic colonization. In this review, we present a brief summary of the role of MSCs in breast tumor development and progression, highlight some of the molecular frameworks underlying their pro-malignant contributions, and present evidence of their promising utility in breast cancer therapy.
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Affiliation(s)
- Zhenbo Tu
- Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Antoine E Karnoub
- Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Boston Veterans Affairs Research Institute, West Roxbury, MA 02132, USA.
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19
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Lin Y, Lin E, Li Y, Chen X, Chen M, Huang J, Guo W, Chen L, Wu L, Zhang X, Zhang W, Jin X, Zhang J, Fu F, Wang C. Thrombospondin 2 is a Functional Predictive and Prognostic Biomarker for Triple-Negative Breast Cancer Patients With Neoadjuvant Chemotherapy. Pathol Oncol Res 2022; 28:1610559. [DOI: 10.3389/pore.2022.1610559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 07/20/2022] [Indexed: 11/13/2022]
Abstract
Background: Triple-negative breast cancer (TNBC) is characterized by a more aggressive biological behavior and unfavorable outcome. Circulating and histological expression of THBS2 has been demonstrated to be a novel diagnostic and prognostic biomarker in patients with various types of tumors. However, few studies have evaluated the predictive and prognostic value of THBS2 in TNBC specifically.Methods: In total, 185 triple-negative breast cancer patients (TNBC) with preoperative neoadjuvant chemotherapy were enrolled in this study. Serum THBS2 (sTHBS2) level was measured both prior to the start of NAC and at surgery by enzyme-linked immunosorbent assay (ELISA). Histological THBS2 (hTHBS2) expression in patients with residual tumors was evaluated by immunohistochemistry (IHC) staining method. Correlations between variables and treatment response were studied. Kaplan-Meier plots and Cox proportional hazard regression model were applied for survival analysis. Functional activities of THBS2 in TNBC cells were determined by CCK-8 assay, colony formation, wound healing, and transwell assay.Results: Of the 185 patients, 48 (25.9%) achieved pathological complete response (pCR) after completion of NAC. Elevated pCR rates were observed in patients with a lower level of sTHBS2 at surgery and higher level of sTHBS2 change (OR = 0.88, 95%CI: 0.79–0.98, p = 0.020 and OR = 1.12, 95%CI: 1.02–1.23, p = 0.015, respectively). In survival analysis, hTHBS2 expression in residual tumor was of independent prognostic value for both disease-free survival (HR = 2.21, 95%CI = 1.24–3.94, p = 0.007) and overall survival (HR = 2.07, 95%CI = 1.09–3.92, p = 0.026). For functional studies, THBS2 was indicated to inhibit proliferation, migration, and invasion abilities of TNBC cells in vitro.Conclusion: Our findings confirmed the value of serum THBS2 level to predict pCR for TNBC patients and the prognostic performance of histological THBS2 expression in non-pCR responders after NAC. THBS2 might serve as a promising functional biomarker for patients with triple-negative breast cancer.
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20
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Alves JC, Santos A, Jorge P, Carreira LM. A first report on the efficacy of a single intra-articular administration of blood cell secretome, triamcinolone acetonide, and the combination of both in dogs with osteoarthritis. BMC Vet Res 2022; 18:309. [PMID: 35962448 PMCID: PMC9375423 DOI: 10.1186/s12917-022-03413-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 08/08/2022] [Indexed: 11/17/2022] Open
Abstract
Background Osteoarthritis represents a significant welfare problem for many dogs, with limited therapeutic options other than palliative pain control. To evaluate the effect of the intra-articular administration of blood cell secretome and triamcinolone, 15 dogs with bilateral hip osteoarthritis were randomly assigned to a blood cell secretome (BCSG, n = 5), triamcinolone (TG) or their combination group (BCS + TG, n = 5). BCSG received a single intra-articular administration of 3 ml of blood cell secretome, TG 0.5 ml of triamcinolone acetonide 40 mg/ml, and BCS + TG received the combined products. The volume to administrate was corrected to 3.5 ml with saline. On days 0, 8, 15, 30, 60, 90, 120, 150, and 180, a copy of the Canine Brief Pain Inventory (divided into pain interference score—PIS and Pain Severity Score—PSS), Liverpool Osteoarthritis in Dogs (LOAD), Hudson Visual Analogue Scale (HVAS), and Canine Orthopedic Index (COI, divided into function, gait, stiffness, and quality of life) was completed. Results were analyzed with the Kruskal–Wallis test and the Kaplan–Meier estimators were conducted and compared with the Log Rank test, p < 0.05. Results Animals in the sample had a mean age of 9.0 ± 2.9 years and a bodyweight of 28.8 ± 4.1 kg. Hips were classified as moderate (8) and severe (7) osteoarthritis. No differences were found between groups at T0 regarding considered evaluations. Significant differences were observed between groups in pain scores from + 8d- + 150d, with BCS + TG exhibiting better results. The same was observed for HVAS and LOAD, from + 8d- + 120d. Improvements were also observed in several dimensions of the COI. Kaplan–Meier estimators showed that BCS + TG produced longer periods with better results, followed by BCSG and TG. Conclusion The intra-articular administration of blood cell secretome improved the clinical signs and scores of several clinical metrology instruments in dogs with hip OA, particularly when combined with triamcinolone. Further studies are required.
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Affiliation(s)
- J C Alves
- Divisão de Medicina Veterinária, Guarda Nacional Republicana (GNR), Rua Presidente Arriaga, 9, 1200-771, Lisbon, Portugal. .,Environment and Development, MED - Mediterranean Institute for Agriculture, Instituto de Investigação E Formação Avançada, Universidade de Évora, Pólo da Mitra, Ap. 94, 7006-554, Évora, Portugal.
| | - A Santos
- Divisão de Medicina Veterinária, Guarda Nacional Republicana (GNR), Rua Presidente Arriaga, 9, 1200-771, Lisbon, Portugal
| | - P Jorge
- Divisão de Medicina Veterinária, Guarda Nacional Republicana (GNR), Rua Presidente Arriaga, 9, 1200-771, Lisbon, Portugal
| | - L Miguel Carreira
- Faculty of Veterinary Medicine, University of Lisbon (FMV/ULisboa), Lisbon, Portugal.,Interdisciplinary Centre for Research in Animal Health (CIISA), University of Lisbon, (FMV/ULisboa), Lisbon, Portugal.,Anjos of Assis Veterinary Medicine Centre (CMVAA), Barreiro, Portugal
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21
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Jing G, Yang L, Wang H, Niu J, Li Y, Wang S. Interference of layered double hydroxide nanoparticles with pathways for biomedical applications. Adv Drug Deliv Rev 2022; 188:114451. [PMID: 35843506 DOI: 10.1016/j.addr.2022.114451] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 06/18/2022] [Accepted: 07/09/2022] [Indexed: 11/01/2022]
Abstract
Recent decades have witnessed a surge of explorations into the application of multifarious materials, especially biomedical applications. Among them, layered double hydroxides (LDHs) have been widely developed as typical inorganic layer materials to achieve remarkable advancements. Multiple physicochemical properties endow LDHs with excellent merits in biomedical applications. Moreover, LDH nanoplatforms could serve as "molecular switches", which are capable of the controlled release of payloads under specific physiological pH conditions but are stable during circulation in the bloodstream. In addition, LDHs themselves are composed of several specific cations and possess favorable biological effects or regulatory roles in various cellular functions. These advantages have caused LDHs to become increasingly of interest in the area of nanomedicine. Recent efforts have been devoted to revealing the potential factors that interfere with the biological pathways of LDH-based nanoparticles, such as their applications in shaping the functions of immune cells and in determining the fate of stem cells and tumor treatments, which are comprehensively described herein. In addition, several intracellular signaling pathways interfering with by LDHs in the above applications were also systematically expatiated. Finally, the future development and challenges of LDH-based nanomedicine are discussed in the context of the ultimate goal of practical clinical application.
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Affiliation(s)
- Guoxin Jing
- Research Center for Translational Medicine at East Hospital, School of Life Science and Technology, Tongji University, Shanghai, PR China
| | - Linnan Yang
- Central Laboratory, First Affiliated Hospital, Anhui Medical University, Hefei, PR China
| | - Hong Wang
- Research Center for Translational Medicine at East Hospital, School of Life Science and Technology, Tongji University, Shanghai, PR China
| | - Jintong Niu
- Research Center for Translational Medicine at East Hospital, School of Life Science and Technology, Tongji University, Shanghai, PR China
| | - Youyuan Li
- Research Center for Translational Medicine at East Hospital, School of Life Science and Technology, Tongji University, Shanghai, PR China
| | - Shilong Wang
- Research Center for Translational Medicine at East Hospital, School of Life Science and Technology, Tongji University, Shanghai, PR China.
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22
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Shin S, Lee S, Choi S, Park N, Kwon Y, Jeong J, Ju S, Chang Y, Park K, Ha C, Lee C. Characterization of the Secretome of a Specific Cell Expressing Mutant Methionyl-tRNA Synthetase in Co-Culture Using Click Chemistry. Int J Mol Sci 2022; 23:ijms23126527. [PMID: 35742968 PMCID: PMC9223471 DOI: 10.3390/ijms23126527] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 06/08/2022] [Accepted: 06/08/2022] [Indexed: 11/21/2022] Open
Abstract
Co-culture system, in which two or more distinct cell types are cultured together, is advantageous in that it can mimic the environment of the in vivo niche of the cells. In this study, we presented a strategy to analyze the secretome of a specific cell type under the co-culture condition in serum-supplemented media. For the cell-specific secretome analysis, we expressed the mouse mutant methionyl-tRNA synthetase for the incorporation of the non-canonical amino acid, azidonorleucine into the newly synthesized proteins in cells of which the secretome is targeted. The azidonorleucine-tagged secretome could be enriched, based on click chemistry, and distinguished from any other contaminating proteins, either from the cell culture media or the other cells co-cultured with the cells of interest. In order to have more reliable true-positive identifications of cell-specific secretory bodies, we established criteria to exclude any identified human peptide matched to bovine proteins. As a result, we identified a maximum of 719 secreted proteins in the secretome analysis under this co-culture condition. Last, we applied this platform to profile the secretome of mesenchymal stem cells and predicted its therapeutic potential on osteoarthritis based on secretome analysis.
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Affiliation(s)
- Sungho Shin
- Chemical & Biological Integrative Research Center, Korea Institute of Science and Technology, Seoul 02792, Korea; (S.S.); (S.L.); (N.P.); (Y.K.); (S.J.)
- KHU-KIST Department of Converging Science and Technology, Graduate School, Kyung Hee University, Seoul 02447, Korea;
| | - Seonjeong Lee
- Chemical & Biological Integrative Research Center, Korea Institute of Science and Technology, Seoul 02792, Korea; (S.S.); (S.L.); (N.P.); (Y.K.); (S.J.)
- Division of Bio-Medical Science and Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Korea
| | - Sunyoung Choi
- Department of Orthopedic Surgery, Samsung Medical Center, School of Medicine, Sungkyunkwan University, Seoul 06351, Korea; (S.C.); (C.H.)
