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Abdul-Azees PA, Rajesh R, Block TJ, Dean DD, Yeh CK, Capitano M, Kacena M, Chen XD, Marinković M. CCN Proteins as Matricellular Regulators of Bone in Aging and Disease. Curr Osteoporos Rep 2025; 23:23. [PMID: 40407982 PMCID: PMC12102002 DOI: 10.1007/s11914-025-00915-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/27/2025] [Indexed: 05/26/2025]
Abstract
PURPOSE OF REVIEW This review explores the role of cell communication network (CCN) proteins in regulating skeletal physiology, aging, and disease, particularly within the context of balanced bone remodeling. RECENT FINDINGS Recent conceptualization of paracrine and endocrine networks in bone marrow as a form of osteoimmunological crosstalk suggests a significant role for matricellular signaling in regulating bone homeostasis. As multifunctional adapters of cell-matrix interactions, CCNs are emerging as a focal point for parathyroid hormone (PTH) signaling and regulation of the RANKL/RANK/OPG axis in skeletal aging. Altered bone marrow CCN expression creates a permissive environment for accelerated postmenopausal bone loss and may contribute to the pathogenesis of osteoporosis and other diseases related to skeletal aging. CCNs modulate fundamental signaling mechanisms in bone development, homeostasis and repair. During aging, dysregulation of CCNs may negatively affect skeletal health and contribute to disease progression. As a result, CCNs may constitute promising therapeutic targets for improving and maintaining aging bone health.
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Affiliation(s)
- Parveez Ahamed Abdul-Azees
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229 - 3900, USA
| | - Rahul Rajesh
- Arkansas College of Osteopathic Medicine, Fort Smith, AR, 72916, USA
| | - Travis J Block
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229 - 3900, USA
| | - David D Dean
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229 - 3900, USA
| | - Chih-Ko Yeh
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229 - 3900, USA
- Research Service, South Texas Veterans Health Care System, San Antonio, TX, 78229, USA
- Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX, 78229, USA
| | - Maegan Capitano
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Melissa Kacena
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
- Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
- Research Service, Richard L. Roudebush VA Medical Center, Indianapolis, IN, 46202, USA
| | - Xiao-Dong Chen
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229 - 3900, USA
- Research Service, South Texas Veterans Health Care System, San Antonio, TX, 78229, USA
- Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX, 78229, USA
- Department of Biomedical Engineering, University of Texas at San Antonio, San Antonio, TX, 78249, USA
| | - Miloš Marinković
- Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX, 78229, USA.
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
- Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
- Research Service, Richard L. Roudebush VA Medical Center, Indianapolis, IN, 46202, USA.
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Choudhery MS, Arif T, Mahmood R, Harris DT. Therapeutic Potential of Mesenchymal Stem Cells in Stroke Treatment. Biomolecules 2025; 15:558. [PMID: 40305341 PMCID: PMC12024902 DOI: 10.3390/biom15040558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2025] [Revised: 04/01/2025] [Accepted: 04/08/2025] [Indexed: 05/02/2025] Open
Abstract
Stroke occurs when the blood flow to the brain is interrupted due to a rupture of blood vessels or blockage in the brain. It is the major cause of physical disabilities in adulthood. Despite advances in surgical and pharmacological therapy, functional recovery from stroke is limited, affecting quality of life. Stem cell therapy, which may treat neurological disorders associated with brain traumas, including stroke, is an important focus in stroke research and treatment. Stem cell therapy has primarily used a type of adult stem cells called mesenchymal stem cells (MSCs) due to their universality and ability to develop into multiple lineages to regenerate brain cells and repair brain tissues. A significant number of clinical studies provide evidence of the potential of MSCs to treat stroke. This review summarizes the therapeutic mechanism and applications of MSCs in stroke treatment. We also highlight the current challenges and future prospects of adult MSC therapy for stroke treatment.
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Affiliation(s)
- Mahmood S. Choudhery
- Department of Human Genetics & Molecular Biology, University of Health Sciences, Lahore 54000, Pakistan; (M.S.C.); (T.A.)
| | - Taqdees Arif
- Department of Human Genetics & Molecular Biology, University of Health Sciences, Lahore 54000, Pakistan; (M.S.C.); (T.A.)
| | - Ruhma Mahmood
- Allama Iqbal Medical College, Jinnah Hospital, Lahore 54000, Pakistan;
| | - David T. Harris
- Department of Immunobiology, University of Arizona Health Sciences Biorepository, College of Medicine, University of Arizona, Tucson, AZ 85721, USA
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Li A, Li X, Zhang Z, Huang Z, He L, Yang Y, Dong J, Cai S, Liu X, Zhao H, He Y. Deep learning assisted prediction of osteogenic capability of orthopedic implant surfaces based on early cell morphology. Acta Biomater 2025; 195:559-568. [PMID: 39894326 DOI: 10.1016/j.actbio.2025.01.059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 01/09/2025] [Accepted: 01/30/2025] [Indexed: 02/04/2025]
Abstract
The surface modification of titanium (Ti) and its alloys is crucial for improving their osteogenic capability, as their bio-inert nature limits effective osseointegration despite their prevalent use in orthopedic implants. However, these modification methods produce varied surface properties, making it challenging to standardize criteria for assessing the osteogenic capacity of implant surfaces. Additionally, traditional evaluation experiments are time-consuming and inefficient. To overcome these limitations, this study introduced a high-throughput, efficient screening method for assessing the osteogenic capability of implant surfaces based on early cell morphology and deep learning. The Orthopedic Implants-Osteogenic Differentiation Network (OIODNet) was developed using early cell morphology images and corresponding alkaline phosphatase (ALP) activity values from cells cultured on Ti and its alloy surfaces, achieving performance metrics exceeding 0.98 across all six evaluation parameters. Validation through metal-polyphenol network (MPN) coatings and cell experiments demonstrated a strong correlation between OIODNet's predictions and actual ALP activity outcomes, confirming its accuracy in predicting osteogenic potential based on early cell morphology. The Osteogenic Predictor application offers an intuitive tool for predicting the osteogenic capacity of implant surfaces. Overall, this research highlights the potential to accelerate progress at the intersection of artificial intelligence and biomaterials, paving the way for more efficient screening of osteogenic capabilities in orthopedic implants. STATEMENT OF SIGNIFICANCE: By leveraging deep learning, this study introduces the Orthopedic Implants-Osteogenic Differentiation Network (OIODNet), which utilizes early cell morphology data and alkaline phosphatase (ALP) activity values to provide a high-throughput, accurate method for predicting osteogenic capability. With performance metrics exceeding 0.98, OIODNet's accuracy was further validated through experiments involving metal-polyphenol network (MPN) coatings, showing a strong correlation between the model's predictions and experimental outcomes. This research offers a powerful tool for more efficient screening of implant surfaces, marking a transformative step in the integration of artificial intelligence and biomaterials, while opening new avenues for advancing orthopedic implant technologies.
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Affiliation(s)
- Andi Li
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China
| | - Xinyi Li
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China
| | - Zhiwen Zhang
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China
| | - Zihui Huang
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China
| | - Liqiang He
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China
| | - Yuhang Yang
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China
| | - Jiapeng Dong
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China
| | - Shuting Cai
- School of Integrated Circuits, Guangdong University of Technology, Guangzhou 510006, China
| | - Xujie Liu
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China.
| | - Hongli Zhao
- The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou 510317, China.
| | - Yan He
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China.
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Zare E, Hosseini ES, Azad FS, Javid A, Javazm RR, Abessi P, Montazeri F, Hoseini SM. Replicative senescence in amniotic fluid-derived mesenchymal stem cells and its impact on their immunomodulatory properties. Histochem Cell Biol 2025; 163:34. [PMID: 40042688 DOI: 10.1007/s00418-025-02364-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/14/2025] [Indexed: 05/13/2025]
Abstract
The expansion of mesenchymal stem cells (MSCs) for clinical applications is often limited by replicative senescence, a growth arrest induced by various stresses during in vitro culture, yet its impact on the immunomodulatory properties of MSCs remains unclear. This study derived MSCs from the amniotic fluid (AF-MSCs) of seven first-trimester pregnancies, characterized them through flow cytometry, and evaluated their osteogenic differentiation potential before expanding the cells to compare immunoregulatory gene expression in proliferative and senescent states. Additionally, an assessment of the adipogenic differentiation potential of AF-MSCs from three samples was conducted following their recovery from approximately 9 months of cryopreservation, with results showing that these recovered cells retain the capacity for adipogenic differentiation. Molecular analysis revealed no significant differences in the expression of key immunoregulatory genes, such as TGFβ, IL-10, IDO, and VCAM-1, between proliferative and senescent cells, although senescent cells showed downregulation of FASL and upregulation of IL-6, COX1, and HLA-G. Markers of cell proliferation, including FOXM1 and B-MYB, were significantly downregulated in senescent cells, confirming the progression of replicative senescence. Despite expectations, the results indicated that some immunomodulatory markers remained stable or were even enhanced in senescent AF-MSCs. These findings highlight the resilience of AF-MSC immunomodulatory properties during prolonged in vitro expansion, supporting their potential for therapeutic applications despite the challenges posed by replicative senescence.
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Affiliation(s)
- Elham Zare
- Medical Genetics and Molecular Medicine Department, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Biological Sciences, Faculty of Science and Engineering, Science and Arts University, Yazd, Iran
| | - Elham Sadat Hosseini
- Abortion Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Faezeh Sadat Azad
- Department of Biological Sciences, Faculty of Science and Engineering, Science and Arts University, Yazd, Iran
| | - Amane Javid
- Department of Biological Sciences, Faculty of Science and Engineering, Science and Arts University, Yazd, Iran
| | - Reza Rafiei Javazm
- Biotechnology Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Panteha Abessi
- Biotechnology Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Fateme Montazeri
- Abortion Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
| | - Seyed Mehdi Hoseini
- Hematology and Oncology Research Center, Non-Communicable Diseases Research Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
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Zhou X, Tian X, Chen J, Li Y, Lv N, Liu H, Liu T, Yang H, Chen X, Xu Y, He F. Youthful Stem Cell Microenvironments: Rejuvenating Aged Bone Repair Through Mitochondrial Homeostasis Remodeling. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2409644. [PMID: 39823536 PMCID: PMC11905074 DOI: 10.1002/advs.202409644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 12/15/2024] [Indexed: 01/19/2025]
Abstract
Extracellular matrix (ECM) derived from mesenchymal stem cells regulates antioxidant properties and bone metabolism by providing a favorable extracellular microenvironment. However, its functional role and molecular mechanism in mitochondrial function regulation and aged bone regeneration remain insufficiently elucidated. This proteomic analysis has revealed a greater abundance of proteins supporting mitochondrial function in the young ECM (Y-ECM) secreted by young bone marrow-derived mesenchymal stem cells (BMMSCs) compared to the aged ECM (A-ECM). Further studies demonstrate that Y-ECM significantly rejuvenates mitochondrial energy metabolism in adult BMMSCs (A-BMMSCs) through the promotion of mitochondrial respiratory functions and amelioration of oxidative stress. A-BMMSCs cultured on Y-ECM exhibited enhanced multi-lineage differentiation potentials in vitro and ectopic bone formation in vivo. Mechanistically, silencing of silent information regulator type 3 (SIRT3) gene abolished the protective impact of Y-ECM on A-BMMSCs. Notably, a novel composite biomaterial combining hyaluronic acid methacrylate hydrogel microspheres with Y-ECM is developed, which yielded substantial improvements in the healing of bone defects in an aged rat model. Collectively, these findings underscore the pivotal role of Y-ECM in maintaining mitochondrial redox homeostasis and present a promising therapeutic strategy for the repair of aged bone defects.