- Cell and Gene Therapy Institute, Samsung Medical Center, Seoul 06351, Korea;
- Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul 06351, Korea
| | - Narae Park
- Chemical & Biological Integrative Research Center, Korea Institute of Science and Technology, Seoul 02792, Korea; (S.S.); (S.L.); (N.P.); (Y.K.); (S.J.)
- KHU-KIST Department of Converging Science and Technology, Graduate School, Kyung Hee University, Seoul 02447, Korea;
| | - Yumi Kwon
- Chemical & Biological Integrative Research Center, Korea Institute of Science and Technology, Seoul 02792, Korea; (S.S.); (S.L.); (N.P.); (Y.K.); (S.J.)
| | - Jaehoon Jeong
- Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Korea;
| | - Shinyeong Ju
- Chemical & Biological Integrative Research Center, Korea Institute of Science and Technology, Seoul 02792, Korea; (S.S.); (S.L.); (N.P.); (Y.K.); (S.J.)
| | - Yunsil Chang
- Cell and Gene Therapy Institute, Samsung Medical Center, Seoul 06351, Korea;
- Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul 06351, Korea
- Department of Pediatrics, Samsung Medical Center, School of Medicine, Sungkyunkwan University, Seoul 06351, Korea
| | - Kangsik Park
- KHU-KIST Department of Converging Science and Technology, Graduate School, Kyung Hee University, Seoul 02447, Korea;
- Department of Physiology, School of Medicine, Kyung Hee University, Seoul 02447, Korea
| | - Chulwon Ha
- Department of Orthopedic Surgery, Samsung Medical Center, School of Medicine, Sungkyunkwan University, Seoul 06351, Korea; (S.C.); (C.H.)
- Cell and Gene Therapy Institute, Samsung Medical Center, Seoul 06351, Korea;
- Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul 06351, Korea
| | - Cheolju Lee
- Chemical & Biological Integrative Research Center, Korea Institute of Science and Technology, Seoul 02792, Korea; (S.S.); (S.L.); (N.P.); (Y.K.); (S.J.)
- Division of Bio-Medical Science and Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Korea
- Correspondence:
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23
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Kim JH, Kim KI, Yoon WK, Song SJ, Jin W. Intra-articular Injection of Mesenchymal Stem Cells After High Tibial Osteotomy in Osteoarthritic Knee: Two-Year Follow-up of Randomized Control Trial. Stem Cells Transl Med 2022; 11:572-585. [PMID: 35674255 PMCID: PMC9216209 DOI: 10.1093/stcltm/szac023] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 03/20/2022] [Indexed: 02/02/2023] Open
Abstract
Intra-articular injection of adipose-derived mesenchymal stem cell (ADMSC) after medial open-wedge high tibial osteotomy (MOWHTO) would be a promising disease-modifying treatment by correcting biomechanical and biochemical environment for arthritic knee with varus malalignment. However, there is a paucity of clinical evidence of the treatment. This randomized controlled trial (RCT) was aimed to assess regeneration of cartilage defect, functional improvement, and safety of intra-articular injection of ADMSCs after MOWHTO compared with MOWHTO alone for osteoarthritic knee with varus malalignment. This RCT allocated 26 patients into the MOWHTO with ADMSC-injection group (n = 13) and control (MOWHTO-alone) group (n = 13). The primary outcome was the serial changes of cartilage defect on periodic magnetic resonance imaging (MRI) evaluation using valid measurements until postoperative 24 months. Secondary outcomes were the 2-stage arthroscopic evaluation for macroscopic cartilage status and the postoperative functional improvements of patient-reported outcome measures until the latest follow-up. Furthermore, safety profiles after the treatment were evaluated. Cartilage regeneration on serial MRIs showed significantly better in the ADMSC group than in the control group. The arthroscopic assessment revealed that total cartilage regeneration was significantly better in the ADMSC group. Although it was not significant, functional improvements after the treatment showed a tendency to be greater in the ADMSC group than in the control group from 18 months after the treatment. No treatment-related adverse events, serious adverse events, and postoperative complications occurred in all cases. Concomitant intra-articular injection of ADMSCs with MOWHTO had advantages over MOWHTO alone in terms of cartilage regeneration with safety at 2-year follow-up, suggesting potential disease-modifying treatment for knee OA with varus malalignment.
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Affiliation(s)
- Jun-Ho Kim
- Department of Orthopaedic Surgery, Center for Joint Diseases, Kyung Hee University Hospital at Gangdong, Seoul, Republic of Korea
| | - Kang-Il Kim
- Corresponding author: Kang-Il Kim, M.D., Ph D., Department of Orthopedic Surgery, Kyung Hee University Hospital at Gangdong, 892 Dongnam-ro, Gangdong-gu, Seoul 134-727, Republic of Korea. Tel: +82 2 440 6151;
| | - Wan Keun Yoon
- Department of Orthopaedic Surgery, Center for Joint Diseases, Kyung Hee University Hospital at Gangdong, Seoul, Republic of Korea
| | - Sang-Jun Song
- Department of Orthopaedic Surgery, School of Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Wook Jin
- Department of Radiology, Kyung Hee University Hospital at Gandong, Seoul, Republic of Korea
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24
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Barisón MJ, Nogoceke R, Josino R, Horinouchi CDDS, Marcon BH, Correa A, Stimamiglio MA, Robert AW. Functionalized Hydrogels for Cartilage Repair: The Value of Secretome-Instructive Signaling. Int J Mol Sci 2022; 23:ijms23116010. [PMID: 35682690 PMCID: PMC9181449 DOI: 10.3390/ijms23116010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 05/20/2022] [Accepted: 05/23/2022] [Indexed: 02/07/2023] Open
Abstract
Cartilage repair has been a challenge in the medical field for many years. Although treatments that alleviate pain and injury are available, none can effectively regenerate the cartilage. Currently, regenerative medicine and tissue engineering are among the developed strategies to treat cartilage injury. The use of stem cells, associated or not with scaffolds, has shown potential in cartilage regeneration. However, it is currently known that the effect of stem cells occurs mainly through the secretion of paracrine factors that act on local cells. In this review, we will address the use of the secretome—a set of bioactive factors (soluble factors and extracellular vesicles) secreted by the cells—of mesenchymal stem cells as a treatment for cartilage regeneration. We will also discuss methodologies for priming the secretome to enhance the chondroregenerative potential. In addition, considering the difficulty of delivering therapies to the injured cartilage site, we will address works that use hydrogels functionalized with growth factors and secretome components. We aim to show that secretome-functionalized hydrogels can be an exciting approach to cell-free cartilage repair therapy.
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25
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Chen K, Henn D, Januszyk M, Barrera JA, Noishiki C, Bonham CA, Griffin M, Tevlin R, Carlomagno T, Shannon T, Fehlmann T, Trotsyuk AA, Padmanabhan J, Sivaraj D, Perrault DP, Zamaleeva AI, Mays CJ, Greco AH, Kwon SH, Leeolou MC, Huskins SL, Steele SR, Fischer KS, Kussie HC, Mittal S, Mermin-Bunnell AM, Diaz Deleon NM, Lavin C, Keller A, Longaker MT, Gurtner GC. Disrupting mechanotransduction decreases fibrosis and contracture in split-thickness skin grafting. Sci Transl Med 2022; 14:eabj9152. [PMID: 35584231 DOI: 10.1126/scitranslmed.abj9152] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Burns and other traumatic injuries represent a substantial biomedical burden. The current standard of care for deep injuries is autologous split-thickness skin grafting (STSG), which frequently results in contractures, abnormal pigmentation, and loss of biomechanical function. Currently, there are no effective therapies that can prevent fibrosis and contracture after STSG. Here, we have developed a clinically relevant porcine model of STSG and comprehensively characterized porcine cell populations involved in healing with single-cell resolution. We identified an up-regulation of proinflammatory and mechanotransduction signaling pathways in standard STSGs. Blocking mechanotransduction with a small-molecule focal adhesion kinase (FAK) inhibitor promoted healing, reduced contracture, mitigated scar formation, restored collagen architecture, and ultimately improved graft biomechanical properties. Acute mechanotransduction blockade up-regulated myeloid CXCL10-mediated anti-inflammation with decreased CXCL14-mediated myeloid and fibroblast recruitment. At later time points, mechanical signaling shifted fibroblasts toward profibrotic differentiation fates, and disruption of mechanotransduction modulated mesenchymal fibroblast differentiation states to block those responses, instead driving fibroblasts toward proregenerative, adipogenic states similar to unwounded skin. We then confirmed these two diverging fibroblast transcriptional trajectories in human skin, human scar, and a three-dimensional organotypic model of human skin. Together, pharmacological blockade of mechanotransduction markedly improved large animal healing after STSG by promoting both early, anti-inflammatory and late, regenerative transcriptional programs, resulting in healed tissue similar to unwounded skin. FAK inhibition could therefore supplement the current standard of care for traumatic and burn injuries.
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Affiliation(s)
- Kellen Chen
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.,Department of Surgery, University of Arizona College of Medicine, Tucson, AZ 85724, USA
| | - Dominic Henn
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Michael Januszyk
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Janos A Barrera
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Chikage Noishiki
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Clark A Bonham
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Michelle Griffin
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Ruth Tevlin
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Theresa Carlomagno
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Tara Shannon
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Tobias Fehlmann
- Chair for Clinical Bioinformatics, Saarland University, 66123 Saarbrücken, Germany
| | - Artem A Trotsyuk
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Jagannath Padmanabhan
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Dharshan Sivaraj
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - David P Perrault
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Alsu I Zamaleeva
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Chyna J Mays
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Autumn H Greco
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Sun Hyung Kwon
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Melissa C Leeolou
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Savana L Huskins
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Sydney R Steele
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Katharina S Fischer
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Hudson C Kussie
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Smiti Mittal
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Alana M Mermin-Bunnell
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Nestor M Diaz Deleon
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Christopher Lavin
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Andreas Keller
- Chair for Clinical Bioinformatics, Saarland University, 66123 Saarbrücken, Germany.,Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA
| | - Michael T Longaker
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Geoffrey C Gurtner
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.,Department of Surgery, University of Arizona College of Medicine, Tucson, AZ 85724, USA
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26
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Intra-articular Injectates: What to Use and Why. Vet Clin North Am Small Anim Pract 2022; 52:967-975. [PMID: 35562212 DOI: 10.1016/j.cvsm.2022.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Intra-articular injections are a nonsurgical treatment modality that can be used to manage osteoarthritis, naturally occurring or surgically induced acute synovitis, and intra-articular ligamentous or tendon injury. This option may be assistive for patients in which other conservative modalities are ineffective, or in conjunction with other forms of treatment. It may also be used as the primary treatment. Injectates labeled for use in companion animal joints include corticosteroids and viscosupplements. Additional injectates, that are not specifically approved for use in companion animals are but are reported in the literature, include orthobiologics and a radioisotope of Tin-117m.