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Affiliation(s)
- Xinfeng Zhou
- Department of OrthopaedicsThe First Affiliated Hospital of Soochow UniversityOrthopedic InstituteMOE Key Laboratory of Geriatric Diseases and ImmunologySuzhou Medical CollegeSoochow UniversitySuzhouJiangsu215000China
| | - Xin Tian
- Department of OrthopaedicsThe First Affiliated Hospital of Soochow UniversityOrthopedic InstituteMOE Key Laboratory of Geriatric Diseases and ImmunologySuzhou Medical CollegeSoochow UniversitySuzhouJiangsu215000China
| | - Jianan Chen
- Department of OrthopaedicsThe First Affiliated Hospital of Soochow UniversityOrthopedic InstituteMOE Key Laboratory of Geriatric Diseases and ImmunologySuzhou Medical CollegeSoochow UniversitySuzhouJiangsu215000China
| | - Yantong Li
- Department of OrthopaedicsThe First Affiliated Hospital of Soochow UniversityOrthopedic InstituteMOE Key Laboratory of Geriatric Diseases and ImmunologySuzhou Medical CollegeSoochow UniversitySuzhouJiangsu215000China
| | - Nanning Lv
- Department of OrthopaedicsThe First Affiliated Hospital of Soochow UniversityOrthopedic InstituteMOE Key Laboratory of Geriatric Diseases and ImmunologySuzhou Medical CollegeSoochow UniversitySuzhouJiangsu215000China
| | - Hao Liu
- Department of OrthopaedicsThe First Affiliated Hospital of Soochow UniversityOrthopedic InstituteMOE Key Laboratory of Geriatric Diseases and ImmunologySuzhou Medical CollegeSoochow UniversitySuzhouJiangsu215000China
| | - Tao Liu
- Department of OrthopaedicsThe First Affiliated Hospital of Soochow UniversityOrthopedic InstituteMOE Key Laboratory of Geriatric Diseases and ImmunologySuzhou Medical CollegeSoochow UniversitySuzhouJiangsu215000China
| | - Huilin Yang
- Department of OrthopaedicsThe First Affiliated Hospital of Soochow UniversityOrthopedic InstituteMOE Key Laboratory of Geriatric Diseases and ImmunologySuzhou Medical CollegeSoochow UniversitySuzhouJiangsu215000China
| | - Xi Chen
- Department of PathologyThe Third Affiliated Hospital of Soochow UniversityChangzhouJiangsu213000China
| | - Yong Xu
- Department of OrthopaedicsThe First Affiliated Hospital of Soochow UniversityOrthopedic InstituteMOE Key Laboratory of Geriatric Diseases and ImmunologySuzhou Medical CollegeSoochow UniversitySuzhouJiangsu215000China
- Department of OrthopaedicsThe Third Affiliated Hospital of Soochow UniversityChangzhouJiangsu213000China
| | - Fan He
- Department of OrthopaedicsThe First Affiliated Hospital of Soochow UniversityOrthopedic InstituteMOE Key Laboratory of Geriatric Diseases and ImmunologySuzhou Medical CollegeSoochow UniversitySuzhouJiangsu215000China
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Sun H, Zhai H, Han K, Ma H, Tan Y, Li S, Liu Z, Cheng L, Lu Q, Zhou L, Liu P. Clinical outcomes of autologous adipose-derived mesenchymal stem cell combined with high tibial osteotomy for knee osteoarthritis are correlated with stem cell stemness and senescence. J Transl Med 2024; 22:1039. [PMID: 39558365 PMCID: PMC11575038 DOI: 10.1186/s12967-024-05814-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Accepted: 10/29/2024] [Indexed: 11/20/2024] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) have been proposed to treat osteoarthritis (OA) for many years. However, clinical outcomes have been inconsistent due to biological variation between patients, differences in tissue source and preparation of the MSCs, and type of donor (e.g. allogenic versus autologous). Here, we test the hypothesis that inconsistent clinical outcomes are related to variations in the stemness and senescence of the injected autologous adipose-derived (AD) MSCs. METHODS In the prospective randomized trial, 45 knee OA patients were divided into two groups: Group 1 (n = 22) patients treated with high tibial osteotomy (HTO) alone and Group 2 (n = 23) patients treated with HTO followed by intra-articular injection of autologous AD-MSCs (HTO + AD-MSCs). MRI and X-ray were performed pre-operation and 12 months post-operation. WOMAC and VAS score were collected four times, every 6 months over a 24-month follow-up. We observed the proliferation and stemness of AD-MSCs selected from the 5 patients showing the most improvement and from the 5 patients with the least improvement, and completed further in vitro experiments including beta-galactosidase activity, reactive oxygen species and bioinformatic analysis. RESULTS The results showed that patients treated with HTO + AD-MSCs had a significant reduction in knee OA severity as compared to patients treated with HTO alone. Moreover, we discovered that proliferation and colony forming efficiency of AD-MSCs selected from the 5 patients showing the most improvement performed significantly better than cells selected from the 5 patients with the least improvement. AD-MSCs from the patients with the most improvement also had lower amounts of senescent cells and intracellular reactive oxygen species. CONCLUSIONS Clinical outcomes of autologous AD-MSCs therapy in knee osteoarthritis are correlated with stem cell stemness and senescence. Our study highlights emerging opportunities and trends in precision medicine that could potentially improve autologous MSC-based therapies.
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Affiliation(s)
- Houyi Sun
- Department of Orthopedics, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Haoxin Zhai
- Department of Orthopedics, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Kaifei Han
- Department of Orthopedics, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
- Department of Joint Surgery, Weifang People's Hospital, Weifang, 261000, Shandong, People's Republic of China
| | - Heran Ma
- Qilu Cell Therapy Technology Co., Ltd, Jinan, China
| | - Yi Tan
- Qilu Cell Therapy Technology Co., Ltd, Jinan, China
| | - Shihao Li
- Department of Orthopedics, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Zhicheng Liu
- Department of Orthopedics, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Lei Cheng
- Department of Orthopedics, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Qunshan Lu
- Department of Orthopedics, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China.
| | - Libo Zhou
- Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
| | - Peilai Liu
- Department of Orthopedics, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China.
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Lee SS, Al Halawani A, Teo JD, Weiss AS, Yeo GC. The Matrix Protein Tropoelastin Prolongs Mesenchymal Stromal Cell Vitality and Delays Senescence During Replicative Aging. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2402168. [PMID: 39120048 PMCID: PMC11497112 DOI: 10.1002/advs.202402168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 06/26/2024] [Indexed: 08/10/2024]
Abstract
Cellular senescence leads to the functional decline of regenerative cells such as mesenchymal stromal/stem cells (MSCs), which gives rise to chronic conditions and contributes to poor cell therapy outcomes. Aging tissues are associated with extracellular matrix (ECM) dysregulation, including loss of elastin. However, the role of the ECM in modulating senescence is underexplored. In this work, it is shown that tropoelastin, the soluble elastin precursor, is not only a marker of young MSCs but also actively preserves cell fitness and delays senescence during replicative aging. MSCs briefly exposed to tropoelastin exhibit upregulation of proliferative genes and concurrent downregulation of senescence genes. The seno-protective benefits of tropoelastin persist during continuous, long-term MSC culture, and significantly extend the MSC replicative lifespan. Tropoelastin-expanded MSCs further maintain youth-associated phenotype and function compared to age-matched controls, including preserved clonogenic potential, minimal senescence-associated beta-galactosidase activity, maintained cell sizes, reduced expression of senescence markers, suppressed secretion of senescence-associated factors, and increased production of youth-associated proteins. This work points to the utility of exogenously-supplemented tropoelastin for manufacturing MSCs that robustly maintain regenerative potential with age. It further reveals the active role of classical structural ECM proteins in driving cellular age-associated fitness, potentially leading to future interventions for aging-related pathologies.
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Affiliation(s)
- Sunny Shinchen Lee
- School of Life & Environmental Sciences and Charles Perkins CentreThe University of SydneyCamperdownNSW2006Australia
| | - Aleen Al Halawani
- School of Life & Environmental Sciences and Charles Perkins CentreThe University of SydneyCamperdownNSW2006Australia
| | - Jonathan D. Teo
- School of Medical Sciences and Charles Perkins CentreThe University of SydneyCamperdownNSW2006Australia
| | - Anthony S. Weiss
- School of Life & Environmental Sciences and Charles Perkins CentreThe University of SydneyCamperdownNSW2006Australia
- Sydney Nano InstituteThe University of SydneyCamperdownNSW2006Australia
| | - Giselle C. Yeo
- School of Life & Environmental Sciences and Charles Perkins CentreThe University of SydneyCamperdownNSW2006Australia
- Sydney Nano InstituteThe University of SydneyCamperdownNSW2006Australia
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Amiri F, Mistriotis P. Leveraging Cell Migration Dynamics to Discriminate Between Senescent and Presenescent Human Mesenchymal Stem Cells. Cell Mol Bioeng 2024; 17:385-399. [PMID: 39513008 PMCID: PMC11538215 DOI: 10.1007/s12195-024-00807-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Accepted: 06/11/2024] [Indexed: 11/15/2024] Open
Abstract
Purpose The suboptimal clinical performance of human mesenchymal stem cells (hMSCs) has raised concerns about their therapeutic potential. One major contributing factor to this issue is the heterogeneous nature of hMSCs. Senescent cell accumulation during stem cell expansion is a key driver of MSC heterogeneity. Current methodologies to eradicate senescent hMSCs have either shown limited success or lack clinical relevance. This study leverages the inherent capacity of hMSCs to migrate toward damaged tissues as a means to discern senescent from presenescent stem cells. Given the established deficiency of senescent cells to migrate through physiologically relevant environments, we hypothesized that a microfluidic device, designed to emulate key facets of in vivo cell motility, could serve as a platform for identifying presenescent cells. Methods We employed a Y-shaped microchannel assay, which allows fine-tuning of fluid flow rates and the degree of confinement. Results Highly migratory hMSCs detected by the device not only demonstrate increased speed, smaller size, and higher proliferative capacity but also manifest reduced DNA damage and senescence compared to non-migratory cells. Additionally, this assay detects presenescent cells in experiments with mixed early and late passage cells. The introduction of fluid flow through the device can further increase the fraction of highly motile stem cells, improving the assay's effectiveness to remove senescent hMSCs. Conclusions Collectively, this assay facilitates the detection and isolation of a highly potent stem cell subpopulation. Given the positive correlation between the migratory potential of administered MSCs and the long-term clinical outcome, delivering homogeneous, highly motile presenescent hMSCs may benefit patient outcomes. Supplementary Information The online version contains supplementary material available at 10.1007/s12195-024-00807-0.
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Affiliation(s)
- Farshad Amiri
- Department of Chemical Engineering, Auburn University, Auburn, AL USA
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Mohamed GA, Lench DH, Grewal P, Rosenberg M, Voeks J. Stem cell therapy: a new hope for stroke and traumatic brain injury recovery and the challenge for rural minorities in South Carolina. Front Neurol 2024; 15:1419867. [PMID: 39184380 PMCID: PMC11342809 DOI: 10.3389/fneur.2024.1419867] [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: 05/02/2024] [Accepted: 07/16/2024] [Indexed: 08/27/2024] Open
Abstract
Stroke and traumatic brain injury (TBI) are a significant cause of death and disability nationwide. Both are considered public health concerns in rural communities in the state of South Carolina (SC), particularly affecting the African American population resulting in considerable morbidity, mortality, and economic burden. Stem cell therapy (SCT) has emerged as a potential intervention for both diseases with increasing research trials showing promising results. In this perspective article, the authors aim to discuss the current research in the field of SCT, the results of early phase trials, and the utilization of outcome measures and biomarkers of recovery. We searched PubMed from inception to December 2023 for articles on stem cell therapy in stroke and traumatic brain injury and its impact on rural communities, particularly in SC. Early phase trials of SCT in Stroke and Traumatic Brain injury yield promising safety profile and efficacy results, but the findings have not yet been consistently replicated. Early trials using mesenchymal stem cells for stroke survivors showed safety, feasibility, and improved functional outcomes using broad and domain-specific outcome measures. Neuroimaging markers of recovery such as Functional Magnetic Resonance Imaging (fMRI) and electroencephalography (EEG) combined with neuromodulation, although not widely used in SCT research, could represent a breakthrough when evaluating brain injury and its functional consequences. This article highlights the role of SCT as a promising intervention while addressing the underlying social determinants of health that affect therapeutic outcomes in relation to rural communities such as SC. It also addresses the challenges ethical concerns of stem cell sourcing, the high cost of autologous cell therapies, and the technical difficulties in ensuring transplanted cell survival and strategies to overcome barriers to clinical trial enrollment such as the ethical concerns of stem cell sourcing, the high cost of autologous cell therapies, and the technical difficulties in ensuring transplanted cell survival and equitable healthcare.
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Affiliation(s)
- Ghada A. Mohamed
- Department of Neurology, Medical University of South Carolina, Charleston, SC, United States
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Stone AP, Rand E, Thornes G, Kay AG, Barnes AL, Hitchcock IS, Genever PG. Extracellular matrices of stromal cell subtypes regulate phenotype and contribute to the stromal microenvironment in vivo. Stem Cell Res Ther 2024; 15:178. [PMID: 38886845 PMCID: PMC11184721 DOI: 10.1186/s13287-024-03786-1] [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: 10/02/2023] [Accepted: 06/09/2024] [Indexed: 06/20/2024] Open
Abstract
BACKGROUND Bone marrow stromal cells (BMSCs) are highly heterogeneous, which may reflect their diverse biological functions, including tissue maintenance, haematopoietic support and immune control. The current understanding of the mechanisms that drive the onset and resolution of heterogeneity, and how BMSCs influence other cells in their environment is limited. Here, we determined how the secretome and importantly the extracellular matrix of BMSCs can influence cellular phenotype. METHODS We used two immortalised clonal BMSC lines isolated from the same heterogeneous culture as model stromal subtypes with distinct phenotypic traits; a multipotent stem-cell-like stromal line (Y201) and a nullipotent non-stem cell stromal line (Y202), isolated from the same donor BMSC pool. Label-free quantitative phase imaging was used to track cell morphology and migration of the BMSC lines over 96 h in colony-forming assays. We quantified the secreted factors of each cell line by mass spectrometry and confirmed presence of proteins in human bone marrow by immunofluorescence. RESULTS Transfer of secreted signals from a stem cell to a non-stem cell resulted in a change in morphology and enhanced migration to more closely match stem cell-like features. Mass spectrometry analysis revealed a significant enrichment of extracellular matrix (ECM) proteins in the Y201 stem cell secretome compared to Y202 stromal cells. We confirmed that Y201 produced a more robust ECM in culture compared to Y202. Growth of Y202 on ECM produced by Y201 or Y202 restored migration and fibroblastic morphology, suggesting that it is the deficiency of ECM production that contributes to its phenotype. The proteins periostin and aggrecan, were detected at 71- and 104-fold higher levels in the Y201 versus Y202 secretome and were subsequently identified by immunofluorescence at rare sites on the endosteal surfaces of mouse and human bone, underlying CD271-positive stromal cells. These proteins may represent key non-cellular components of the microenvironment for bona-fide stem cells important for cell maintenance and phenotype in vivo. CONCLUSIONS We identified plasticity in BMSC morphology and migratory characteristics that can be modified through secreted proteins, particularly from multipotent stem cells. Overall, we demonstrate the importance of specific ECM proteins in co-ordination of cellular phenotype and highlight how non-cellular components of the BMSC microenvironment may provide insights into cell population heterogeneity and the role of BMSCs in health and disease.