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27
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Moon SW, Park S, Oh M, Wang JH. Outcomes of human umbilical cord blood-derived mesenchymal stem cells in enhancing tendon-graft healing in anterior cruciate ligament reconstruction: an exploratory study. Knee Surg Relat Res 2021; 33:32. [PMID: 34530924 PMCID: PMC8447562 DOI: 10.1186/s43019-021-00104-4] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 05/03/2021] [Indexed: 11/30/2022] Open
Abstract
Background The study investigated whether allogeneic human umbilical cord blood-derived MSCs (hUCB-MSCs) could be safely used without treatment-related adverse events, reducing tunnel enlargement, and improve clinical results in human anterior cruciate ligament (ACL) reconstruction. Methods Thirty patients were enrolled consecutively. They were divided into three groups by randomization. In the negative control group, ACL reconstruction surgery without additional treatment was performed. In the experimental group, a hUCB-MSC and hyaluronic acid mixture was applied to the tendon-bone interface of the femoral tunnels during ACL reconstruction surgery. In the positive control group, only hyaluronic acid was applied. Finally, 27 patients were analyzed after the exclusion of three patients. The incidence of treatment-related adverse events, clinical outcomes, including second-look arthroscopic findings, and the amount of tunnel enlargement, were evaluated. Results There were no treatment-related adverse events in the treatment groups. Tunnel enlargement in the experimental group (579.74 ± 389.85 mm3) was not significantly different from those in the negative (641.97 ± 455.84 mm3) and positive control (421.96 ± 274.83 mm3) groups (p = 0.6468). There were no significant differences between the groups in clinical outcomes such as KT-2000 measurement (p = 0.793), pivot shift test (p = 0.9245), International Knee Documentation Committee subjective score (p = 0.9195), Tegner activity level (p = 0.9927), and second-look arthroscopic findings (synovial coverage of the graft, p = 0.7984; condition of the graft, p = 0.8402). Conclusions Allogeneic hUCB-MSCs were used safely for ACL reconstruction without treatment-related adverse event in a 2-year follow-up. However, our study did not suggest any evidence to show clinical advantage such as the prevention of tunnel enlargement postoperatively and a decrease in knee laxity or improvement of clinical outcomes. Trial registration CRIS, Registration Number: KCT0000917. Registered on 12 November 2013; https://cris.nih.go.kr/cris/index.jsp
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Affiliation(s)
- Sang Won Moon
- Department of Orthopaedic Surgery, Inje University Haeundae Paik Hospital, Busan, Korea
| | - Sinhyung Park
- Department of Orthopaedic Surgery, Soonchunhyang University Hospital Bucheon, Gyeonggi-do, Korea
| | - Minkyung Oh
- Clinical Trial Center, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea
| | - Joon Ho Wang
- Department of Orthopaedic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Korea. .,Department of Health Sciences and Technology and Department of Medical Device Management and Research, SAIHST, Sungkyunkwan University, Seoul, 06351, Korea.
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28
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Proteomic Analysis Reveals Commonly Secreted Proteins of Mesenchymal Stem Cells Derived from Bone Marrow, Adipose Tissue, and Synovial Membrane to Show Potential for Cartilage Regeneration in Knee Osteoarthritis. Stem Cells Int 2021; 2021:6694299. [PMID: 34306096 PMCID: PMC8264516 DOI: 10.1155/2021/6694299] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 05/28/2021] [Accepted: 06/08/2021] [Indexed: 12/24/2022] Open
Abstract
Paracrine factors secreted by mesenchymal stem cells (MSCs) reportedly modulate inflammation and reparative processes in damaged tissues and have been explored for knee osteoarthritis (OA) therapy. Although various studies have reported the effects of paracrine factors in knee OA, it is not yet clear which paracrine factors directly affect the regeneration of damaged cartilage and which are secreted under various knee OA conditions. In this study, we cultured MSCs derived from three types of tissues and treated each type with IL-1β and TNF-α or not to obtain conditioned medium. Each conditioned medium was used to analyse the paracrine factors related to cartilage regeneration using liquid chromatography-tandem mass spectrometry. Bone marrow-, adipose tissue-, and synovial membrane-MSCs (all-MSCs) exhibited expression of 93 proteins under normal conditions and 105 proteins under inflammatory conditions. It was confirmed that the types of secreted proteins differed depending on the environmental conditions, and the proteins were validated using ELISA. The results of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis using a list of proteins secreted by all-MSCs under each condition confirmed that the secreted proteins were closely related to cartilage repair under inflammatory conditions. Protein-protein interaction networks were confirmed to change depending on environmental differences and were found to enhance the secretion of paracrine factors related to cartilage regeneration under inflammatory conditions. In conclusion, our results demonstrated that compared with knee OA conditions, the differential expression proteins may contribute to the regeneration of damaged cartilage. In addition, the detailed information on commonly secreted proteins by all-MSCs provides a comprehensive basis for understanding the potential of paracrine factors to influence tissue repair and regeneration in knee OA.
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29
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Chung MJ, Son JY, Park S, Park SS, Hur K, Lee SH, Lee EJ, Park JK, Hong IH, Kim TH, Jeong KS. Mesenchymal Stem Cell and MicroRNA Therapy of Musculoskeletal Diseases. Int J Stem Cells 2021; 14:150-167. [PMID: 33377459 PMCID: PMC8138662 DOI: 10.15283/ijsc20167] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 11/24/2020] [Accepted: 11/30/2020] [Indexed: 02/06/2023] Open
Abstract
The therapeutic effects of mesenchymal stem cells (MSCs) in musculoskeletal diseases (MSDs) have been verified in many human and animal studies. Although some tissues contain MSCs, the number of cells harvested from those tissues and rate of proliferation in vitro are not enough for continuous transplantation. In order to produce and maintain stable MSCs, many attempts are made to induce differentiation from pluripotent stem cells (iPSCs) into MSCs. In particular, it is also known that the paracrine action of stem cell-secreted factors could promote the regeneration and differentiation of target cells in damaged tissue. MicroRNAs (miRNAs), one of the secreted factors, are small non-coding RNAs that regulate the translation of a gene. It is known that miRNAs help communication between stem cells and their surrounding niches through exosomes to regulate the proliferation and differentiation of stem cells. While studies have so far been underway targeting therapeutic miRNAs of MSDs, studies on specific miRNAs secreted from MSCs are still minimal. Hence, our ultimate goal is to obtain sufficient amounts of exosomes from iPSC-MSCs and develop them into therapeutic agents, furthermore to select specific miRNAs and provide safe cell-free clinical setting as a cell-free status with purpose of delivering them to target cells. This review article focuses on stem cell therapy on MSDs, specific microRNAs regulating MSDs and updates on novel approaches.
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Affiliation(s)
- Myung-Jin Chung
- Department of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Korea
| | - Ji-Yoon Son
- Department of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Korea
| | - SunYoung Park
- Department of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Korea.,Stem Cell Therapeutic Research Institute, Kyungpook National University, Daegu, Korea
| | - Soon-Seok Park
- Department of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Korea
| | - Keun Hur
- School of Medicine, Kyungpook National University, Daegu, Korea
| | - Sang-Han Lee
- Department of Food Science & Biotechnology, Kyungpook National University, Daegu, Korea
| | - Eun-Joo Lee
- Department of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Korea
| | - Jin-Kyu Park
- Department of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Korea.,Stem Cell Therapeutic Research Institute, Kyungpook National University, Daegu, Korea
| | - Il-Hwa Hong
- Department of Veterinary Pathology, College of Veterinary Medicine, Gyeongsang National University, Jinju, Korea
| | - Tae-Hwan Kim
- Department of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Korea
| | - Kyu-Shik Jeong
- Department of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Korea.,Stem Cell Therapeutic Research Institute, Kyungpook National University, Daegu, Korea
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30
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Fu Y, Paggi CA, Dudakovic A, van Wijnen AJ, Post JN, Karperien M. Engineering Cartilage Tissue by Co-culturing of Chondrocytes and Mesenchymal Stromal Cells. Methods Mol Biol 2021; 2221:53-70. [PMID: 32979198 DOI: 10.1007/978-1-0716-0989-7_5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Co-culture of chondrocytes and mesenchymal stromal cells (MSCs) has been shown to be beneficial in engineering cartilage tissue in vitro. In these co-cultures, MSCs increase the proliferation and matrix deposition of chondrocytes. The MSCs accomplish this beneficial effect by so-called trophic actions. Thus, large cartilage constructs can be made with a relatively small number of chondrocytes. In this chapter, we describe different methods for making co-cultures of MSCs and chondrocytes. We also provide detailed protocols for analyzing MSC-chondrocyte co-cultures with cell tracking, proliferation assays, species-specific polymerase chain reactions (PCR), rheological analysis, compression analysis, RNA-sequencing analysis, short tandem repeats analysis, and biochemical examination.
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Affiliation(s)
- Yao Fu
- Department of Developmental BioEngineering, TechMed Centre, University of Twente, Enschede, The Netherlands
| | - Carlo A Paggi
- Department of Developmental BioEngineering, TechMed Centre, University of Twente, Enschede, The Netherlands
| | - Amel Dudakovic
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA
| | - Andre J van Wijnen
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA
| | - Janine N Post
- Department of Developmental BioEngineering, TechMed Centre, University of Twente, Enschede, The Netherlands
| | - Marcel Karperien
- Department of Developmental BioEngineering, TechMed Centre, University of Twente, Enschede, The Netherlands.
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31
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Um S, Ha J, Choi SJ, Oh W, Jin HJ. Prospects for the therapeutic development of umbilical cord blood-derived mesenchymal stem cells. World J Stem Cells 2020; 12:1511-1528. [PMID: 33505598 PMCID: PMC7789129 DOI: 10.4252/wjsc.v12.i12.1511] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 10/23/2020] [Accepted: 11/12/2020] [Indexed: 02/06/2023] Open
Abstract
Umbilical cord blood (UCB) is a primitive and abundant source of mesenchymal stem cells (MSCs). UCB-derived MSCs have a broad and efficient therapeutic capacity to treat various diseases and disorders. Despite the high latent self-renewal and differentiation capacity of these cells, the safety, efficacy, and yield of MSCs expanded for ex vivo clinical applications remains a concern. However, immunomodulatory effects have emerged in various disease models, exhibiting specific mechanisms of action, such as cell migration and homing, angiogenesis, anti-apoptosis, proliferation, anti-cancer, anti-fibrosis, anti-inflammation and tissue regeneration. Herein, we review the current literature pertaining to the UCB-derived MSC application as potential treatment strategies, and discuss the concerns regarding the safety and mass production issues in future applications.