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Affiliation(s)
- Andrew P Stone
- Department of Biology, York Biomedical Research Institute, University of York, York, UK.
- Brandeis University, Waltham, MA, USA.
| | - Emma Rand
- Department of Biology, York Biomedical Research Institute, University of York, York, UK
| | - Gabriel Thornes
- Department of Biology, York Biomedical Research Institute, University of York, York, UK
| | - Alasdair G Kay
- Department of Biology, York Biomedical Research Institute, University of York, York, UK
| | - Amanda L Barnes
- Department of Biology, York Biomedical Research Institute, University of York, York, UK
| | - Ian S Hitchcock
- Department of Biology, York Biomedical Research Institute, University of York, York, UK
| | - Paul G Genever
- Department of Biology, York Biomedical Research Institute, University of York, York, UK
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11
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Chen S, Liang B, Xu J. Unveiling heterogeneity in MSCs: exploring marker-based strategies for defining MSC subpopulations. J Transl Med 2024; 22:459. [PMID: 38750573 PMCID: PMC11094970 DOI: 10.1186/s12967-024-05294-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 05/11/2024] [Indexed: 05/19/2024] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) represent a heterogeneous cell population distributed throughout various tissues, demonstrating remarkable adaptability to microenvironmental cues and holding immense promise for disease treatment. However, the inherent diversity within MSCs often leads to variability in therapeutic outcomes, posing challenges for clinical applications. To address this heterogeneity, purification of MSC subpopulations through marker-based isolation has emerged as a promising approach to ensure consistent therapeutic efficacy. In this review, we discussed the reported markers of MSCs, encompassing those developed through candidate marker strategies and high-throughput approaches, with the aim of explore viable strategies for addressing the heterogeneity of MSCs and illuminate prospective research directions in this field.
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Affiliation(s)
- Si Chen
- Shenzhen University Medical School, Shenzhen University, Shenzhen, 518000, People's Republic of China
| | - Bowei Liang
- Shenzhen University Medical School, Shenzhen University, Shenzhen, 518000, People's Republic of China
| | - Jianyong Xu
- Shenzhen Key Laboratory of Reproductive Immunology for Peri-Implantation, Guangdong Engineering Technology Research Center of Reproductive Immunology for Peri-Implantation, Shenzhen Zhongshan Obstetrics & Gynecology Hospital (formerly Shenzhen Zhongshan Urology Hospital), Fuqiang Avenue 1001, Shenzhen, 518060, Guangdong, People's Republic of China.
- Guangdong Engineering Technology Research Center of Reproductive Immunology for Peri-Implantation, Shenzhen, 518000, People's Republic of China.
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12
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Wang MC, Yu WL, Ding YC, Huang JJ, Lin CY, Tseng WJ. Persistent Mesodermal Differentiation Capability of Bone Marrow MSCs Isolated from Aging Patients with Low-Energy Traumatic Hip Fracture and Osteoporosis: A Clinical Evidence. Int J Mol Sci 2024; 25:5273. [PMID: 38791313 PMCID: PMC11120803 DOI: 10.3390/ijms25105273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 05/02/2024] [Accepted: 05/07/2024] [Indexed: 05/26/2024] Open
Abstract
A low-energy hit, such as a slight fall from a bed, results in a bone fracture, especially in the hip, which is a life-threatening risk for the older adult and a heavy burden for the social economy. Patients with low-energy traumatic bone fractures usually suffer a higher level of bony catabolism accompanied by osteoporosis. Bone marrow-derived stem cells (BMSCs) are critical in osteogenesis, leading to metabolic homeostasis in the healthy bony microenvironment. However, whether the BMSCs derived from the patients who suffered osteoporosis and low-energy traumatic hip fractures preserve a sustained mesodermal differentiation capability, especially in osteogenesis, is yet to be explored in a clinical setting. Therefore, we aimed to collect BMSCs from clinical hip fracture patients with osteoporosis, followed by osteogenic differentiation comparison with BMSCs from healthy young donors. The CD markers identification, cytokines examination, and adipogenic differentiation were also evaluated. The data reveal that BMSCs collected from elderly osteoporotic patients secreted approximately 122.8 pg/mL interleukin 6 (IL-6) and 180.6 pg/mL vascular endothelial growth factor (VEGF), but no PDGF-BB, IL-1b, TGF-b1, IGF-1, or TNF-α secretion. The CD markers and osteogenic and adipogenic differentiation capability in BMSCs from these elderly osteoporotic patients and healthy young donors are equivalent and compliant with the standards defined by the International Society of Cell Therapy (ISCT). Collectively, our data suggest that the elderly osteoporotic patients-derived BMSCs hold equivalent differentiation and proliferation capability and intact surface markers identical to BMSCs collected from healthy youth and are available for clinical cell therapy.
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Affiliation(s)
- Mei-Chih Wang
- Biomedical Technology & Device Research Laboratories, Industrial Technology Research Institute, Hsinchu 31057, Taiwan; (M.-C.W.); (W.-L.Y.); (Y.-C.D.); (J.-J.H.)
- Department of Biotechnology and Pharmaceutical Technology, Yuanpei University of Medical Technology, Hsinchu 300102, Taiwan
| | - Wei-Lin Yu
- Biomedical Technology & Device Research Laboratories, Industrial Technology Research Institute, Hsinchu 31057, Taiwan; (M.-C.W.); (W.-L.Y.); (Y.-C.D.); (J.-J.H.)
| | - Yun-Chiao Ding
- Biomedical Technology & Device Research Laboratories, Industrial Technology Research Institute, Hsinchu 31057, Taiwan; (M.-C.W.); (W.-L.Y.); (Y.-C.D.); (J.-J.H.)
| | - Jun-Jae Huang
- Biomedical Technology & Device Research Laboratories, Industrial Technology Research Institute, Hsinchu 31057, Taiwan; (M.-C.W.); (W.-L.Y.); (Y.-C.D.); (J.-J.H.)
| | - Chin-Yu Lin
- Department of Biomedical Sciences and Engineering, Tzu Chi University, Hualien 97004, Taiwan
- Institute of New Drug Development, College of Medicine, China Medical University, Taichung 40402, Taiwan
| | - Wo-Jan Tseng
- Department of Orthopedic Surgery, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu 300195, Taiwan
- Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 300093, Taiwan
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13
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Hu J, Ou-Yang ZY, Zhao YQ, Zhao J, Tan L, Liu Q, Wang MY, Ye Q, Feng Y, Zhong MM, Chen NX, Su XL, Zhang Q, Feng YZ, Guo Y. Evaluation of the Efficacy of Stem Cells Therapy in the Periodontal Regeneration: A Meta-Analysis and Mendelian Randomization Study. Stem Cell Rev Rep 2024; 20:980-995. [PMID: 38388709 DOI: 10.1007/s12015-024-10690-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/31/2024] [Indexed: 02/24/2024]
Abstract
Stem cell therapy for periodontal defects has shown good promise in preclinical studies. The purpose of this study was to evaluate the impact of stem cell support on the regeneration of both soft and hard tissues in periodontal treatment. PubMed, Cochrane Library, Embase, and Web of Science were searched and patients with periodontal defects who received stem cell therapy were included in this study. The quality of the included articles was assessed using Cochrane's tool for evaluating bias, and heterogeneity was analyzed using the I2 method. An Mendelian randomization investigation was conducted using abstract data from the IEU public databases obtained through GWAS. Nine articles were included for the meta-analysis. Stem cell therapy effectively rebuilds periodontal tissues in patients with periodontal defects, as evidenced by a reduction in probing depth, clinical attachment level and bone defect depth . And delta-like homolog 1 is a protective factor against periodontal defects alternative indicator of tooth loosening. The findings of this research endorse the utilization of stem cell treatment for repairing periodontal defects in individuals suffering from periodontitis. It is recommended that additional extensive clinical investigations be carried out to validate the efficacy of stem cell therapy and encourage its widespread adoption.
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Affiliation(s)
- Jing Hu
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ze-Yue Ou-Yang
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ya-Qiong Zhao
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jie Zhao
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Li Tan
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Qiong Liu
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Min-Yuan Wang
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Qin Ye
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yao Feng
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Meng-Mei Zhong
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ning-Xin Chen
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xiao-Lin Su
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Qian Zhang
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yun-Zhi Feng
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
| | - Yue Guo
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
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14
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Wu Y, Iwasaki K, Hashimoto Y. Induction of mesenchymal stem cell (MSC) differentiation from iPS cells using MSC medium. Dent Mater J 2024; 43:20-27. [PMID: 38008439 DOI: 10.4012/dmj.2023-130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2023]
Abstract
Mesenchymal stem cells (MSCs) and induced pluripotent stem (iPS) cells have great potential as cell sources for tissue engineering and regenerative medicine. This study aimed to investigate whether iPS cells can be differentiated into MSCs using MSCGM, a commercially available MSC culture system. The cells were characterized by flow cytometry, immunostaining, and gene expression analyses. We also examined their potential to differentiate into osteoblasts and chondrocytes. Our results showed that iPS cells cultured in MSCGM (iPS-MSCGM) exhibited a fibroblast-like morphology and expressed CD73 and CD90 genes, as well as positive markers for CD73, CD90, and CD105. Moreover, iPS-MSCGM cells demonstrated the ability to differentiate into osteoblasts and chondrocytes in vitro. This study demonstrates a new and simple method for inducing the differentiation of iPS cells to MSCs using MSCGM.
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Affiliation(s)
- Yufan Wu
- Department of Biomaterials, Osaka Dental University
| | - Kengo Iwasaki
- Division of Creative and Integrated Medicine, Advanced Medical Research Center, Translational Research Institute for Medical Innovation (TRIMI), Osaka Dental University
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15
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Zong Q, Bundkirchen K, Neunaber C, Noack S. Effect of High BMI on Human Bone Marrow-Derived Mesenchymal Stromal Cells. Cell Transplant 2024; 33:9636897241226546. [PMID: 38258516 PMCID: PMC10807335 DOI: 10.1177/09636897241226546] [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: 05/08/2023] [Revised: 12/22/2023] [Accepted: 01/02/2024] [Indexed: 01/24/2024] Open
Abstract
Bone marrow-derived mesenchymal stromal cells (BMSCs) are attractive candidates in tissue engineering and regenerative medicine. Growing evidence has suggested that a high body mass index (BMI) can affect the properties of BMSCs, resulting in a reduced quality of the cells. However, the results are not consistent. Therefore, this study aimed to investigate the influences of high BMI on human BMSCs (hBMSCs). To avoid gender bias, BMSCs from females and males were studied independently. Finally, hBMSCs from 89 females and 152 males were separately divided into the normal BMI group (18.5 kg/m2 ≤ BMI < 25 kg/m2) and the high BMI group (BMI > 25 kg/m2). The cells were analyzed for the colony-forming potential; proliferation capacity; in vitro adipogenic, osteogenic, and chondrogenic differentiation potentials; and the expression of 32 common surface antigens. The results showed that high BMI did not change the number of colonies at passage 1 in females and males. In contrast, significantly reduced colony numbers at passage 4 (P4) were found in both female and male donors with high BMI. The doubling time of hBMSCs was comparable between the normal and the high BMI groups of females and males. Furthermore, the results of trilineage differentiation did not differ between the different BMI groups of males. In females, the high and the normal BMI groups also showed similar adipogenic and chondrogenic differentiation, while osteogenic differentiation was significantly enhanced in the high-BMI group. Regarding the expression of surface antigens, the expressions of CD200 and SSEA4 on hBMSCs were reduced in the high-BMI group of females and males, respectively. In conclusion, high BMI suppressed the clonogenicity of female and male hBMSCs at P4, improved the in vitro osteogenesis of female hBMSCs, and decreased the expressions of CD200 on hBMSCs in females and SSEA4 in males.