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Affiliation(s)
- Soyoun Um
- Research Team for Immune Cell Therapy, Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, South Korea
| | - Jueun Ha
- Research Team for Osteoarthritis, Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, South Korea
| | - Soo Jin Choi
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, South Korea
| | - Wonil Oh
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, South Korea
| | - Hye Jin Jin
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, South Korea
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Kim YS, Suh DS, Tak DH, Chung PK, Koh YG. Mesenchymal Stem Cell Implantation in Knee Osteoarthritis: Midterm Outcomes and Survival Analysis in 467 Patients. Orthop J Sports Med 2020; 8:2325967120969189. [PMID: 33415176 PMCID: PMC7750771 DOI: 10.1177/2325967120969189] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 06/26/2020] [Indexed: 12/11/2022] Open
Abstract
Background A cell-based tissue engineering approach that uses mesenchymal stem cells (MSCs) has addressed the issue of articular cartilage repair in knees with osteoarthritis (OA). Purpose To evaluate the midterm outcomes, analyze the survival rates, and identify the factors affecting the survival rate of MSC implantation to treat knee OA. Study Design Case series; Level of evidence, 4. Methods We retrospectively evaluated 467 patients (483 knees) who underwent MSC implantation on a fibrin glue scaffold for knee OA with a minimum 5-year follow-up. Clinical outcomes were determined based on the International Knee Documentation Committee (IKDC) and Tegner activity scale results measured preoperatively and during follow-up. Standard radiographs were evaluated using Kellgren-Lawrence grading. Statistical analyses were performed to determine the survival rate and the effect of different factors on the clinical outcomes. Results The mean IKDC scores (baseline, 39.2 ± 7.2; 1 year, 66.6 ± 9.6; 3 years, 67.2 ± 9.9; 5 years, 66.1 ± 9.7; 9 years, 62.8 ± 8.5) and Tegner scores (baseline, 2.3 ± 1.0; 1 year, 3.4 ± 0.9; 3 years, 3.5 ± 0.9; 5 years, 3.4 ± 0.9; 9 years, 3.2 ± 0.9) were significantly improved until 3 years postoperatively and gradually decreased from 3- to 9-year follow-up (P < .05 for all, except for Tegner score at 5 years vs 1 year [P = .237]). Gradual deterioration of radiological outcomes according to the Kellgren-Lawrence grade was found during follow-up. Survival rates based on either a decrease in IKDC or an advancement of radiographic OA with Kellgren-Lawrence scores were 99.8%, 94.5%, and 74.5% at 5, 7, and 9 years, respectively. Based on multivariate analyses, older age and the presence of bipolar kissing lesion were associated with significantly worse outcomes (P = .002 and .013, respectively), and a larger number of MSCs was associated with significantly better outcomes (P < .001) after MSC implantation. Conclusion MSC implantation provided encouraging outcomes with acceptable duration of symptom relief at midterm follow-up in patients with early knee OA. Patient age, presence of bipolar kissing lesion, and number of MSCs were independent factors associated with failure of MSC implantation.
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Affiliation(s)
- Yong Sang Kim
- Center for Stem Cell & Arthritis Research, Department of Orthopaedic Surgery, Yonsei Sarang Hospital, Seoul, Republic of Korea
| | - Dong Suk Suh
- Center for Stem Cell & Arthritis Research, Department of Orthopaedic Surgery, Yonsei Sarang Hospital, Seoul, Republic of Korea
| | - Dae Hyun Tak
- Center for Stem Cell & Arthritis Research, Department of Orthopaedic Surgery, Yonsei Sarang Hospital, Seoul, Republic of Korea
| | - Pill Ku Chung
- Center for Stem Cell & Arthritis Research, Department of Orthopaedic Surgery, Yonsei Sarang Hospital, Seoul, Republic of Korea
| | - Yong Gon Koh
- Center for Stem Cell & Arthritis Research, Department of Orthopaedic Surgery, Yonsei Sarang Hospital, Seoul, Republic of Korea
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Udalamaththa VL, Kaluarachchi A, Wijeratne S, Udagama PV. Therapeutic uses of post-partum tissue-derived mesenchymal stromal cell secretome. Indian J Med Res 2020; 152:541-552. [PMID: 34145093 PMCID: PMC8224162 DOI: 10.4103/ijmr.ijmr_1450_18] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Indexed: 12/24/2022] Open
Abstract
Human post-partum tissue mesenchymal stromal cells (hPPT-MSCs) are widely used in research to investigate their differentiation capabilities and therapeutic effects as potential agents in cell-based therapy. This is ascribed to the advantages offered by the use of MSCs isolated from hPPT over other MSC sources. A paradigm shift in related research is evident that focuses on the secretome of the human MSCs (hMSCs), as therapeutic effects of hMSCs are attributed more so to their secreted growth factors, cytokines and chemokines and to the extracellular vesicles (EVs), all of which are components of the hMSC secretome. Positive therapeutic effects of the hPPT-MSC secretome have been demonstrated in diseases related to skin, kidney, heart, nervous system, cartilage and bones, that have aided fast recovery by replacing damaged, non-functional tissues, via differentiating and regenerating cells. Although certain limitations such as short half -life of the secretome components and irregular secreting patterns exist in secretome therapy, these issues are successfully addressed with the use of cutting-edge technologies such as genome editing and recombinant cytokine treatment. If the current limitations can be successfully overcome, the hPPT-MSC secretome including its EVs may be developed into a cost-effective therapeutic agent amenable to be used against a wide range of diseases/disorders.
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Affiliation(s)
| | - Athula Kaluarachchi
- Department of Obstetrics & Gynaecology, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
| | | | - Preethi Vidya Udagama
- Department of Zoology & Environment Sciences, Faculty of Science, University of Colombo, Colombo, Sri Lanka
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34
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Kangari P, Talaei-Khozani T, Razeghian-Jahromi I, Razmkhah M. Mesenchymal stem cells: amazing remedies for bone and cartilage defects. Stem Cell Res Ther 2020; 11:492. [PMID: 33225992 PMCID: PMC7681994 DOI: 10.1186/s13287-020-02001-1] [Citation(s) in RCA: 157] [Impact Index Per Article: 31.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 10/27/2020] [Indexed: 12/15/2022] Open
Abstract
Skeletal disorders are among the leading debilitating factors affecting millions of people worldwide. The use of stem cells for tissue repair has raised many promises in various medical fields, including skeletal disorders. Mesenchymal stem cells (MSCs) are multipotent stromal cells with mesodermal and neural crest origin. These cells are one of the most attractive candidates in regenerative medicine, and their use could be helpful in repairing and regeneration of skeletal disorders through several mechanisms including homing, angiogenesis, differentiation, and response to inflammatory condition. The most widely studied sources of MSCs are bone marrow (BM), adipose tissue, muscle, umbilical cord (UC), umbilical cord blood (UCB), placenta (PL), Wharton's jelly (WJ), and amniotic fluid. These cells are capable of differentiating into osteoblasts, chondrocytes, adipocytes, and myocytes in vitro. MSCs obtained from various sources have diverse capabilities of secreting many different cytokines, growth factors, and chemokines. It is believed that the salutary effects of MSCs from different sources are not alike in terms of repairing or reformation of injured skeletal tissues. Accordingly, differential identification of MSCs' secretome enables us to make optimal choices in skeletal disorders considering various sources. This review discusses and compares the therapeutic abilities of MSCs from different sources for bone and cartilage diseases.
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Affiliation(s)
- Parisa Kangari
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Tahereh Talaei-Khozani
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
- Tissue Engineering Laboratory, Department of Anatomy, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Mahboobeh Razmkhah
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
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35
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Liu JF, Chen PC, Chang TM, Hou CH. Thrombospondin-2 stimulates MMP-9 production and promotes osteosarcoma metastasis via the PLC, PKC, c-Src and NF-κB activation. J Cell Mol Med 2020; 24:12826-12839. [PMID: 33021341 PMCID: PMC7686970 DOI: 10.1111/jcmm.15874] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 08/20/2020] [Accepted: 08/27/2020] [Indexed: 12/11/2022] Open
Abstract
Osteosarcoma is an extremely common primary bone malignancy that is highly metastatic, with most deaths resulting from pulmonary metastases. The extracellular matrix protein thrombospondin‐2 (TSP‐2) is key to many biological processes, such as inflammation, wound repair and tissue remodelling. However, it is unclear as to what biological role TSP‐2 plays in human metastatic osteosarcoma. The immunochemistry analysis from osteosarcoma specimens identified marked up‐regulation of TSP‐2 in late‐stage osteosarcoma. Furthermore, we found that TSP‐2 increased the levels of matrix metallopeptidase 9 (MMP‐9) expression and thereby increased the migratory potential of human osteosarcoma cells. Osteosarcoma cells pre‐treated with an MMP‐9 monoclonal antibody (mAb), an MMP‐9 inhibitor, or transfected with MMP‐9 small interfering RNA (siRNA) reduced the capacity of TSP‐2 to potentiate cell migration. TSP‐2 treatment activated the PLCβ, PKCα, c‐Src and nuclear kappa factor B (NF‐κB) signalling pathways, while the specific siRNA, inhibitors and mutants of these cascades reduced TSP‐2‐induced stimulation of migration activity. Knockdown of TSP‐2 expression markedly reduced cell metastasis in cellular and animal experiments. It appears that an interaction between TSP‐2 and integrin αvβ3 activates the PLCβ, PKCα and c‐Src signalling pathways and subsequently activates NF‐κB signalling, increasing MMP‐9 expression and stimulating migratory activity amongst human osteosarcoma cells.
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Affiliation(s)
- Ju-Fang Liu
- School of Oral Hygiene, College of Oral Medicine, Taipei Medical University, Taipei City, Taiwan.,Translational Medicine Center, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei City, Taiwan.,Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - Po-Chun Chen
- Translational Medicine Center, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei City, Taiwan.,Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.,Department of Biotechnology, College of Medical and Health Science, Asia University, Taichung, Taiwan
| | - Tsung-Ming Chang
- School of Medicine, Institute of Physiology, National Yang-Ming University, Taipei City, Taiwan
| | - Chun-Han Hou
- Department of Orthopedic Surgery, National Taiwan University Hospital, Taipei City, Taiwan
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Semba S, Kitamura N, Tsuda M, Goto K, Kurono S, Ohmiya Y, Kurokawa T, Gong JP, Yasuda K, Tanaka S. Synthetic poly(2-acrylamido-2-methylpropanesulfonic acid) gel induces chondrogenic differentiation of ATDC5 cells via a novel protein reservoir function. J Biomed Mater Res A 2020; 109:354-364. [PMID: 32496623 DOI: 10.1002/jbm.a.37028] [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: 06/25/2019] [Revised: 04/12/2020] [Accepted: 04/19/2020] [Indexed: 11/09/2022]
Abstract
We previously demonstrated that a synthetic negatively charged poly(2-acrylamido-2-methylpropanesulfonic acid) (PAMPS) gel induced chondrogenic differentiation of ATDC5 cells. In this study, we clarified the underlying molecular mechanism, in particular, focusing on the events that occurred at the interface between the gel and the cells. Gene expression profiling revealed that the expression of extracellular components was enhanced in the ATDC5 cells that were cultured on the PAMPS gel, suggesting that extracellular proteins secreted from the ATDC5 cells might be adsorbed in the PAMPS gel, thereby contributing to the induction of chondrogenic differentiation. Therefore, we created "Treated-PAMPS gel," which adsorbed various proteins secreted from the cultured ATDC5 cells during 7 days. Proteomic analysis identified 27 proteins, including extracellular matrix proteins such as Types I, III, and V collagens and thrombospondin (THBS) in the Treated-PAMPS gel. The Treated-PAMPS gel preferentially induced expression of chondrogenic markers, namely, aggrecan and Type II collagen, in the ATDC5 cells compared with the untreated PAMPS gel. Addition of recombinant THBS1 to the ATDC5 cells significantly enhanced the PAMPS-induced chondrogenic differentiation, whereas knockdown of THBS1 completely abolished this response. In conclusion, we demonstrated that the PAMPS gel has the potential to induce chondrogenic differentiation through novel reservoir functions, and the adsorbed THBS plays a significant role in the induction.
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Affiliation(s)
- Shingo Semba
- Department of Sports Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Nobuto Kitamura
- Department of Sports Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.,Global Station for Soft Matter, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo, Japan
| | - Masumi Tsuda
- Global Station for Soft Matter, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo, Japan.,Department of Cancer Pathology, Faculty of Medicine, Hokkaido University, Sapporo, Japan.,Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo, Japan
| | - Keiko Goto
- Department of Sports Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Sadamu Kurono
- Laboratory of Molecular Signature Analysis, Division of Health Science, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yoshihiro Ohmiya
- Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology, Ibaraki, Japan
| | - Takayuki Kurokawa
- Global Station for Soft Matter, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo, Japan.,Laboratory of Soft & Wet Matter, Faculty of Advanced Life Science, Hokkaido University, Sapporo, Japan
| | - Jian Ping Gong
- Global Station for Soft Matter, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo, Japan.,Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo, Japan.,Laboratory of Soft & Wet Matter, Faculty of Advanced Life Science, Hokkaido University, Sapporo, Japan
| | - Kazunori Yasuda
- Department of Sports Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.,Global Station for Soft Matter, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo, Japan
| | - Shinya Tanaka
- Global Station for Soft Matter, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo, Japan.,Department of Cancer Pathology, Faculty of Medicine, Hokkaido University, Sapporo, Japan.,Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo, Japan
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37
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Lee K, Go G, Yoo A, Kang B, Choi E, Park JO, Kim CS. Wearable Fixation Device for a Magnetically Controllable Therapeutic Agent Carrier: Application to Cartilage Repair. Pharmaceutics 2020; 12:E593. [PMID: 32604748 PMCID: PMC7355457 DOI: 10.3390/pharmaceutics12060593] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 06/23/2020] [Accepted: 06/24/2020] [Indexed: 11/17/2022] Open
Abstract
Recently, significant research efforts have been devoted toward the development of magnetically controllable drug delivery systems, however, drug fixation after targeting remains a challenge hindering long-term therapeutic efficacy. To overcome this issue, we present a wearable therapeutic fixation device for fixing magnetically controllable therapeutic agent carriers (MCTACs) at defect sites and its application to cartilage repair using stem cell therapeutics. The developed device comprises an array of permanent magnets based on the Halbach array principle and a wearable band capable of wrapping the target body. The design of the permanent magnet array, in terms of the number of magnets and array configuration, was determined through univariate search optimization and 3D simulation. The device was fabricated for a given rat model and yielded a strong magnetic flux density (exceeding 40 mT) in the region of interest that was capable of fixing the MCTAC at the desired defect site. Through in-vitro and in-vivo experiments, we successfully demonstrated that MCTACs, both a stem cell spheroid and a micro-scaffold for cartilage repair, could be immobilized at defect sites. This research is expected to advance precise drug delivery technology based on MCTACs, enabling subject-specific routine life therapeutics. Further studies involving the proposed wearable fixation device will be conducted considering prognostics under actual clinical settings.
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Affiliation(s)
- Kyungmin Lee
- School of Mechanical Engineering, Chonnam National University, Gwangju 61186, Korea; (K.L.); (G.G.); (E.C.)
- Korea Institute of Medical Microrobotics, Gwangju 61011, Korea; (A.Y.); (B.K.)
| | - Gwangjun Go
- School of Mechanical Engineering, Chonnam National University, Gwangju 61186, Korea; (K.L.); (G.G.); (E.C.)
- Korea Institute of Medical Microrobotics, Gwangju 61011, Korea; (A.Y.); (B.K.)
| | - Ami Yoo
- Korea Institute of Medical Microrobotics, Gwangju 61011, Korea; (A.Y.); (B.K.)
| | - Byungjeon Kang
- Korea Institute of Medical Microrobotics, Gwangju 61011, Korea; (A.Y.); (B.K.)
| | - Eunpyo Choi
- School of Mechanical Engineering, Chonnam National University, Gwangju 61186, Korea; (K.L.); (G.G.); (E.C.)
- Korea Institute of Medical Microrobotics, Gwangju 61011, Korea; (A.Y.); (B.K.)
| | - Jong-Oh Park
- School of Mechanical Engineering, Chonnam National University, Gwangju 61186, Korea; (K.L.); (G.G.); (E.C.)
- Korea Institute of Medical Microrobotics, Gwangju 61011, Korea; (A.Y.); (B.K.)
| | - Chang-Sei Kim
- School of Mechanical Engineering, Chonnam National University, Gwangju 61186, Korea; (K.L.); (G.G.); (E.C.)
- Korea Institute of Medical Microrobotics, Gwangju 61011, Korea; (A.Y.); (B.K.)
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Song JS, Hong KT, Kong CG, Kim NM, Jung JY, Park HS, Kim YJ, Chang KB, Kim SJ. High tibial osteotomy with human umbilical cord blood-derived mesenchymal stem cells implantation for knee cartilage regeneration. World J Stem Cells 2020; 12:514-526. [PMID: 32742568 PMCID: PMC7360989 DOI: 10.4252/wjsc.v12.i6.514] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 04/24/2020] [Accepted: 05/12/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND High tibial osteotomy (HTO) is a well-established method for the treatment of medial compartment osteoarthritis of the knee with varus deformity. However, HTO alone cannot adequately repair the arthritic joint, necessitating cartilage regeneration therapy. Cartilage regeneration procedures with concomitant HTO are used to improve the clinical outcome in patients with varus deformity.
AIM To evaluate cartilage regeneration after implantation of allogenic human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) with concomitant HTO.
METHODS Data for patients who underwent implantation of hUCB-MSCs with concomitant HTO were evaluated. The patients included in this study were over 40 years old, had a varus deformity of more than 5°, and a full-thickness International Cartilage Repair Society (ICRS) grade IV articular cartilage lesion of more than 4 cm2 in the medial compartment of the knee. All patients underwent second-look arthroscopy during hardware removal. Cartilage regeneration was evaluated macroscopically using the ICRS grading system in second-look arthroscopy. We also assessed the effects of patient characteristics, such as trochlear lesions, age, and lesion size, using patient medical records.
RESULTS A total of 125 patients were included in the study, with an average age of 58.3 ± 6.8 years (range: 43-74 years old); 95 (76%) were female and 30 (24%) were male. The average hip-knee-ankle (HKA) angle for measuring varus deformity was 7.6° ± 2.4° (range: 5.0-14.2°). In second-look arthroscopy, the status of medial femoral condyle (MFC) cartilage was as follows: 73 (58.4%) patients with ICRS grade I, 37 (29.6%) with ICRS grade II, and 15 (12%) with ICRS grade III. No patients were staged with ICRS grade IV. Additionally, the scores [except International Knee Documentation Committee (IKDC) at 1 year] of the ICRS grade I group improved more significantly than those of the ICRS grade II and III groups.
CONCLUSION Implantation of hUCB-MSCs with concomitant HTO is an effective treatment for patients with medial compartment osteoarthritis and varus deformity. Regeneration of cartilage improves the clinical outcomes for the patients.
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Affiliation(s)
- Jun-Seob Song
- Department of Orthopedic Surgery, Gangnam JS Hospital, Seoul 06053, South Korea
| | - Ki-Taek Hong
- Department of Orthopedic Surgery, Gangnam JS Hospital, Seoul 06053, South Korea
| | - Chae-Gwan Kong
- Department of Orthopedic Surgery, College of Medicine, The Catholic University of Korea, Uijeongbu-si 11765, South Korea
| | - Na-Min Kim
- Department of Orthopedic Surgery, Gangnam JS Hospital, Seoul 06053, South Korea
| | - Jae-Yub Jung
- Department of Orthopedic Surgery, Gangnam JS Hospital, Seoul 06053, South Korea
| | - Han-Soo Park
- Department of Orthopedic Surgery, Gangnam JS Hospital, Seoul 06053, South Korea
| | - Young Ju Kim
- Department of Nursing Education & Administration, Uijeongbu St. Mary’s Hospital, The Catholic University of Korea, Uijeongbu-si 11765, South Korea
| | - Ki Bong Chang
- Department of Orthopedic Surgery, College of Medicine, The Catholic University of Korea, Uijeongbu-si 11765, South Korea
| | - Seok Jung Kim
- Department of Orthopedic Surgery, College of Medicine, The Catholic University of Korea, Uijeongbu-si 11765, South Korea
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Jeon HJ, Yoon KA, An ES, Kang TW, Sim YB, Ahn J, Choi EK, Lee S, Seo KW, Kim YB, Kang KS. Therapeutic Effects of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Combined with Cartilage Acellular Matrix Mediated Via Bone Morphogenic Protein 6 in a Rabbit Model of Articular Cruciate Ligament Transection. Stem Cell Rev Rep 2020; 16:596-611. [PMID: 32112264 DOI: 10.1007/s12015-020-09958-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Osteoarthritis (OA) is a general joint disease. Cartilage damage is associated with a decrease in the density of chondrocytes. Mesenchymal stem cells (MSCs) differentiate into adipocytes, osteocytes and chondrocytes, and are an excellent source of cell therapy. Cartilage-derived extracellular matrix (ECM) promotes chondrogenesis of MSCs. However, the role of MSCs stimulated by ECM is not well known in OA. The purpose of this study is to determine the role of specific factors generated by the application of ECM and umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) in managing OA symptoms. Cartilage acellular matrix (CAM), which is a cartilage-derived ECM, was used to promote the chondrogenesis of UCB-MSCs. Induced MSCs were analyzed using chondrogenic markers (aggrecan, collagen type 2, and SOX9) and bone morphogenic protein 6 (BMP6). BMP6 is known to be involved in early chondrogenesis of MSCs. As a result, treatment with CAM significantly increased the expression of chondrogenic markers and BMP6 in UCB-MSCs. Treatment with recombinant human BMP6 also dramatically increased the levels of chondrogenic markers in UCB-MSCs. In addition, UCB-MSCs and CAM were used to evaluate OA symptom improvement in a rabbit articular cruciate ligament transection (ACLT) model. Application of UCB-MSCs and CAM enhanced not only the structure and synthesis of proteoglycan and collagen type 2 but also anti-inflammatory effects in both rabbit joint and synovial fluid. Moreover, the detection of human cells and involvement of BMP6 were confirmed in rabbit cartilage tissues. This study indicates that therapeutic potential of UCB-MSCs with CAM is mediated via BMP6 in OA.
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Affiliation(s)
- Hyo-Jin Jeon
- Institute for Stem Cell and Regenerative Medicine in Kangstem Biotech, Seoul, Republic of Korea
| | - Kyung-Ae Yoon
- Institute for Stem Cell and Regenerative Medicine in Kangstem Biotech, Seoul, Republic of Korea
| | - Eun Suk An
- College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungbuk National University, Cheongju, Republic of Korea
| | - Tae-Wook Kang
- Institute for Stem Cell and Regenerative Medicine in Kangstem Biotech, Seoul, Republic of Korea
| | - Yun-Beom Sim
- Institute for Stem Cell and Regenerative Medicine in Kangstem Biotech, Seoul, Republic of Korea
| | - Jongchan Ahn
- Institute for Stem Cell and Regenerative Medicine in Kangstem Biotech, Seoul, Republic of Korea
| | - Ehn-Kyung Choi
- College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungbuk National University, Cheongju, Republic of Korea
| | - Seunghee Lee
- Institute for Stem Cell and Regenerative Medicine in Kangstem Biotech, Seoul, Republic of Korea
| | - Kwang-Won Seo
- Institute for Stem Cell and Regenerative Medicine in Kangstem Biotech, Seoul, Republic of Korea.
| | - Yun-Bae Kim
- College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungbuk National University, Cheongju, Republic of Korea.
| | - Kyung-Sun Kang
- Institute for Stem Cell and Regenerative Medicine in Kangstem Biotech, Seoul, Republic of Korea.
- Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
- Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
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Arrigoni C, D’Arrigo D, Rossella V, Candrian C, Albertini V, Moretti M. Umbilical Cord MSCs and Their Secretome in the Therapy of Arthritic Diseases: A Research and Industrial Perspective. Cells 2020; 9:cells9061343. [PMID: 32481562 PMCID: PMC7348802 DOI: 10.3390/cells9061343] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 05/20/2020] [Accepted: 05/26/2020] [Indexed: 02/06/2023] Open
Abstract
The prevalence of arthritic diseases is increasing in developed countries, but effective treatments are currently lacking. The injection of mesenchymal stem cells (MSCs) represents a promising approach to counteract the degenerative and inflammatory environment characterizing those pathologies, such as osteoarthritis (OA). However, the majority of clinical approaches based on MSCs are used within an autologous paradigm, with important limitations. For this reason, allogeneic MSCs isolated from cord blood (cbMSCs) and Wharton’s jelly (wjMSCs) gained increasing interest, demonstrating promising results in this field. Moreover, recent evidences shows that MSCs beneficial effects can be related to their secretome rather than to the presence of cells themselves. Among the trophic factors secreted by MSCs, extracellular vesicles (EVs) are emerging as a promising candidate for the treatment of arthritic joints. In the present review, the application of umbilical cord MSCs and their secretome as innovative therapeutic approaches in the treatment of arthritic joints will be examined. With the prospective of routine clinical applications, umbilical cord MSCs and EVs will be discussed also within an industrial and regulatory perspective.
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Affiliation(s)
- Chiara Arrigoni
- Regenerative Medicine Technologies Laboratory, Ente Ospedaliero Cantonale (EOC), via Tesserete 46, 6900 Lugano, Switzerland; (C.A.); (D.D.)
| | - Daniele D’Arrigo
- Regenerative Medicine Technologies Laboratory, Ente Ospedaliero Cantonale (EOC), via Tesserete 46, 6900 Lugano, Switzerland; (C.A.); (D.D.)
| | - Valeria Rossella
- Swiss Stem Cells Biotech, Via Pizzamiglio 12, 6833 Vacallo, Switzerland; (V.R.); (V.A.)
| | - Christian Candrian
- Unità di Ortopedia e Traumatologia, Ospedale Regionale di Lugano, Ente Ospedaliero Cantonale (EOC), via Tesserete 46, 6900 Lugano, Switzerland;
- Faculty of Biomedical Sciences, Università della Svizzera Italiana, Via Buffi 13, 6900 Lugano, Switzerland
| | - Veronica Albertini
- Swiss Stem Cells Biotech, Via Pizzamiglio 12, 6833 Vacallo, Switzerland; (V.R.); (V.A.)
| | - Matteo Moretti
- Regenerative Medicine Technologies Laboratory, Ente Ospedaliero Cantonale (EOC), via Tesserete 46, 6900 Lugano, Switzerland; (C.A.); (D.D.)
- Cell and Tissue Engineering Laboratory, IRCCS Istituto Ortopedico Galeazzi, via R. Galeazzi 4., 20161 Milano, Italy
- Correspondence: ; Tel.: +41-91-811-7076
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Kim GB, Shon OJ. Current perspectives in stem cell therapies for osteoarthritis of the knee. Yeungnam Univ J Med 2020; 37:149-158. [PMID: 32279478 PMCID: PMC7384917 DOI: 10.12701/yujm.2020.00157] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 04/01/2020] [Indexed: 12/15/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are emerging as an attractive option for osteoarthritis (OA) of the knee joint, due to their marked disease-modifying ability and chondrogenic potential. MSCs can be isolated from various organ tissues, such as bone marrow, adipose tissue, synovium, umbilical cord blood, and articular cartilage with similar phenotypic characteristics but different proliferation and differentiation potentials. They can be differentiated into a variety of connective tissues such as bone, adipose tissue, cartilage, intervertebral discs, ligaments, and muscles. Although several studies have reported on the clinical efficacy of MSCs in knee OA, the results lack consistency. Furthermore, there is no consensus regarding the proper cell dosage and application method to achieve the optimal effect of stem cells. Therefore, the purpose of this study is to review the characteristics of various type of stem cells in knee OA, especially MSCs. Moreover, we summarize the clinical issues faced during the application of MSCs.
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Affiliation(s)
- Gi Beom Kim
- Department of Orthopedic Surgery, Yeungnam University College of Medicine, Daegu, Korea
| | - Oog-Jin Shon
- Department of Orthopedic Surgery, Yeungnam University College of Medicine, Daegu, Korea
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42
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Engineered cartilage utilizing fetal cartilage-derived progenitor cells for cartilage repair. Sci Rep 2020; 10:5722. [PMID: 32235934 PMCID: PMC7109068 DOI: 10.1038/s41598-020-62580-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Accepted: 01/29/2020] [Indexed: 01/01/2023] Open
Abstract
The aim of this study was to develop a fetal cartilage-derived progenitor cell (FCPC) based cartilage gel through self-assembly for cartilage repair surgery, with clinically useful properties including adhesiveness, plasticity, and continued chondrogenic remodeling after transplantation. Characterization of the gels according to in vitro self-assembly period resulted in increased chondrogenic features over time. Adhesion strength of the cartilage gels were significantly higher compared to alginate gel, with the 2-wk group showing a near 20-fold higher strength (1.8 ± 0.15 kPa vs. 0.09 ± 0.01 kPa, p < 0.001). The in vivo remodeling process analysis of the 2 wk cultured gels showed increased cartilage repair characteristics and stiffness over time, with higher integration-failure stress compared to osteochondral autograft controls at 4 weeks (p < 0.01). In the nonhuman primate investigation, cartilage repair scores were significantly better in the gel group compared to defects alone after 24 weeks (p < 0.001). Cell distribution analysis at 24 weeks showed that human cells remained within the transplanted defects only. A self-assembled, FCPC-based cartilage gel showed chondrogenic repair potential as well as adhesive properties, beneficial for cartilage repair.
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Yin L, Yang Z, Wu Y, Denslin V, Yu CC, Tee CA, Lim CT, Han J, Lee EH. Label-free separation of mesenchymal stem cell subpopulations with distinct differentiation potencies and paracrine effects. Biomaterials 2020; 240:119881. [PMID: 32092592 DOI: 10.1016/j.biomaterials.2020.119881] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 01/23/2020] [Accepted: 02/11/2020] [Indexed: 12/23/2022]
Abstract
Mesenchymal stem cells (MSCs) have the capability to differentiate into multiple cell lineages, and produce trophic factors to facilitate tissue repair and regeneration, and disease regression. However, the heterogeneity of MSCs, whether inherent or developed during culture expansion, has a significant impact on their therapeutic efficacy. Therefore, the ability to identify and select an efficacious subpopulation of MSCs targeting specific tissue damage or disease holds great clinical significance. In this study, we separated three subpopulations from culture expanded human bone marrow derived MSCs according to cell size, using a high-throughput label-free microfluidic cell sorting technology. The size-sorted MSC subpopulations varied in tri-lineage differentiation potencies. The large MSCs showed the strongest osteogenesis, medium-size MSCs were advantageous in chondrogenesis and adipogenesis, and the small MSCs showed the weakest tri-lineage differentiation. The size-sorted MSC subpopulations also exhibited different secretome profiles. The large MSC secretome possessed highest levels of osteogenic promotor proteins and senescence-associated factors, but lower levels of osteogenic inhibitor proteins compared to the medium-size MSC secretome. The medium-size MSC secretome had high levels of chondrogenic promotor proteins, and contained lower levels of chondrogenic inhibitor proteins compared to the large MSC secretome. The secretome of size-sorted MSC subpopulations showed differences in paracrine effects. We found that the secretome of large MSCs enhanced osteogenic and adipogenic potencies during MSC culture expansion, but also induced cell senescence; and the secretome of medium-size MSCs promoted chondrogenesis. This study demonstrates size-dependent differentiation potency and secretome profile of MSC subpopulations, and provides an effective and practical technology to isolate the respective subpopulations, which may be used for more targeted tissue repair and regeneration.
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Affiliation(s)
- Lu Yin
- Critical Analytics for Manufacturing of Personalised Medicine Interdisciplinary Research Group, Singapore-MIT Alliance in Research and Technology, 1 Create Way, #04-13/14, Singapore, 138602, Singapore
| | - Zheng Yang
- Critical Analytics for Manufacturing of Personalised Medicine Interdisciplinary Research Group, Singapore-MIT Alliance in Research and Technology, 1 Create Way, #04-13/14, Singapore, 138602, Singapore; NUS Tissue Engineering Program, Life Sciences Institute, National University of Singapore 27 Medical Drive1, DSO (Kent Bridge) Building, Level 4, Singapore, 11751, Singapore; Department of Orthopaedic Surgery, National University of Singapore, 1E Kent Ridge Road, NUHS Tower block 11, Singapore, 119288, Singapore
| | - Yingnan Wu
- NUS Tissue Engineering Program, Life Sciences Institute, National University of Singapore 27 Medical Drive1, DSO (Kent Bridge) Building, Level 4, Singapore, 11751, Singapore; Department of Orthopaedic Surgery, National University of Singapore, 1E Kent Ridge Road, NUHS Tower block 11, Singapore, 119288, Singapore
| | - Vinitha Denslin
- NUS Tissue Engineering Program, Life Sciences Institute, National University of Singapore 27 Medical Drive1, DSO (Kent Bridge) Building, Level 4, Singapore, 11751, Singapore; Department of Orthopaedic Surgery, National University of Singapore, 1E Kent Ridge Road, NUHS Tower block 11, Singapore, 119288, Singapore
| | - Chia Chen Yu
- Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, 77 Massachusetts Ave, Cambridge, MA 02139, USA
| | - Ching Ann Tee
- Critical Analytics for Manufacturing of Personalised Medicine Interdisciplinary Research Group, Singapore-MIT Alliance in Research and Technology, 1 Create Way, #04-13/14, Singapore, 138602, Singapore; Department of Orthopaedic Surgery, National University of Singapore, 1E Kent Ridge Road, NUHS Tower block 11, Singapore, 119288, Singapore
| | - Chwee Teck Lim
- Critical Analytics for Manufacturing of Personalised Medicine Interdisciplinary Research Group, Singapore-MIT Alliance in Research and Technology, 1 Create Way, #04-13/14, Singapore, 138602, Singapore; Mechanobiology Institute, National University of Singapore, 5A Engineering Drive 1, T-Lab, #10-01, Singapore, 117411, Singapore; Department of Biomedical Engineering, National University of Singapore, 4 Engineering Drive 3, Engineering Block 4, #04-08, Singapore, 117583, Singapore; Institute for Health Innovation and Technology, National University of Singapore, MD6, 14 Medical Drive, #14-01, Singapore, 117599, Singapore
| | - Jongyoon Han
- Critical Analytics for Manufacturing of Personalised Medicine Interdisciplinary Research Group, Singapore-MIT Alliance in Research and Technology, 1 Create Way, #04-13/14, Singapore, 138602, Singapore; Department of Electrical Engineering and Computer Science, Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
| | - Eng Hin Lee
- Critical Analytics for Manufacturing of Personalised Medicine Interdisciplinary Research Group, Singapore-MIT Alliance in Research and Technology, 1 Create Way, #04-13/14, Singapore, 138602, Singapore; NUS Tissue Engineering Program, Life Sciences Institute, National University of Singapore 27 Medical Drive1, DSO (Kent Bridge) Building, Level 4, Singapore, 11751, Singapore; Department of Orthopaedic Surgery, National University of Singapore, 1E Kent Ridge Road, NUHS Tower block 11, Singapore, 119288, Singapore.