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Affiliation(s)
- Qiang Zong
- Department of Trauma Surgery, Hannover Medical School, Hannover, Germany
| | - Katrin Bundkirchen
- Department of Trauma Surgery, Hannover Medical School, Hannover, Germany
| | - Claudia Neunaber
- Department of Trauma Surgery, Hannover Medical School, Hannover, Germany
| | - Sandra Noack
- Department of Trauma Surgery, Hannover Medical School, Hannover, Germany
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16
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Rasouli M, Naeimzadeh Y, Hashemi N, Hosseinzadeh S. Age-Related Alterations in Mesenchymal Stem Cell Function: Understanding Mechanisms and Seeking Opportunities to Bypass the Cellular Aging. Curr Stem Cell Res Ther 2024; 19:15-32. [PMID: 36642876 DOI: 10.2174/1574888x18666230113144016] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 10/28/2022] [Accepted: 11/23/2022] [Indexed: 01/17/2023]
Abstract
Undoubtedly, mesenchymal stem cells (MSCs) are the most common cell therapy candidates in clinical research and therapy. They not only exert considerable therapeutic effects to alleviate inflammation and promote regeneration, but also show low-immunogenicity properties, which ensure their safety following allogeneic transplantation. Thanks to the necessity of providing a sufficient number of MSCs to achieve clinically efficient outcomes, prolonged in vitro cultivation is indisputable. However, either following long-term in vitro expansion or aging in elderly individuals, MSCs face cellular senescence. Senescent MSCs undergo an impairment in their function and therapeutic capacities and secrete degenerative factors which negatively affect young MSCs. To this end, designing novel investigations to further elucidate cellular senescence and to pave the way toward finding new strategies to reverse senescence is highly demanded. In this review, we will concisely discuss current progress on the detailed mechanisms of MSC senescence and various inflicted changes following aging in MSC. We will also shed light on the examined strategies underlying monitoring and reversing senescence in MSCs to bypass the comprised therapeutic efficacy of the senescent MSCs.
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Affiliation(s)
- Mehdi Rasouli
- Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Yasaman Naeimzadeh
- Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Nader Hashemi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Simzar Hosseinzadeh
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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17
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Massaro F, Corrillon F, Stamatopoulos B, Dubois N, Ruer A, Meuleman N, Bron D, Lagneaux L. Age-related changes in human bone marrow mesenchymal stromal cells: morphology, gene expression profile, immunomodulatory activity and miRNA expression. Front Immunol 2023; 14:1267550. [PMID: 38130717 PMCID: PMC10733451 DOI: 10.3389/fimmu.2023.1267550] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 11/21/2023] [Indexed: 12/23/2023] Open
Abstract
Introduction Mesenchymal stromal cells (MSC) are one of the main cellular components of bone marrow (BM) microenvironment. MSC play a key role in tissue regeneration, but they are also capable of immunomodulating activity. With host aging, MSC undergo age-related changes, which alter these functions, contributing to the set-up of "inflammaging", which is known to be the basis for the development of several diseases of the elderly, including cancer. However, there's few data investigating this facet of MSC, mainly obtained using murine models or replicative senescence. The aim of this research was to identify morphological, molecular and functional alterations of human bone marrow-derived MSC from young (yBM-MSC) and old (oBM-MSC) healthy donors. Methods MSC were identified by analysis of cell-surface markers according to the ISCT criteria. To evaluate response to inflammatory status, MSC were incubated for 24h in the presence of IL-1β, IFN-α, IFN-ɣ and TNF-α. Macrophages were obtained by differentiation of THP-1 cells through PMA exposure. For M1 polarization experiments, a 24h incubation with LPS and IFN-ɣ was performed. MSC were plated at the bottom of the co-culture transwell system for all the time of cytokine exposure. Gene expression was evaluated by real-time PCR after RNA extraction from BM-MSC or THP-1 culture. Secreted cytokines levels were quantitated through ELISA assays. Results Aging MSC display changes in size, morphology and granularity. Higher levels of β-Gal, reactive oxygen species (ROS), IL-6 and IL-8 and impaired colony-forming and cell cycle progression abilities were found in oBM-MSC. Gene expression profile seems to vary according to subjects' age and particularly in oBM-MSC seem to be characterized by an impaired immunomodulating activity, with a reduced inhibition of macrophage M1 status. The comparative analysis of microRNA (miRNA) expression in yBM-MSC and oBM-MSC revealed a significant difference for miRNA known to be involved in macrophage polarization and particularly miR-193b-3p expression is strongly increased after co-culture of macrophages with yBM-MSC. Conclusion There are profound differences in terms of morphology, gene and miRNA expression and immunomodulating properties among yBM-MSC and oBM-MSC, supporting the critical role of aging BM microenvironment on senescence, immune-mediated disorders and cancer pathogenesis.
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Affiliation(s)
- Fulvio Massaro
- Department of Hematology, Jules Bordet Institute, Université Libre de Bruxelles (ULB), Brussels, Belgium
- PhD Program in Clinical and Experimental Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Florent Corrillon
- Laboratory of Clinical Cell Therapy, Jules Bordet Institute, ULB Cancer Research Center (U-CRC) - Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Basile Stamatopoulos
- Laboratory of Clinical Cell Therapy, Jules Bordet Institute, ULB Cancer Research Center (U-CRC) - Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Nathan Dubois
- Laboratory of Clinical Cell Therapy, Jules Bordet Institute, ULB Cancer Research Center (U-CRC) - Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Achille Ruer
- Laboratory of Clinical Cell Therapy, Jules Bordet Institute, ULB Cancer Research Center (U-CRC) - Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Nathalie Meuleman
- Department of Hematology, Jules Bordet Institute, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Dominique Bron
- Department of Hematology, Jules Bordet Institute, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Laurence Lagneaux
- Laboratory of Clinical Cell Therapy, Jules Bordet Institute, ULB Cancer Research Center (U-CRC) - Université Libre de Bruxelles (ULB), Brussels, Belgium
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18
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Sun W, Lv J, Guo S, Lv M. Cellular microenvironment: a key for tuning mesenchymal stem cell senescence. Front Cell Dev Biol 2023; 11:1323678. [PMID: 38111850 PMCID: PMC10725964 DOI: 10.3389/fcell.2023.1323678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Accepted: 11/17/2023] [Indexed: 12/20/2023] Open
Abstract
Mesenchymal stem cells (MSCs) possess the ability to self-renew and differentiate into multiple cell types, making them highly suitable for use as seed cells in tissue engineering. These can be derived from various sources and have been found to play crucial roles in several physiological processes, such as tissue repair, immune regulation, and intercellular communication. However, the limited capacity for cell proliferation and the secretion of senescence-associated secreted phenotypes (SASPs) pose challenges for the clinical application of MSCs. In this review, we provide a comprehensive summary of the senescence characteristics of MSCs and examine the different features of cellular microenvironments studied thus far. Additionally, we discuss the mechanisms by which cellular microenvironments regulate the senescence process of MSCs, offering insights into preserving their functionality and enhancing their effectiveness.
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Affiliation(s)
| | | | - Shu Guo
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Mengzhu Lv
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, China
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19
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Amend B, Buttgereit L, Abruzzese T, Harland N, Abele H, Jakubowski P, Stenzl A, Gorodetsky R, Aicher WK. Regulation of Immune Checkpoint Antigen CD276 (B7-H3) on Human Placenta-Derived Mesenchymal Stromal Cells in GMP-Compliant Cell Culture Media. Int J Mol Sci 2023; 24:16422. [PMID: 38003612 PMCID: PMC10671289 DOI: 10.3390/ijms242216422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 11/10/2023] [Accepted: 11/13/2023] [Indexed: 11/26/2023] Open
Abstract
Therapies utilizing autologous mesenchymal cell delivery are being investigated as anti-inflammatory and regenerative treatments for a broad spectrum of age-related diseases, as well as various chronic and acute pathological conditions. Easily available allogeneic full-term human placenta mesenchymal stromal cells (pMSCs) were used as a potential pro-regenerative, cell-based therapy in degenerative diseases, which could be applied also to elderly individuals. To explore the potential of allogeneic pMSCs transplantation for pro-regenerative applications, such cells were isolated from five different term-placentas, obtained from the dissected maternal, endometrial (mpMSCs), and fetal chorion tissues (fpMSCs), respectively. The proliferation rate of the cells in the culture, as well as their shape, in vitro differentiation potential, and the expression of mesenchymal lineage and stem cell markers, were investigated. Moreover, we studied the expression of immune checkpoint antigen CD276 as a possible modulation of the rejection of transplanted non-HLA-matched homologous or even xeno-transplanted pMSCs. The expression of the cell surface markers was also explored in parallel in the cryosections of the relevant intact placenta tissue samples. The expansion of pMSCs in a clinical-grade medium complemented with 5% human platelet lysate and 5% human serum induced a significant expression of CD276 when compared to mpMSCs expanded in a commercial medium. We suggest that the expansion of mpMSCs, especially in a medium containing platelet lysate, elevated the expression of the immune-regulatory cell surface marker CD276. This may contribute to the immune tolerance towards allogeneic pMSC transplantations in clinical situations and even in xenogenic animal models of human diseases. The endurance of the injected comparably young human-term pMSCs may promote prolonged effects in clinical applications employing non-HLA-matched allogeneic cell therapy for various degenerative disorders, especially in aged adults.
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Affiliation(s)
- Bastian Amend
- Department of Urology, University Hospital, Eberhard Karls University, 72076 Tuebingen, Germany
| | - Lea Buttgereit
- Centre for Medical Research, Department of Urology, Eberhard Karls University, 72076 Tuebingen, Germany
| | - Tanja Abruzzese
- Centre for Medical Research, Department of Urology, Eberhard Karls University, 72076 Tuebingen, Germany
| | - Niklas Harland
- Department of Urology, University Hospital, Eberhard Karls University, 72076 Tuebingen, Germany
| | - Harald Abele
- Department of Gynaecology and Obstetrics, University Hospital, Eberhard Karls University, 72076 Tuebingen, Germany
| | - Peter Jakubowski
- Department of Gynaecology and Obstetrics, University Hospital, Eberhard Karls University, 72076 Tuebingen, Germany
| | - Arnulf Stenzl
- Department of Urology, University Hospital, Eberhard Karls University, 72076 Tuebingen, Germany
| | - Raphael Gorodetsky
- Biotechnology and Radiobiology Laboratory, Sharett Institute of Oncology, Hadassah-Hebrew University Medical Centre, Jerusalem 91120, Israel
| | - Wilhelm K. Aicher
- Centre for Medical Research, Department of Urology, Eberhard Karls University, 72076 Tuebingen, Germany
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Turlo AJ, Hammond DE, Ramsbottom KA, Soul J, Gillen A, McDonald K, Peffers MJ. Mesenchymal Stromal Cell Secretome Is Affected by Tissue Source and Donor Age. Stem Cells 2023; 41:1047-1059. [PMID: 37591507 PMCID: PMC10631804 DOI: 10.1093/stmcls/sxad060] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 07/21/2023] [Indexed: 08/19/2023]
Abstract
Variation in mesenchymal stromal cell (MSC) function depending on their origin is problematic, as it may confound clinical outcomes of MSC therapy. Current evidence suggests that the therapeutic benefits of MSCs are attributed to secretion of biologically active factors (secretome). However, the effect of donor characteristics on the MSC secretome remains largely unknown. Here, we examined the influence of donor age, sex, and tissue source, on the protein profile of the equine MSC secretome. We used dynamic metabolic labeling with stable isotopes combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify secreted proteins in MSC conditioned media (CM). Seventy proteins were classified as classically secreted based on the rate of label incorporation into newly synthesized proteins released into the extracellular space. Next, we analyzed CM of bone marrow- (n = 14) and adipose-derived MSCs (n = 16) with label-free LC-MS/MS. Clustering analysis of 314 proteins detected across all samples identified tissue source as the main factor driving variability in MSC CM proteomes. Linear modelling applied to the subset of 70 secreted proteins identified tissue-related difference in the abundance of 23 proteins. There was an age-related decrease in the abundance of CTHRC1 and LOX, further validated with orthogonal techniques. Due to the lack of flow cytometry characterization of MSC surface markers, the analysis could not account for the potential effect of cell population heterogeneity. This study provides evidence that tissue source and donor age contribute to differences in the protein composition of MSC secretomes which may influence the effects of MSC therapy.
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Affiliation(s)
- Agnieszka J Turlo
- Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK
| | - Dean E Hammond
- epartment of Cellular and Molecular Physiology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
| | - Kerry A Ramsbottom
- Computational Biology Facility, Liverpool Shared Research Facilities, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK
| | - Jamie Soul
- Computational Biology Facility, Liverpool Shared Research Facilities, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK
| | - Alexandra Gillen
- Department of Veterinary Science, Philip Leverhulme Equine Hospital, University of Liverpool, UK
| | | | - Mandy J Peffers
- Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK
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21
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Marinkovic M, Tran ON, Wang H, Abdul-Azees P, Dean DD, Chen XD, Yeh CK. Extracellular matrix turnover in salivary gland disorders and regenerative therapies: Obstacles and opportunities. J Oral Biol Craniofac Res 2023; 13:693-703. [PMID: 37719063 PMCID: PMC10502366 DOI: 10.1016/j.jobcr.2023.08.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 08/28/2023] [Indexed: 09/19/2023] Open
Abstract
Salivary gland (SG) extracellular matrix (ECM) has a major influence on tissue development, homeostasis, and tissue regeneration after injury. During aging, disease, and physical insult, normal remodeling of the SG microenvironment (i.e. ECM) becomes dysregulated, leading to alterations in matrix composition which disrupt tissue architecture/structure, alter cell activity, and negatively impact gland function. Matrix metalloproteinases (MMPs) are a large and diverse family of metalloendopeptidases which play a major role in matrix degradation and are intimately involved in regulating development and cell function; dysregulation of these enzymes leads to the production of a fibrotic matrix. In the SG this altered fibrotic ECM (or cell microenvironment) negatively impacts normal cell function and the effectiveness of gene and stem cell therapies which serve as a foundation for many SG regenerative therapies. For this reason, prospective regenerative strategies should prioritize the maintenance and/or restoration of a healthy SG ECM. Mesenchymal stem cells (MSCs) have great potential for mitigating damage to the SG microenvironment by ameliorating inflammation, reducing fibrosis, and repairing the damaged milieu of extracellular regulatory cues, including the matrix. This review addresses our current understanding of the impact of aging and disease on the SG microenvironment and suggests critical deficiencies and opportunities in ECM-targeted therapeutic interventions.
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Affiliation(s)
- Milos Marinkovic
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229-3900, USA
- Research Service, South Texas Veterans Health Care System, San Antonio, TX, 78229-4404, USA
| | - Olivia N. Tran
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229-3900, USA
| | - Hanzhou Wang
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229-3900, USA
| | - Parveez Abdul-Azees
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229-3900, USA
- Research Service, South Texas Veterans Health Care System, San Antonio, TX, 78229-4404, USA
| | - David D. Dean
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229-3900, USA
- Department of Biomedical Engineering, University of Texas at San Antonio, San Antonio, TX, 78249, USA
| | - Xiao-Dong Chen
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229-3900, USA
- Research Service, South Texas Veterans Health Care System, San Antonio, TX, 78229-4404, USA
- Department of Biomedical Engineering, University of Texas at San Antonio, San Antonio, TX, 78249, USA
| | - Chih-Ko Yeh
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229-3900, USA
- Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX, 78229-4404, USA
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22
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Jiang X, Li W, Ge L, Lu M. Mesenchymal Stem Cell Senescence during Aging:From Mechanisms to Rejuvenation Strategies. Aging Dis 2023; 14:1651-1676. [PMID: 37196126 PMCID: PMC10529739 DOI: 10.14336/ad.2023.0208] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 02/08/2023] [Indexed: 05/19/2023] Open
Abstract
In cell transplantation therapy, mesenchymal stem cells(MSCs)are ideal seed cells due to their easy acquisition and cultivation, strong regenerative capacity, multi-directional differentiation abilities, and immunomodulatory effects. Autologous MSCs are better applicable compared with allogeneic MSCs in clinical practice. The elderly are the main population for cell transplantation therapy, but as donor aging, MSCs in the tissue show aging-related changes. When the number of generations of in vitro expansion is increased, MSCs will also exhibit replicative senescence. The quantity and quality of MSCs decline during aging, which limits the efficacy of autologous MSCs transplantation therapy. In this review, we examine the changes in MSC senescence as a result of aging, discuss the progress of research on mechanisms and signalling pathways of MSC senescence, and discuss possible rejuvenation strategies of aged MSCs to combat senescence and enhance the health and therapeutic potential of MSCs.
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Affiliation(s)
- Xinchen Jiang
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, China.
- Hunan provincical key laboratory of Neurorestoratology, the Second Affiliated Hospital, Hunan Normal University, Changsha, China.
| | - Wenshui Li
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, China.
- Hunan provincical key laboratory of Neurorestoratology, the Second Affiliated Hospital, Hunan Normal University, Changsha, China.
| | - Lite Ge
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, China.
- Hunan provincical key laboratory of Neurorestoratology, the Second Affiliated Hospital, Hunan Normal University, Changsha, China.
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, 410011, China, Changsha
| | - Ming Lu
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, China.
- Hunan provincical key laboratory of Neurorestoratology, the Second Affiliated Hospital, Hunan Normal University, Changsha, China.
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23
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Smolinska A, Bzinkowska A, Rybkowska P, Chodkowska M, Sarnowska A. Promising Markers in the Context of Mesenchymal Stem/Stromal Cells Subpopulations with Unique Properties. Stem Cells Int 2023; 2023:1842958. [PMID: 37771549 PMCID: PMC10533301 DOI: 10.1155/2023/1842958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 08/11/2023] [Accepted: 08/25/2023] [Indexed: 09/30/2023] Open
Abstract
The heterogeneity of the mesenchymal stem/stromal cells (MSCs) population poses a challenge to researchers and clinicians, especially those observed at the population level. What is more, the lack of precise evidences regarding MSCs developmental origin even further complicate this issue. As the available evidences indicate several possible pathways of MSCs formation, this diverse origin may be reflected in the unique subsets of cells found within the MSCs population. Such populations differ in specialization degree, proliferation, and immunomodulatory properties or exhibit other additional properties such as increased angiogenesis capacity. In this review article, we attempted to identify such outstanding populations according to the specific surface antigens or intracellular markers. Described groups were characterized depending on their specialization and potential therapeutic application. The reports presented here cover a wide variety of properties found in the recent literature, which is quite scarce for many candidates mentioned in this article. Even though the collected information would allow for better targeting of specific subpopulations in regenerative medicine to increase the effectiveness of MSC-based therapies.
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Affiliation(s)
- Agnieszka Smolinska
- Translational Platform for Regenerative Medicine, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106, Warsaw, Poland
| | - Aleksandra Bzinkowska
- Translational Platform for Regenerative Medicine, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106, Warsaw, Poland
| | - Paulina Rybkowska
- Translational Platform for Regenerative Medicine, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106, Warsaw, Poland
| | - Magdalena Chodkowska
- Translational Platform for Regenerative Medicine, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106, Warsaw, Poland
| | - Anna Sarnowska
- Translational Platform for Regenerative Medicine, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106, Warsaw, Poland
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24
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Mavrogonatou E, Papadopoulou A, Pratsinis H, Kletsas D. Senescence-associated alterations in the extracellular matrix: deciphering their role in the regulation of cellular function. Am J Physiol Cell Physiol 2023; 325:C633-C647. [PMID: 37486063 DOI: 10.1152/ajpcell.00178.2023] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 07/18/2023] [Accepted: 07/18/2023] [Indexed: 07/25/2023]
Abstract
The extracellular matrix (ECM) is a dynamic structural network that provides a physical scaffolding, as well as biochemical factors that maintain normal tissue homeostasis and thus its disruption is implicated in many pathological conditions. On the other hand, senescent cells express a particular secretory phenotype, affecting the composition and organization of the surrounding ECM and modulating their microenvironment. As accumulation of senescent cells may be linked to the manifestation of several age-related conditions, senescence-associated ECM alterations may serve as targets for novel anti-aging treatment modalities. Here, we will review characteristic changes in the ECM elicited by cellular senescence and we will discuss the complex interplay between ECM and senescent cells, in relation to normal aging and selected age-associated pathologies.
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Affiliation(s)
- Eleni Mavrogonatou
- Laboratory of Cell Proliferation and Ageing, Institute of Biosciences and Applications, National Centre for Scientific Research "Demokritos," Athens, Greece
| | - Adamantia Papadopoulou
- Laboratory of Cell Proliferation and Ageing, Institute of Biosciences and Applications, National Centre for Scientific Research "Demokritos," Athens, Greece
| | - Harris Pratsinis
- Laboratory of Cell Proliferation and Ageing, Institute of Biosciences and Applications, National Centre for Scientific Research "Demokritos," Athens, Greece
| | - Dimitris Kletsas
- Laboratory of Cell Proliferation and Ageing, Institute of Biosciences and Applications, National Centre for Scientific Research "Demokritos," Athens, Greece
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25
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Cen Y, Qi J, Chen L, Xia C, Zheng M, Liu Y, Lou G. Decreased miR-17-92 cluster correlates with senescence features, disrupted oxidative homeostasis, and impaired therapeutic efficacy of mesenchymal stem cells. Am J Physiol Cell Physiol 2023; 325:C443-C455. [PMID: 37366574 DOI: 10.1152/ajpcell.00515.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 06/23/2023] [Accepted: 06/23/2023] [Indexed: 06/28/2023]
Abstract
Aging and replicative cellular senescence are associated with the reduced therapeutic potential of mesenchymal stem cells (MSCs) on a variety of diseases. This study aimed to determine the mechanism in MSC senescence and further explore a modification strategy to reverse senescence-associated cell dysfunction to improve the therapeutic efficacy of MSCs on acute liver failure (ALF). We found that the adipose tissue-derived MSCs from old mice (oAMSCs) exhibited senescence phenotypes and showed reduced therapeutic efficacy in lipopolysaccharide and D-galactosamine-induced ALF, as shown by the increased hepatic necrosis, liver histology activity index scores, serum liver function indicator levels, and inflammatory cytokine levels. The expression of miR-17-92 cluster members, especially miR-17 and miR-20a, was obviously decreased in oAMSCs and replicatively senescent AMSCs, and was consistent with the decreased oncogene c-Myc level during AMSC senescence and may mediate c-Myc stemness addiction. Further experiments revealed that c-Myc-regulated miR-17-92 expression contributed to increased p21 expression and redox system dysregulation during AMSC senescence. Furthermore, modification of AMSCs with the two key miRNAs in the miR-17-92 cluster mentioned above reversed the senescence features of oAMSCs and restored the therapeutic effect of senescent AMSCs on ALF. In conclusion, the cellular miR-17-92 cluster level is correlated with AMSC senescence and can be used both as an index for evaluating and as a modification target for improving the therapeutic potential of AMSCs.NEW & NOTEWORTHY We reported for the first time that c-Myc-regulated miR-17-92 contributed to increased p21 expression and redox system dysregulation during AMSC senescence and was associated with the reduced therapeutic effects of senescent AMSCs on ALF. Moreover, modifying the expression of the miR-17-92 cluster members, especially miR-17 and/or miR-20a, could reverse AMSC senescence. Thus, miR-17-92 cluster can be used both as an index for evaluating and as a modification strategy for improving the therapeutic potential of AMSCs.
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Affiliation(s)
- Yelei Cen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jinjin Qi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Liang Chen
- Thyroid Disease Diagnosis and Treatment Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Caixia Xia
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Department of Infectious Diseases, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Min Zheng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yanning Liu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Guohua Lou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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26
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BORZONE FRANCISCORAÚL, GIORELLO MARÍABELÉN, MARTINEZ LEANDROMARCELO, SANMARTIN MARÍACECILIA, FELDMAN LEONARDO, DIMASE FEDERICO, BATAGELJ EMILIO, YANNARELLI GUSTAVO, CHASSEING NORMAALEJANDRA. Senescent mesenchymal stem/stromal cells in pre-metastatic bone marrow of untreated advanced breast cancer patients. Oncol Res 2023; 31:361-374. [PMID: 37305388 PMCID: PMC10229310 DOI: 10.32604/or.2023.028104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 03/30/2023] [Indexed: 06/13/2023] Open
Abstract
Breast cancer is the predominant form of carcinoma among women worldwide, with 70% of advanced patients developing bone metastases, with a high mortality rate. In this sense, the bone marrow (BM) mesenchymal stem/stromal cells (MSCs) are critical for BM/bone homeostasis, and failures in their functionality, transform the BM into a pre-metastatic niche (PMN). We previously found that BM-MSCs from advanced breast cancer patients (BCPs, infiltrative ductal carcinoma, stage III-B) have an abnormal profile. This work aims to study some of the metabolic and molecular mechanisms underlying MSCs shift from a normal to an abnormal profile in this group of patients. A comparative analysis was undertaken, which included self-renewal capacity, morphology, proliferation capacity, cell cycle, reactive oxygen species (ROS) levels, and senescence-associated β‑galactosidase (SA‑β‑gal) staining of BM-derived MSCs isolated from 14 BCPs and 9 healthy volunteers (HVs). Additionally, the expression and activity of the telomerase subunit TERT, as well as telomere length, were measured. Expression levels of pluripotency, osteogenic, and osteoclastogenic genes (OCT-4, SOX-2, M-CAM, RUNX-2, BMP-2, CCL-2, M-CSF, and IL-6) were also determined. The results showed that MSCs from BCPs had reduced ,self-renewal and proliferation capacity. These cells also exhibited inhibited cell cycle progression and phenotypic changes, such as an enlarged and flattened appearance. Additionally, there was an increase in ROS and senescence levels and a decrease in the functional capacity of TERT to preserve telomere length. We also found an increase in pro-inflammatory/pro-osteoclastogenic gene expression and a decrease in pluripotency gene expression. We conclude that these changes could be responsible for the abnormal functional profile that MSCs show in this group of patients.