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Parate D, Kadir ND, Celik C, Lee EH, Hui JHP, Franco-Obregón A, Yang Z. Pulsed electromagnetic fields potentiate the paracrine function of mesenchymal stem cells for cartilage regeneration. Stem Cell Res Ther 2020; 11:46. [PMID: 32014064 PMCID: PMC6998094 DOI: 10.1186/s13287-020-1566-5] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 01/15/2020] [Accepted: 01/20/2020] [Indexed: 12/17/2022] Open
Abstract
Background The mesenchymal stem cell (MSC) secretome, via the combined actions of its plethora of biologically active factors, is capable of orchestrating the regenerative responses of numerous tissues by both eliciting and amplifying biological responses within recipient cells. MSCs are “environmentally responsive” to local micro-environmental cues and biophysical perturbations, influencing their differentiation as well as secretion of bioactive factors. We have previously shown that exposures of MSCs to pulsed electromagnetic fields (PEMFs) enhanced MSC chondrogenesis. Here, we investigate the influence of PEMF exposure over the paracrine activity of MSCs and its significance to cartilage regeneration. Methods Conditioned medium (CM) was generated from MSCs subjected to either 3D or 2D culturing platforms, with or without PEMF exposure. The paracrine effects of CM over chondrocytes and MSC chondrogenesis, migration and proliferation, as well as the inflammatory status and induced apoptosis in chondrocytes and MSCs was assessed. Results We show that benefits of magnetic field stimulation over MSC-derived chondrogenesis can be partly ascribed to its ability to modulate the MSC secretome. MSCs cultured on either 2D or 3D platforms displayed distinct magnetic sensitivities, whereby MSCs grown in 2D or 3D platforms responded most favorably to PEMF exposure at 2 mT and 3 mT amplitudes, respectively. Ten minutes of PEMF exposure was sufficient to substantially augment the chondrogenic potential of MSC-derived CM generated from either platform. Furthermore, PEMF-induced CM was capable of enhancing the migration of chondrocytes and MSCs as well as mitigating cellular inflammation and apoptosis. Conclusions The findings reported here demonstrate that PEMF stimulation is capable of modulating the paracrine function of MSCs for the enhancement and re-establishment of cartilage regeneration in states of cellular stress. The PEMF-induced modulation of the MSC-derived paracrine function for directed biological responses in recipient cells or tissues has broad clinical and practical ramifications with high translational value across numerous clinical applications. Electronic supplementary material The online version of this article (10.1186/s13287-020-1566-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Dinesh Parate
- Department of Surgery, National University of Singapore, Singapore, 119228, Singapore.,Biolonic Currents Electromagnetic Pulsing Systems Laboratory, BICEPS, National University of Singapore, Singapore, Singapore.,Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, NUHS Tower Block, Level 11, 1E Kent Ridge Road, Singapore, 119288, Singapore
| | - Nurul Dinah Kadir
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, NUHS Tower Block, Level 11, 1E Kent Ridge Road, Singapore, 119288, Singapore
| | - Cenk Celik
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, NUHS Tower Block, Level 11, 1E Kent Ridge Road, Singapore, 119288, Singapore
| | - Eng Hin Lee
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, NUHS Tower Block, Level 11, 1E Kent Ridge Road, Singapore, 119288, Singapore.,Tissue Engineering Program, Life Sciences Institute, National University of Singapore, DSO (Kent Ridge) Building, #04-01, 27 Medical Drive, Singapore, 117510, Singapore
| | - James H P Hui
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, NUHS Tower Block, Level 11, 1E Kent Ridge Road, Singapore, 119288, Singapore.,Tissue Engineering Program, Life Sciences Institute, National University of Singapore, DSO (Kent Ridge) Building, #04-01, 27 Medical Drive, Singapore, 117510, Singapore
| | - Alfredo Franco-Obregón
- Department of Surgery, National University of Singapore, Singapore, 119228, Singapore. .,Biolonic Currents Electromagnetic Pulsing Systems Laboratory, BICEPS, National University of Singapore, Singapore, Singapore. .,Institute for Health Innovation & Technology, iHealthtech, National University of Singapore, Singapore, Singapore.
| | - Zheng Yang
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, NUHS Tower Block, Level 11, 1E Kent Ridge Road, Singapore, 119288, Singapore. .,Tissue Engineering Program, Life Sciences Institute, National University of Singapore, DSO (Kent Ridge) Building, #04-01, 27 Medical Drive, Singapore, 117510, Singapore.
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Implantation of allogenic umbilical cord blood-derived mesenchymal stem cells improves knee osteoarthritis outcomes: Two-year follow-up. Regen Ther 2020; 14:32-39. [PMID: 31988992 PMCID: PMC6965506 DOI: 10.1016/j.reth.2019.10.003] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Revised: 09/20/2019] [Accepted: 10/22/2019] [Indexed: 12/12/2022] Open
Abstract
Introduction Clinical outcomes after the implantation of allogenic human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) in osteoarthritic knees have been rarely reported. Our study aimed to investigate clinical outcomes of osteoarthritic patients who underwent hUCB-MSC implantation. Methods In this case series (level of evidence: 4), from January 2014 to December 2015, 128 patients with full-thickness cartilage lesions (International Cartilage Repair Society grade 4 and Kellgren–Lawrence grade ≤3) who underwent hUCB-MSC implantation were retrospectively evaluated with a minimum of 2-year follow-up. After removing the sclerotic subchondral bone with an arthroscopic burr, 4-mm-diameter holes were created at 2-mm intervals, and hyaluronic acid and hUCB-MSCs were subsequently mixed and implanted in the holes and other articular defect sites. Clinical outcomes were evaluated preoperatively, 1 year postoperatively, and 2 years postoperatively (minimum) using visual analog scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and International Knee Documentation Committee (IKDC) scores. To assess clinical outcomes, patients were divided into two or three groups according to the lesion size, lesion location, number of lesions, body mass index, and age; statistical analyses were performed using these data. Results The mean (±standard deviation) VAS, WOMAC, and IKDC scores at 1 and 2 years after surgery including hUCB-MSC implantation improved significantly compared to the preoperative scores (P < 0.001). There were significant differences in the lesion location (P < 0.05). Medial femoral condyle lesions resulted in worse outcomes compared with lateral femoral condyle and trochlea lesions. No adverse reactions or postoperative complications were noted. Conclusions Implantation of hUCB-MSCs is effective for treating knee osteoarthritis based on a follow-up lasting a minimum of 2 years.
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Key Words
- ACI, autologous chondrocyte implantation
- AT-MSCs, adipose tissue-derived MSCs
- Allogenic
- BM-MSCs, bone marrow-derived MSCs
- BMI, body mass index
- HA, hyaluronic acid
- Human umbilical cord blood
- IKDC, International Knee Documentation Committee
- KL, Kellgren–Lawrence
- Knee osteoarthritis
- LFC, lateral femoral condyle
- MFC, medial femoral condyle
- MRI, magnetic resonance imaging
- Mesenchymal stem cells
- OA, osteoarthritis
- OAT, osteochondral autologous transplantation
- VAS, visual analog scale
- WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index
- hUCB-MSCs, human umbilical cord blood-derived mesenchymal stem cells
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Shin K, Cha Y, Ban YH, Seo DW, Choi EK, Park D, Kang SK, Ra JC, Kim YB. Anti-osteoarthritis effect of a combination treatment with human adipose tissue-derived mesenchymal stem cells and thrombospondin 2 in rabbits. World J Stem Cells 2019; 11:1115-1129. [PMID: 31875872 PMCID: PMC6904861 DOI: 10.4252/wjsc.v11.i12.1115] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 10/14/2019] [Accepted: 11/04/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Osteoarthritis (OA), a chronic age-related disease characterized by the slowly progressive destruction of articular cartilage, is one of the leading causes of disability. As a new strategy for treatment of OA, mesenchymal stem cells (MSCs) have the potential for articular cartilage regeneration. Meanwhile, thrombospondin 2 (TSP2) promotes the chondrogenic differentiation of MSCs. AIM To investigate whether TSP2 induces chondrogenic differentiation of human adipose-derived MSCs (hADMSCs) and potentiates the therapeutic effects of hADMSCs in OA rabbits. METHODS We investigated the chondrogenic potential of TSP2 in hADMSCs by analyzing the expression of chondrogenic markers as well as NOTCH signaling genes in normal and TSP2 small interfering RNA (siRNA)-treated stem cells. Anterior cruciate ligament transection surgery was performed in male New Zealand white rabbits, and 8 wk later, hADMSCs (1.7 × 106 or 1.7 × 107 cells) were injected into the injured knees alone or in combination with intra-articular injection of TSP2 (100 ng/knee) at 2-d intervals. OA progression was monitored by gross, radiological, and histological examinations. RESULTS In hADMSC culture, treatment with TSP2 increased the expression of chondrogenic markers (SOX9 and collagen II) as well as NOTCH signaling genes (JAGGED1 and NOTCH3), which were inhibited by TSP2 siRNA treatment. In vivo, OA rabbits treated with hADMSCs or TSP2 alone exhibited lower degree of cartilage degeneration, osteophyte formation, and extracellular matrix loss 8 wk after cell transplantation. Notably, such cartilage damage was further alleviated by the combination of hADMSCs and TSP2. In addition, synovial inflammatory cytokines, especially tumor-necrosis factor-α, markedly decreased following the combination treatment. CONCLUSION The results indicate that TSP2 enhances chondrogenic differentiation of hADMSCs via JAGGED1/NOTCH3 signaling, and that combination therapy with hADMSCs and TSP2 exerts synergistic effects in the cartilage regeneration of OA joints.
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Affiliation(s)
- Kyungha Shin
- College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Chungbuk, South Korea
| | - Yeseul Cha
- College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Chungbuk, South Korea
| | - Young-Hwan Ban
- College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Chungbuk, South Korea
| | - Da Woom Seo
- College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Chungbuk, South Korea
| | - Ehn-Kyoung Choi
- College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Chungbuk, South Korea
| | - Dongsun Park
- Department of Biology Education, Korea National University of Education, Cheongju 28173, Chungbuk, South Korea
| | - Sung Keun Kang
- Biostar Stem Cell Research Institute, R-BIO Co., Ltd., Seoul 07238, South Korea
| | - Jeong Chan Ra
- Biostar Stem Cell Research Institute, R-BIO Co., Ltd., Seoul 07238, South Korea
| | - Yun-Bae Kim
- College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Chungbuk, South Korea.