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Affiliation(s)
- FRANCISCO RAÚL BORZONE
- Laboratorio de Inmunohematología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - MARÍA BELÉN GIORELLO
- Laboratorio de Inmunohematología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - LEANDRO MARCELO MARTINEZ
- Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, USA
| | - MARÍA CECILIA SANMARTIN
- Laboratorio de Inmunohematología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
- Laboratorio de Regulación Génica y Células Madre, Instituto de Medicina Traslacional, Trasplante y Bioingeniería (IMeTTyB), Universidad Favaloro-CONICET, Buenos Aires, Argentina
| | - LEONARDO FELDMAN
- Facultad de Ciencias de la Salud, Universidad Nacional del Centro de la Provincia de Buenos Aires (UNCPB), Tandil, Buenos Aires, Argentina
| | - FEDERICO DIMASE
- Servicio de Hematología, Hospital Militar Central, Buenos Aires, Argentina
| | - EMILIO BATAGELJ
- Servicio de Oncología, Hospital Militar Central, Buenos Aires, Argentina
| | - GUSTAVO YANNARELLI
- Laboratorio de Regulación Génica y Células Madre, Instituto de Medicina Traslacional, Trasplante y Bioingeniería (IMeTTyB), Universidad Favaloro-CONICET, Buenos Aires, Argentina
| | - NORMA ALEJANDRA CHASSEING
- Laboratorio de Inmunohematología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
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27
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Marinkovic M, Tran ON, Wang H, Abdul-Azees P, Dean DD, Chen XD, Yeh CK. Autologous mesenchymal stem cells offer a new paradigm for salivary gland regeneration. Int J Oral Sci 2023; 15:18. [PMID: 37165024 PMCID: PMC10172302 DOI: 10.1038/s41368-023-00224-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 02/20/2023] [Accepted: 03/29/2023] [Indexed: 05/12/2023] Open
Abstract
Salivary gland (SG) dysfunction, due to radiotherapy, disease, or aging, is a clinical manifestation that has the potential to cause severe oral and/or systemic diseases and compromise quality of life. Currently, the standard-of-care for this condition remains palliative. A variety of approaches have been employed to restore saliva production, but they have largely failed due to damage to both secretory cells and the extracellular matrix (niche). Transplantation of allogeneic cells from healthy donors has been suggested as a potential solution, but no definitive population of SG stem cells, capable of regenerating the gland, has been identified. Alternatively, mesenchymal stem cells (MSCs) are abundant, well characterized, and during SG development/homeostasis engage in signaling crosstalk with the SG epithelium. Further, the trans-differentiation potential of these cells and their ability to regenerate SG tissues have been demonstrated. However, recent findings suggest that the "immuno-privileged" status of allogeneic adult MSCs may not reflect their status post-transplantation. In contrast, autologous MSCs can be recovered from healthy tissues and do not present a challenge to the recipient's immune system. With recent advances in our ability to expand MSCs in vitro on tissue-specific matrices, autologous MSCs may offer a new therapeutic paradigm for restoration of SG function.
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Affiliation(s)
- Milos Marinkovic
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
- Research Service, South Texas Veterans Health Care System, San Antonio, TX, USA
| | - Olivia N Tran
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Hanzhou Wang
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Parveez Abdul-Azees
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
- Research Service, South Texas Veterans Health Care System, San Antonio, TX, USA
| | - David D Dean
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
- Department of Biomedical Engineering, University of Texas at San Antonio, San Antonio, TX, USA
| | - Xiao-Dong Chen
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
- Research Service, South Texas Veterans Health Care System, San Antonio, TX, USA.
- Department of Biomedical Engineering, University of Texas at San Antonio, San Antonio, TX, USA.
| | - Chih-Ko Yeh
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
- Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX, USA.
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28
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Abatay-Sel F, Erol A, Suleymanoglu M, Demirayak G, Kekik-Cinar C, Kuruca DS, Savran-Oguz F. The in vitro treatment of mesenchymal stem cells for colorectal cancer cells. Med Oncol 2023; 40:103. [PMID: 36811793 DOI: 10.1007/s12032-023-01972-4] [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: 12/28/2022] [Accepted: 02/03/2023] [Indexed: 02/24/2023]
Abstract
Colorectal cancer is the most common tumor of the gastrointestinal system. The conventional treatment options for colorectal cancer are troublesome for both patients and clinicians. Recently, mesenchymal stem cells (MSCs) have been the novel focus for cell therapy due to their migration to tumor sites. In this study, the apoptotic effect of MSCs on colorectal cancer cell lines has been aimed. HCT-116 and HT-29 were selected as the colorectal cancer cell lines. Human umbilical cord blood and Wharton's jelly were used as mesenchymal stem cell sources. To discriminate against the apoptotic effect of MSC on cancer, we also used peripheral blood mononuclear cells (PBMC) as a healthy control group. Cord blood-MSC and PBMC were obtained by ficoll-paque density gradient, and Wharton's jelly-MSC by explant method. Transwell co-culture systems were used as cancer cells or PBMC/MSCs at ratios of 1/5 and 1/10, with incubation times of 24 h and 72 h. The Annexin V/PI-FITC-based apoptosis assay was performed by flow cytometry. Caspase-3 and HTRA2/Omi proteins were measured by ELISA. For both ratios in both cancer cells, it was found that the apoptotic effect of Wharton's jelly-MSC was significantly higher in 72-h incubations (p < 0.006), whereas the effect of cord blood mesenchymal stem cell in 24-h incubations were higher (p < 0.007). In this study, we showed that human cord blood and tissue-derived MSCs treatment led to colorectal cancers to apoptosis. We anticipate that further in vivo studies may shed light on the apoptotic effect of MSC.
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Affiliation(s)
- Figen Abatay-Sel
- Department of Medical Biology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey. .,Institute of Graduate Studies in Health Science, Istanbul University, Istanbul, Turkey.
| | - Ayse Erol
- Department of Medical Biology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Mediha Suleymanoglu
- Department of Medical Biology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Gokhan Demirayak
- Department of Gynecologic Oncology, Bakırköy Sadi Konuk Education and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Cigdem Kekik-Cinar
- Department of Medical Biology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Durdane Serap Kuruca
- Department of Physiology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Fatma Savran-Oguz
- Department of Medical Biology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
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29
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Fonseca LN, Bolívar-Moná S, Agudelo T, Beltrán LD, Camargo D, Correa N, Del Castillo MA, Fernández de Castro S, Fula V, García G, Guarnizo N, Lugo V, Martínez LM, Melgar V, Peña MC, Pérez WA, Rodríguez N, Pinzón A, Albarracín SL, Olaya M, Gutiérrez-Gómez ML. Cell surface markers for mesenchymal stem cells related to the skeletal system: A scoping review. Heliyon 2023; 9:e13464. [PMID: 36865479 PMCID: PMC9970931 DOI: 10.1016/j.heliyon.2023.e13464] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 01/26/2023] [Accepted: 01/31/2023] [Indexed: 02/12/2023] Open
Abstract
Multipotent mesenchymal stromal cells (MSCs) have been described as bone marrow stromal cells, which can form cartilage, bone or hematopoietic supportive stroma. In 2006, the International Society for Cell Therapy (ISCT) established a set of minimal characteristics to define MSCs. According to their criteria, these cells must express CD73, CD90 and CD105 surface markers; however, it is now known they do not represent true stemness epitopes. The objective of the present work was to determine the surface markers for human MSCs associated with skeletal tissue reported in the literature (1994-2021). To this end, we performed a scoping review for hMSCs in axial and appendicular skeleton. Our findings determined the most widely used markers were CD105 (82.9%), CD90 (75.0%) and CD73 (52.0%) for studies performed in vitro as proposed by the ISCT, followed by CD44 (42.1%), CD166 (30.9%), CD29 (27.6%), STRO-1 (17.7%), CD146 (15.1%) and CD271 (7.9%) in bone marrow and cartilage. On the other hand, only 4% of the articles evaluated in situ cell surface markers. Even though most studies use the ISCT criteria, most publications in adult tissues don't evaluate the characteristics that establish a stem cell (self-renewal and differentiation), which will be necessary to distinguish between a stem cell and progenitor populations. Collectively, MSCs require further understanding of their characteristics if they are intended for clinical use.
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Affiliation(s)
- Luisa Nathalia Fonseca
- Master Student in Biological Sciences - School of Science, Pontificia Universidad Javeriana. Bogotá, Colombia
| | - Santiago Bolívar-Moná
- Medical Student - Stem Cell Research Group – School of Medicine, Pontificia Universidad Javeriana. Bogotá, Colombia
| | - Tatiana Agudelo
- Medical Student - Stem Cell Research Group – School of Medicine, Pontificia Universidad Javeriana. Bogotá, Colombia
| | - Liz Daniela Beltrán
- Medical Student - Stem Cell Research Group – School of Medicine, Pontificia Universidad Javeriana. Bogotá, Colombia
| | - Daniel Camargo
- Medical Student - Stem Cell Research Group – School of Medicine, Pontificia Universidad Javeriana. Bogotá, Colombia
| | - Nestor Correa
- Medical Student - Stem Cell Research Group – School of Medicine, Pontificia Universidad Javeriana. Bogotá, Colombia
| | - María Alexandra Del Castillo
- Medical Student - Stem Cell Research Group – School of Medicine, Pontificia Universidad Javeriana. Bogotá, Colombia
| | | | - Valeria Fula
- Medical Student - Stem Cell Research Group – School of Medicine, Pontificia Universidad Javeriana. Bogotá, Colombia
| | - Gabriela García
- Medical Student - Stem Cell Research Group – School of Medicine, Pontificia Universidad Javeriana. Bogotá, Colombia
| | - Natalia Guarnizo
- Medical Student - Stem Cell Research Group – School of Medicine, Pontificia Universidad Javeriana. Bogotá, Colombia
| | - Valentina Lugo
- Medical Student - Stem Cell Research Group – School of Medicine, Pontificia Universidad Javeriana. Bogotá, Colombia
| | - Liz Mariana Martínez
- Medical Student - Stem Cell Research Group – School of Medicine, Pontificia Universidad Javeriana. Bogotá, Colombia
| | - Verónica Melgar
- Medical Student - Stem Cell Research Group – School of Medicine, Pontificia Universidad Javeriana. Bogotá, Colombia
| | - María Clara Peña
- Medical Student - Stem Cell Research Group – School of Medicine, Pontificia Universidad Javeriana. Bogotá, Colombia
| | - Wilfran Arbey Pérez
- Medical Student - Stem Cell Research Group – School of Medicine, Pontificia Universidad Javeriana. Bogotá, Colombia
| | - Nicolás Rodríguez
- Medical Student - Stem Cell Research Group – School of Medicine, Pontificia Universidad Javeriana. Bogotá, Colombia
| | - Andrés Pinzón
- Department of Orthopedics and Traumatology - School of Medicine, Pontificia Universidad Javeriana. Bogotá, Colombia
| | - Sonia Luz Albarracín
- Department of Nutrition and Biochemistry -School of Science, Pontificia Universidad Javeriana. Bogotá, Colombia
| | - Mercedes Olaya
- Department of Pathology - School of Medicine, Pontificia Universidad Javeriana. Bogotá, Colombia
| | - María Lucía Gutiérrez-Gómez
- Department of Morphology - School of Medicine, Pontificia Universidad Javeriana. Bogotá, Colombia
- Institute of Human Genetics - School of Medicine, Pontificia Universidad Javeriana. Bogotá, Colombia
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Wong PF, Dharmani M, Ramasamy TS. Senotherapeutics for mesenchymal stem cell senescence and rejuvenation. Drug Discov Today 2023; 28:103424. [PMID: 36332835 DOI: 10.1016/j.drudis.2022.103424] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 10/04/2022] [Accepted: 10/27/2022] [Indexed: 11/06/2022]
Abstract
Mesenchymal stem cells (MSCs) are susceptible to replicative senescence and senescence-associated functional decline, which hampers their use in regenerative medicine. Senotherapeutics are drugs that target cellular senescence through senolytic and senomorphic functions to induce apoptosis and suppress chronic inflammation caused by the senescence-associated secreted phenotype (SASP), respectively. Therefore, senotherapeutics could delay aging-associated degeneration. They could also be used to eliminate senescent MSCs during in vitro expansion or bioprocessing for transplantation. In this review, we discuss the role of senotherapeutics in MSC senescence, rejuvenation, and transplantation, with examples of some tested compounds in vitro. The prospects, challenges, and the way forward in clinical applications of senotherapeutics in cell-based therapeutics are also discussed.
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Affiliation(s)
- Pooi-Fong Wong
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603 Wilayah Persekutuan Kuala Lumpur, Malaysia
| | - Murugan Dharmani
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603 Wilayah Persekutuan Kuala Lumpur, Malaysia
| | - Thamil Selvee Ramasamy
- Stem Cell Biology Laboratory, Department of Molecular Medicine, Faculty of Medicine, Universiti Malaya, 50603 Wilayah Persekutuan Kuala Lumpur, Malaysia.
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Sekelova T, Danisovic L, Cehakova M. Rejuvenation of Senescent Mesenchymal Stem Cells to Prevent Age-Related Changes in Synovial Joints. Cell Transplant 2023; 32:9636897231200065. [PMID: 37766590 PMCID: PMC10540599 DOI: 10.1177/09636897231200065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 08/13/2023] [Accepted: 08/24/2023] [Indexed: 09/29/2023] Open
Abstract
Mesenchymal/medicinal stem/signaling cells (MSCs), well known for regenerative potential, have been involved in hundreds of clinical trials. Even if equipped with reparative properties, aging significantly decreases their biological activity, representing a major challenge for MSC-based therapies. Age-related joint diseases, such as osteoarthritis, are associated with the accumulation of senescent cells, including synovial MSCs. An impaired ability of MSCs to self-renew and differentiate is one of the main contributors to the human aging process. Moreover, senescent MSCs (sMSCs) are characterized by the senescence-messaging secretome (SMS), which is typically manifested by the release of molecules with an adverse effect. Many factors, from genetic and metabolic pathways to environmental stressors, participate in the regulation of the senescent phenotype of MSCs. To better understand cellular senescence in MSCs, this review discusses the characteristics of sMSCs, their role in cartilage and synovial joint aging, and current rejuvenation approaches to delay/reverse age-related pathological changes, providing evidence from in vivo experiments as well.
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Affiliation(s)
- Tatiana Sekelova
- National Institute of Rheumatic Diseases, Piestany, Slovakia
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia
| | - Lubos Danisovic
- National Institute of Rheumatic Diseases, Piestany, Slovakia
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia
| | - Michaela Cehakova
- National Institute of Rheumatic Diseases, Piestany, Slovakia
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia
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Davies DM, van den Handel K, Bharadwaj S, Lengefeld J. Cellular enlargement - A new hallmark of aging? Front Cell Dev Biol 2022; 10:1036602. [PMID: 36438561 PMCID: PMC9688412 DOI: 10.3389/fcell.2022.1036602] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Accepted: 10/17/2022] [Indexed: 12/03/2023] Open
Abstract
Years of important research has revealed that cells heavily invest in regulating their size. Nevertheless, it has remained unclear why accurate size control is so important. Our recent study using hematopoietic stem cells (HSCs) in vivo indicates that cellular enlargement is causally associated with aging. Here, we present an overview of these findings and their implications. Furthermore, we performed a broad literature analysis to evaluate the potential of cellular enlargement as a new aging hallmark and to examine its connection to previously described aging hallmarks. Finally, we highlight interesting work presenting a correlation between cell size and age-related diseases. Taken together, we found mounting evidence linking cellular enlargement to aging and age-related diseases. Therefore, we encourage researchers from seemingly unrelated areas to take a fresh look at their data from the perspective of cell size.
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Affiliation(s)
- Daniel M. Davies
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Kim van den Handel
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Soham Bharadwaj
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Jette Lengefeld
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland
- Center for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
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Ho KKW, Lee WYW, Griffith JF, Ong MTY, Li G. Randomized control trial of mesenchymal stem cells versus hyaluronic acid in patients with knee osteoarthritis - A Hong Kong pilot study. J Orthop Translat 2022; 37:69-77. [PMID: 36262962 PMCID: PMC9550852 DOI: 10.1016/j.jot.2022.07.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 06/11/2022] [Accepted: 07/26/2022] [Indexed: 11/25/2022] Open
Abstract
Objective This pilot study evaluated the efficacy of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) versus hyaluronic acid (HA) in surgically naïve patients with knee osteoarthritis (OA). Methods Single-centre, single-blind randomized study of patients with knee OA. Twenty patients were randomized into groups of 10 each for intra-articular injection of cultured BM-MSCs (6 ml of BM-MSCs at 1 × 106 cells/mL) or HA (6 ml). Clinical assessments of pain, quality of life, radiographic imaging, and magnetic resonance imaging (MRI) compositional change were performed at baseline and 12 months follow-up. Results Compared with HA, BM-MSCs injection resulted in significant improvement in qualify of life and reduction in pain as reflected by visual analogue scale (VAS) pain score, Western Ontario and McMaster Universities Arthritis Index (WOMAC) score, and 36-Item Short Form Survey (SF-36) score collectively. T2-relaxation time tended to decrease more in the BM-MSCs group with a 38 ± 24.0% reduction in 6 out of 10 BM-MSC participants; while there was only a 12 ± 7.9% reduction in 4 out of 10 HA participants at the end of follow-up. The remaining participants showed either no response or had relaxation time increased on MRI assessment. Conclusions This pilot study found that autologous BM-MSCs significantly reduced pain, improved functional assessment score, and improved quality of life parameters comparing with HA at one year follow-up. Further clinical trial with larger sample size and longer follow up duration is warranted. The Translational Potential of this Article This pilot RCT demonstrated the feasibility and potential effectiveness of BM-MSCs advanced therapy for patients with knee OA compared to HA injection. Further multi-center clinical trial with a larger sample size and longer follow up duration in accordance with latest regulatory guidelines is warranted to ascertain the long term safety and effectiveness of MSCs therapy for cartilage regeneration in OA. Registration The study was registered in the Centre for Clinical Research Biostatistics - Clinical Trials Registry (CUHK_CCT00469).
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Affiliation(s)
- Kevin Ki-Wai Ho
- Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China
| | - Wayne Yuk-Wai Lee
- Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China.,Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China
| | - James F Griffith
- Department of Imaging and Interventional Radiology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China
| | - Michael Tim-Yun Ong
- Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China
| | - Gang Li
- Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China.,Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China.,Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China
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Parisi L, Rihs S, La Scala GC, Schnyder I, Katsaros C, Degen M. Discovery and characterization of heterogeneous and multipotent fibroblast populations isolated from excised cleft lip tissue. Stem Cell Res Ther 2022; 13:469. [PMID: 36076255 PMCID: PMC9461253 DOI: 10.1186/s13287-022-03154-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 08/22/2022] [Indexed: 11/21/2022] Open
Abstract
Background Regularly discarded lip tissue obtained from corrective surgeries to close the cleft lip represents an easily accessible and rich source for the isolation of primary fibroblasts. Primary fibroblasts have been described to show compelling similarities to mesenchymal stem cells (MSCs). Hence, cleft lip and palate (CLP) lip-derived fibroblasts could be thought as an intriguing cell source for personalized regenerative therapies in CLP-affected patients. Methods Initially, we thoroughly characterized the fibroblastic nature of the lip-derived mesenchymal outgrowths by molecular and functional assays. Next, we compared their phenotype and genotype to that of bone marrow-mesenchymal stem cells (BM-MSCs) and of human lung-derived fibroblasts WI38, by assessing their morphology, surface marker expression, trilineage differentiation potential, colony-forming (CFU) capacity, and immunomodulation property. Finally, to better decipher the heterogeneity of our CLP cultures, we performed a single cell clonal analysis and tested expanded clones for surface marker expression, as well as osteogenic and CFU potential. Results We identified intriguingly similar phenotypic and genotypic properties between CLP lip fibroblasts and BM-MSCs, which makes them distinct from WI38. Furthermore, our own data in combination with the complex anatomy of the lip tissue indicated heterogeneity in our CLP cultures. Using a clonal analysis, we discovered single cell-derived clones with increased levels of the MSC markers CD106 and CD146 and clones with variabilities in their commitment to differentiate into bone-forming cells and in their potential to form single cell-derived colonies. However, we were not able to gain clones possessing superior MSC-like capacities when compared to the heterogeneous parental CLP population. Additionally, all clones could still generate contractile forces and retained robust levels of the fibroblast specific marker FSP1, which was not detectable in BM-MSCs. Conclusions Our results suggest that we isolate heterogeneous populations of fibroblasts from discarded CLP lip tissue, which show a prominently multipotent character in their entirety avoiding the need for elaborate subpopulation selections in vitro. These findings suggest that CLP lip fibroblasts might be a novel potential cell source for personalized regenerative medicine of clinical benefit for CLP patients. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-03154-x.
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Affiliation(s)
- Ludovica Parisi
- Laboratory for Oral Molecular Biology, Department of Orthodontics and Dentofacial Orthopedics, University of Bern, Bern, Switzerland
| | - Silvia Rihs
- Laboratory for Oral Molecular Biology, Department of Orthodontics and Dentofacial Orthopedics, University of Bern, Bern, Switzerland
| | - Giorgio C La Scala
- Division of Pediatric Surgery, Department of Pediatrics, University Hospital of Geneva, Geneva, Switzerland
| | - Isabelle Schnyder
- University Clinic for Pediatric Surgery, Bern University Hospital, Bern, Switzerland
| | - Christos Katsaros
- Laboratory for Oral Molecular Biology, Department of Orthodontics and Dentofacial Orthopedics, University of Bern, Bern, Switzerland
| | - Martin Degen
- Laboratory for Oral Molecular Biology, Department of Orthodontics and Dentofacial Orthopedics, University of Bern, Bern, Switzerland.
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Marinkovic M, Dai Q, Gonzalez AO, Tran ON, Block TJ, Harris SE, Salmon AB, Yeh CK, Dean DD, Chen XD. Matrix-bound Cyr61/CCN1 is required to retain the properties of the bone marrow mesenchymal stem cell niche but is depleted with aging. Matrix Biol 2022; 111:108-132. [PMID: 35752272 PMCID: PMC10069241 DOI: 10.1016/j.matbio.2022.06.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 05/30/2022] [Accepted: 06/22/2022] [Indexed: 11/17/2022]
Abstract
Previously, we showed that extracellular matrices (ECMs), produced ex vivo by various types of stromal cells, direct bone marrow mesenchymal stem cells (BM-MSCs) in a tissue-specific manner and recapitulate physiologic changes characteristic of the aging microenvironment. In particular, BM-MSCs obtained from elderly donors and cultured on ECM produced by young BM stromal cells showed improved quantity, quality and osteogenic differentiation. In the present study, we searched for matrix components that are required for a functional BM-MSC niche by comparing ECMs produced by BM stromal cells from "young" (≤25 y/o) versus "elderly" (≥60 y/o) donors. With increasing donor age, ECM fibrillar organization and mechanical integrity deteriorated, along with the ability to promote BM-MSC proliferation and responsiveness to growth factors. Proteomic analyses revealed that the matricellular protein, Cyr61/CCN1, was present in young, but undetectable in elderly, BM-ECM. To assess the role of Cyr61 in the BM-MSC niche, we used genetic methods to down-regulate the incorporation of Cyr61 during production of young ECM and up-regulate its incorporation in elderly ECM. The results showed that Cyr61-depleted young ECM lost the ability to promote BM-MSC proliferation and growth factor responsiveness. However, up-regulating the incorporation of Cyr61 during synthesis of elderly ECM restored its ability to support BM-MSC responsiveness to osteogenic factors such as BMP-2 and IGF-1. We next examined aging bone and compared bone mineral density and Cyr61 content of L4-L5 vertebral bodies in "young" (9-11 m/o) and "elderly" (21-33 m/o) mice. Our analyses showed that low bone mineral density was associated with decreased amounts of Cyr61 in osseous tissue of elderly versus young mice. Our results strongly demonstrate a novel role for ECM-bound Cyr61 in the BM-MSC niche, where it is responsible for retention of BM-MSC proliferation and growth factor responsiveness, while depletion of Cyr61 from the BM niche contributes to an aging-related dysregulation of BM-MSCs. Our results also suggest new potential therapeutic targets for treating age-related bone loss by restoring specific ECM components to the stem cell niche.
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Affiliation(s)
- Milos Marinkovic
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, United States; Department of Biomedical Engineering, University of Texas at San Antonio, San Antonio, TX 78249, United States; Research Service, South Texas Veterans Health Care System, Audie Murphy VA Medical Center, San Antonio, TX 78229(,) United States
| | - Qiuxia Dai
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, United States
| | - Aaron O Gonzalez
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, United States; Department of Biomedical Engineering, University of Texas at San Antonio, San Antonio, TX 78249, United States
| | - Olivia N Tran
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, United States; Department of Biomedical Engineering, University of Texas at San Antonio, San Antonio, TX 78249, United States
| | - Travis J Block
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, United States; Department of Biomedical Engineering, University of Texas at San Antonio, San Antonio, TX 78249, United States
| | - Stephen E Harris
- Department of Periodontics, University of Texas Health Science Center at San Antonio, TX 78229, United States
| | - Adam B Salmon
- Department of Molecular Medicine, Barshop Institute for Longevity and Aging Studies at The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, United States; Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, Audie Murphy VA Medical Center, San Antonio, TX 78229, United States
| | - Chih-Ko Yeh
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, United States; Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, Audie Murphy VA Medical Center, San Antonio, TX 78229, United States
| | - David D Dean
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, United States; Department of Biomedical Engineering, University of Texas at San Antonio, San Antonio, TX 78249, United States
| | - Xiao-Dong Chen
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, United States; Department of Biomedical Engineering, University of Texas at San Antonio, San Antonio, TX 78249, United States; Research Service, South Texas Veterans Health Care System, Audie Murphy VA Medical Center, San Antonio, TX 78229(,) United States.