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Kwon JH, Kim M, Bae YK, Kim GH, Choi SJ, Oh W, Um S, Jin HJ. Decorin Secreted by Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Induces Macrophage Polarization via CD44 to Repair Hyperoxic Lung Injury. Int J Mol Sci 2019; 20:ijms20194815. [PMID: 31569732 PMCID: PMC6801980 DOI: 10.3390/ijms20194815] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 09/24/2019] [Accepted: 09/26/2019] [Indexed: 12/18/2022] Open
Abstract
Bronchopulmonary dysplasia (BPD), caused by hyperoxia in newborns and infants, results in lung damage and abnormal pulmonary function. However, the current treatments for BPD are steroidal and pharmacological therapies, which cause neurodevelopmental impairment. Treatment with umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) is an efficient alternative approach. To prevent pulmonary inflammation in BPD, this study investigated the hypothesis that a key regulator was secreted by MSCs to polarize inflammatory macrophages into anti-inflammatory macrophages at inflammation sites. Lipopolysaccharide-induced macrophages co-cultured with MSCs secreted low levels of the inflammatory cytokines, IL-8 and IL-6, but high levels of the anti-inflammatory cytokine, IL-10. Silencing decorin in MSCs suppressed the expression of CD44, which mediates anti-inflammatory activity in macrophages. The effects of MSCs were examined in a rat model of hyperoxic lung damage. Macrophage polarization differed depending on the levels of decorin secreted by MSCs. Moreover, intratracheal injection of decorin-silenced MSCs or MSCs secreting low levels of decorin confirmed impaired alveolarization of damaged lung tissues by down-regulation of decorin. In tissues, a decrease in the anti-inflammatory macrophage marker, CD163, was observed via CD44. Thus, we identified decorin as a key paracrine factor, inducing macrophage polarization via CD44, a master immunoregulator in mesenchymal stem cells.
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Affiliation(s)
- Ji Hye Kwon
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, Korea.
| | - Miyeon Kim
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, Korea.
| | - Yun Kyung Bae
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, Korea.
| | - Gee-Hye Kim
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, Korea.
| | - Soo Jin Choi
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, Korea.
| | - Wonil Oh
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, Korea.
| | - Soyoun Um
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, Korea.
| | - Hye Jin Jin
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, Korea.
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48
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Derakhshani M, Abbaszadeh H, Movassaghpour AA, Mehdizadeh A, Ebrahimi-Warkiani M, Yousefi M. Strategies for elevating hematopoietic stem cells expansion and engraftment capacity. Life Sci 2019; 232:116598. [PMID: 31247209 DOI: 10.1016/j.lfs.2019.116598] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2019] [Revised: 06/22/2019] [Accepted: 06/23/2019] [Indexed: 02/07/2023]
Abstract
Hematopoietic stem cells (HSCs) are a rare cell population in adult bone marrow, mobilized peripheral blood, and umbilical cord blood possessing self-renewal and differentiation capability into a full spectrum of blood cells. Bone marrow HSC transplantation has been considered as an ideal option for certain disorders treatment including hematologic diseases, leukemia, immunodeficiency, bone marrow failure syndrome, genetic defects such as thalassemia, sickle cell anemia, autoimmune disease, and certain solid cancers. Ex vivo proliferation of these cells prior to transplantation has been proposed as a potential solution against limited number of stem cells. In such culture process, MSCs have also been shown to exhibit high capacity for secretion of soluble mediators contributing to the principle biological and therapeutic activities of HSCs. In addition, endothelial cells have been introduced to bridge the blood and sub tissues in the bone marrow, as well as, HSCs regeneration induction and survival. Cell culture in the laboratory environment requires cell growth strict control to protect against contamination, symmetrical cell division and optimal conditions for maximum yield. In this regard, microfluidic systems provide culture and analysis capabilities in micro volume scales. Moreover, two-dimensional cultures cannot fully demonstrate extracellular matrix found in different tissues and organs as an abstract representation of three dimensional cell structure. Microfluidic systems can also strongly describe the effects of physical factors such as temperature and pressure on cell behavior.
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Affiliation(s)
- Mehdi Derakhshani
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hossein Abbaszadeh
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Akbar Movassaghpour
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Mehdizadeh
- Endocrine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Majid Ebrahimi-Warkiani
- School of Biomedical Engineering, University Technology of Sydney, Sydney, New South Wales, 2007, Australia
| | - Mehdi Yousefi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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49
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Lee WS, Kim HJ, Kim KI, Kim GB, Jin W. Intra-Articular Injection of Autologous Adipose Tissue-Derived Mesenchymal Stem Cells for the Treatment of Knee Osteoarthritis: A Phase IIb, Randomized, Placebo-Controlled Clinical Trial. Stem Cells Transl Med 2019; 8:504-511. [PMID: 30835956 PMCID: PMC6525553 DOI: 10.1002/sctm.18-0122] [Citation(s) in RCA: 307] [Impact Index Per Article: 51.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Accepted: 01/08/2019] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have been the focus of an emerging treatment for osteoarthritis. However, few studies reported about outcomes of an intra-articular injection of autologous adipose-derived mesenchymal stem cells (AD-MSCs). This study aimed to assess the efficacy and safety of a single intra-articular injection of AD-MSCs for patients with knee osteoarthritis. It was a prospective double-blinded, randomized controlled, phase IIb clinical trial. AD-MSCs were administered for 12 patients (MSC group), and the group was compared with 12 knees with injection of normal saline (control group) up to 6 months. All procedures were performed in the outpatient clinic. Primary outcome measure was the Western Ontario and McMaster Universities Osteoarthritis index (WOMAC) score. Secondary outcome measure included various clinical and radiologic examination, and safety after injection. Change of cartilage defect after injection was evaluated using magnetic resonance imaging (MRI). Single injection of AD-MSCs led to a significant improvement of the WOMAC score at 6 months. In the control group, there was no significant change in the WOMAC score at 6 months. No serious adverse events were observed in both groups during the follow-up period. In MRI, there was no significant change of cartilage defect at 6 months in MSC group whereas the defect in the control group was increased. An intra-articular injection of autologous AD-MSCs provided satisfactory functional improvement and pain relief for patients with knee osteoarthritis in the outpatient setting, without causing adverse events at 6 months' follow-up. Larger sample size and long-term follow-up are required. Stem Cells Translational Medicine 2019;8:504-511.
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Affiliation(s)
- Woo-Suk Lee
- Department of Orthopaedic Surgery, College of Medicine, Gangnam Severance Hospital, Yonsei University, Seoul, South Korea
| | - Hwan Jin Kim
- Department of Orthopaedic Surgery, Center for Joint Diseases and Rheumatism, Kyung Hee University Hospital at Gangdong, Seoul, South Korea.,School of Medicine, Kyung Hee University, Seoul, South Korea
| | - Kang-Il Kim
- Department of Orthopaedic Surgery, Center for Joint Diseases and Rheumatism, Kyung Hee University Hospital at Gangdong, Seoul, South Korea.,School of Medicine, Kyung Hee University, Seoul, South Korea
| | - Gi Beom Kim
- Department of Orthopaedic Surgery, Center for Joint Diseases and Rheumatism, Kyung Hee University Hospital at Gangdong, Seoul, South Korea.,School of Medicine, Kyung Hee University, Seoul, South Korea
| | - Wook Jin
- Department of Radiology, Kyung Hee University Hospital at Gangdong, Seoul, South Korea
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50
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Park YB, Ha CW, Kim JA, Kim S, Park YG. Comparison of Undifferentiated Versus Chondrogenic Predifferentiated Mesenchymal Stem Cells Derived From Human Umbilical Cord Blood for Cartilage Repair in a Rat Model. Am J Sports Med 2019; 47:451-461. [PMID: 30640523 DOI: 10.1177/0363546518815151] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) have gained much interest as a promising cell source for regenerative medicine owing to the noninvasive collection, availability, high expansion capacity, and low immunogenicity. However, few in vivo studies have reported the use of hUCB-MSCs on cartilage repair. Moreover, little study has been conducted on the effects of chondrogenic predifferentiation of hUCB-MSCs on cartilage repair. PURPOSE To compare the effectiveness of transplanting undifferentiated versus chondrogenic predifferentiated mesenchymal stem cells (MSCs) for treating osteochondral defects. STUDY DESIGN Controlled laboratory study. METHODS Critical-sized osteochondral defects were created in the trochlear grooves of rat femurs. In 20 rats, a composite of chondrogenic predifferentiated hUCB-MSCs (chondro-MSCs) and 4% hyaluronic acid (HA) hydrogel was transplanted into defects in the right knees, whereas undifferentiated hUCB-MSCs (undiff-MSCs) and 4% HA hydrogel were transplanted into the left knees. In the control groups, 4% HA hydrogel without MSCs was transplanted into defects in the right knees, and the defects in the left knees were left untreated in 20 rats. The cartilage repair was evaluated at 8 and 16 weeks after surgery. RESULTS Transplanting undiff-MSCs resulted in overall superior cartilage repair as compared with chondro-MSCs, HA alone, or no treatment. The articular surfaces of the defect sites in the undiff-MSC group were relatively smoother than those of the other treatments. The undiff-MSC group showed cellular morphology and arrangement similar to surrounding normal articular cartilage tissue at 16 weeks, both of which were also better than those of the other groups. In addition, the undiff-MSC group showed coloration similar to surrounding normal articular cartilage tissue at 16 weeks in safranin O and type II collagen immunohistochemical staining. The histological scores also revealed that cartilage repair with undiff-MSCs was better than that with chondro-MSCs, HA alone, or no treatment ( P < .05 in all). CONCLUSION This study demonstrated that treatment with undiff-MSCs resulted in more favorable cartilage repair than that with chondro-MSCs in a rat model. These findings indicate that chondrogenic predifferentiation of MSCs before transplantation does not enhance cartilage repair. CLINICAL RELEVANCE The results of this study support the use of undifferentiated MSCs, rather than chondrogenic predifferentiated MSCs, as a stem cell therapy strategy for cartilage repair.
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Affiliation(s)
- Yong-Beom Park
- Department of Orthopedic Surgery, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Republic of Korea
| | - Chul-Won Ha
- Department of Orthopedic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.,Stem Cell and Regenerative Medicine Institute, Samsung Medical Center, Seoul, Republic of Korea.,Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea
| | - Jin-A Kim
- Department of Orthopedic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.,Stem Cell and Regenerative Medicine Institute, Samsung Medical Center, Seoul, Republic of Korea
| | - Seongchan Kim
- Department of Orthopedic Surgery, Jeju National University Hospital, Jeju National University School of Medicine, Jeju, Republic of Korea
| | - Yong-Geun Park
- Department of Orthopedic Surgery, Jeju National University Hospital, Jeju National University School of Medicine, Jeju, Republic of Korea
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