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Tran ON, Wang H, Li S, Malakhov A, Sun Y, Abdul Azees PA, Gonzalez AO, Cao B, Marinkovic M, Singh BB, Dean DD, Yeh CK, Chen XD. Organ-specific extracellular matrix directs trans-differentiation of mesenchymal stem cells and formation of salivary gland-like organoids in vivo. Stem Cell Res Ther 2022; 13:306. [PMID: 35841112 PMCID: PMC9284714 DOI: 10.1186/s13287-022-02993-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 06/27/2022] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Current treatments for salivary gland (SG) hypofunction are palliative and do not address the underlying cause or progression of the disease. SG-derived stem cells have the potential to treat SG hypofunction, but their isolation is challenging, especially when the tissue has been damaged by disease or irradiation for head and neck cancer. In the current study, we test the hypothesis that multipotent bone marrow-derived mesenchymal stem cells (BM-MSCs) in a rat model are capable of trans-differentiating to the SG epithelial cell lineage when induced by a native SG-specific extracellular matrix (SG-ECM) and thus may be a viable substitute for repairing damaged SGs. METHODS Rat BM-MSCs were treated with homogenates of decellularized rat SG-ECM for one hour in cell suspension and then cultured in tissue culture plates for 7 days in growth media. By day 7, the cultures contained cell aggregates and a cell monolayer. The cell aggregates were hand-selected under a dissecting microscope, transferred to a new tissue culture dish, and cultured for an additional 7 days in epithelial cell differentiation media. Cell aggregates and cells isolated from the monolayer were evaluated for expression of SG progenitor and epithelial cell specific markers, cell morphology and ultrastructure, and ability to form SG-like organoids in vivo. RESULTS The results showed that this approach was very effective and guided the trans-differentiation of a subpopulation of CD133-positive BM-MSCs to the SG epithelial cell lineage. These cells expressed amylase, tight junction proteins (Cldn 3 and 10), and markers for SG acinar (Aqp5 and Mist 1) and ductal (Krt 14) cells at both the transcript and protein levels, produced intracellular secretory granules which were morphologically identical to those found in submandibular gland, and formed SG-like organoids when implanted in the renal capsule in vivo. CONCLUSIONS The results of this study suggest the feasibility of using autologous BM-MSCs as an abundant source of stem cells for treating SG hypofunction and restoring the production of saliva in these patients.
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Affiliation(s)
- Olivia N Tran
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229-3900, USA
- Department of Biomedical Engineering, University of Texas at San Antonio, San Antonio, TX, 78249, USA
| | - Hanzhou Wang
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229-3900, USA
| | - Shengxian Li
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229-3900, USA
- Department of Endocrinology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200126, People's Republic of China
| | - Andrey Malakhov
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229-3900, USA
| | - Yuyang Sun
- Department of Periodontics, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229-3900, USA
| | - Parveez A Abdul Azees
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229-3900, USA
| | - Aaron O Gonzalez
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229-3900, USA
- Department of Biomedical Engineering, University of Texas at San Antonio, San Antonio, TX, 78249, USA
| | - Brian Cao
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229-3900, USA
| | - Milos Marinkovic
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229-3900, USA
- Research Service, South Texas Veterans Health Care System, San Antonio, TX, 78229-4404, USA
| | - Brij B Singh
- Department of Periodontics, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229-3900, USA
| | - David D Dean
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229-3900, USA
- Department of Biomedical Engineering, University of Texas at San Antonio, San Antonio, TX, 78249, USA
| | - Chih-Ko Yeh
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229-3900, USA.
- Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX, 78229-4404, USA.
| | - Xiao-Dong Chen
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229-3900, USA.
- Department of Biomedical Engineering, University of Texas at San Antonio, San Antonio, TX, 78249, USA.
- Research Service, South Texas Veterans Health Care System, San Antonio, TX, 78229-4404, USA.
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Zorova LD, Kovalchuk SI, Popkov VA, Chernikov VP, Zharikova AA, Khutornenko AA, Zorov SD, Plokhikh KS, Zinovkin RA, Evtushenko EA, Babenko VA, Pevzner IB, Shevtsova YA, Goryunov KV, Plotnikov EY, Silachev DN, Sukhikh GT, Zorov DB. Do Extracellular Vesicles Derived from Mesenchymal Stem Cells Contain Functional Mitochondria? Int J Mol Sci 2022; 23:ijms23137408. [PMID: 35806411 PMCID: PMC9266972 DOI: 10.3390/ijms23137408] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 06/28/2022] [Accepted: 06/30/2022] [Indexed: 02/06/2023] Open
Abstract
Extracellular vesicles (EV) derived from stem cells have become an effective complement to the use in cell therapy of stem cells themselves, which has led to an explosion of research into the mechanisms of vesicle formation and their action. There is evidence demonstrating the presence of mitochondrial components in EV, but a definitive conclusion about whether EV contains fully functional mitochondria has not yet been made. In this study, two EV fractions derived from mesenchymal stromal stem cells (MSC) and separated by their size were examined. Flow cytometry revealed the presence of mitochondrial lipid components capable of interacting with mitochondrial dyes MitoTracker Green and 10-nonylacridine orange; however, the EV response to the probe for mitochondrial membrane potential was negative. Detailed analysis revealed components from all mitochondria compartments, including house-keeping mitochondria proteins and DNA as well as energy-related proteins such as membrane-localized proteins of complexes I, IV, and V, and soluble proteins from the Krebs cycle. When assessing the functional activity of mitochondria, high variability in oxygen consumption was noted, which was only partially attributed to mitochondrial respiratory activity. Our findings demonstrate that the EV contain all parts of mitochondria; however, their independent functionality inside EV has not been confirmed, which may be due either to the absence of necessary cofactors and/or the EV formation process and, probably the methodology of obtaining EV.
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Affiliation(s)
- Ljubava D. Zorova
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia; (L.D.Z.); (V.A.P.); (S.D.Z.); (R.A.Z.); (V.A.B.); (I.B.P.); (E.Y.P.)
- V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, Moscow 117997, Russia; (A.A.K.); (Y.A.S.); (K.V.G.); (G.T.S.)
| | - Sergei I. Kovalchuk
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia;
| | - Vasily A. Popkov
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia; (L.D.Z.); (V.A.P.); (S.D.Z.); (R.A.Z.); (V.A.B.); (I.B.P.); (E.Y.P.)
- V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, Moscow 117997, Russia; (A.A.K.); (Y.A.S.); (K.V.G.); (G.T.S.)
| | | | - Anastasia A. Zharikova
- Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow 119992, Russia;
| | - Anastasia A. Khutornenko
- V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, Moscow 117997, Russia; (A.A.K.); (Y.A.S.); (K.V.G.); (G.T.S.)
| | - Savva D. Zorov
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia; (L.D.Z.); (V.A.P.); (S.D.Z.); (R.A.Z.); (V.A.B.); (I.B.P.); (E.Y.P.)
- Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow 119992, Russia;
| | | | - Roman A. Zinovkin
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia; (L.D.Z.); (V.A.P.); (S.D.Z.); (R.A.Z.); (V.A.B.); (I.B.P.); (E.Y.P.)
| | | | - Valentina A. Babenko
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia; (L.D.Z.); (V.A.P.); (S.D.Z.); (R.A.Z.); (V.A.B.); (I.B.P.); (E.Y.P.)
- V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, Moscow 117997, Russia; (A.A.K.); (Y.A.S.); (K.V.G.); (G.T.S.)
| | - Irina B. Pevzner
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia; (L.D.Z.); (V.A.P.); (S.D.Z.); (R.A.Z.); (V.A.B.); (I.B.P.); (E.Y.P.)
- V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, Moscow 117997, Russia; (A.A.K.); (Y.A.S.); (K.V.G.); (G.T.S.)
| | - Yulia A. Shevtsova
- V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, Moscow 117997, Russia; (A.A.K.); (Y.A.S.); (K.V.G.); (G.T.S.)
- Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow 119992, Russia;
| | - Kirill V. Goryunov
- V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, Moscow 117997, Russia; (A.A.K.); (Y.A.S.); (K.V.G.); (G.T.S.)
| | - Egor Y. Plotnikov
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia; (L.D.Z.); (V.A.P.); (S.D.Z.); (R.A.Z.); (V.A.B.); (I.B.P.); (E.Y.P.)
- V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, Moscow 117997, Russia; (A.A.K.); (Y.A.S.); (K.V.G.); (G.T.S.)
| | - Denis N. Silachev
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia; (L.D.Z.); (V.A.P.); (S.D.Z.); (R.A.Z.); (V.A.B.); (I.B.P.); (E.Y.P.)
- V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, Moscow 117997, Russia; (A.A.K.); (Y.A.S.); (K.V.G.); (G.T.S.)
- Correspondence: (D.N.S.); (D.B.Z.); Tel.: +7-(495)939-59-44 (D.N.S.); +7-(495)939-59-44 (D.B.Z.)
| | - Gennady T. Sukhikh
- V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, Moscow 117997, Russia; (A.A.K.); (Y.A.S.); (K.V.G.); (G.T.S.)
| | - Dmitry B. Zorov
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia; (L.D.Z.); (V.A.P.); (S.D.Z.); (R.A.Z.); (V.A.B.); (I.B.P.); (E.Y.P.)
- V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, Moscow 117997, Russia; (A.A.K.); (Y.A.S.); (K.V.G.); (G.T.S.)
- Correspondence: (D.N.S.); (D.B.Z.); Tel.: +7-(495)939-59-44 (D.N.S.); +7-(495)939-59-44 (D.B.Z.)
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Dave JR, Chandekar SS, Behera S, Desai KU, Salve PM, Sapkal NB, Mhaske ST, Dewle AM, Pokare PS, Page M, Jog A, Chivte PA, Srivastava RK, Tomar GB. Human gingival mesenchymal stem cells retain their growth and immunomodulatory characteristics independent of donor age. SCIENCE ADVANCES 2022; 8:eabm6504. [PMID: 35749495 PMCID: PMC9232118 DOI: 10.1126/sciadv.abm6504] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 05/06/2022] [Indexed: 05/28/2023]
Abstract
Aging has been reported to deteriorate the quantity and quality of mesenchymal stem cells (MSCs), which affect their therapeutic use in regenerative medicine. A dearth of age-related stem cell research further restricts their clinical applications. The present study explores the possibility of using MSCs derived from human gingival tissues (GMSCs) for studying their ex vivo growth characteristics and differentiation potential with respect to donor age. GMSCs displayed decreased in vitro adipogenesis and in vitro and in vivo osteogenesis with age, but in vitro neurogenesis remained unaffected. An increased expression of p53 and SIRT1 with donor age was correlated to their ability of eliminating tumorigenic events through apoptosis or autophagy, respectively. Irrespective of donor age, GMSCs displayed effective immunoregulation and regenerative potential in a mouse model of LPS-induced acute lung injury. Thus, we suggest the potential of GMSCs for designing cell-based immunomodulatory therapeutic approaches and their further extrapolation for acute inflammatory conditions such as acute respiratory distress syndrome and COVID-19.
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Affiliation(s)
- Jay R. Dave
- Institute of Bioinformatics and Biotechnology, Savitribai Phule Pune University, Pune, 411007 Maharashtra, India
| | - Sayali S. Chandekar
- Institute of Bioinformatics and Biotechnology, Savitribai Phule Pune University, Pune, 411007 Maharashtra, India
| | - Shubhanath Behera
- National Centre for Cell Science, Savitribai Phule Pune University Campus, Pune, 411007 Maharashtra, India
| | - Kaushik U. Desai
- Institute of Bioinformatics and Biotechnology, Savitribai Phule Pune University, Pune, 411007 Maharashtra, India
| | - Pradnya M. Salve
- Institute of Bioinformatics and Biotechnology, Savitribai Phule Pune University, Pune, 411007 Maharashtra, India
| | - Neha B. Sapkal
- Institute of Bioinformatics and Biotechnology, Savitribai Phule Pune University, Pune, 411007 Maharashtra, India
| | - Suhas T. Mhaske
- Institute of Bioinformatics and Biotechnology, Savitribai Phule Pune University, Pune, 411007 Maharashtra, India
| | - Ankush M. Dewle
- Institute of Bioinformatics and Biotechnology, Savitribai Phule Pune University, Pune, 411007 Maharashtra, India
| | - Parag S. Pokare
- Institute of Bioinformatics and Biotechnology, Savitribai Phule Pune University, Pune, 411007 Maharashtra, India
| | - Megha Page
- Department of Dentistry, Deenanath Mangeshkar Hospital and Research Centre, Pune, 411004 Maharashtra, India
| | - Ajay Jog
- Department of Dentistry, Deenanath Mangeshkar Hospital and Research Centre, Pune, 411004 Maharashtra, India
| | - Pankaj A. Chivte
- Saraswati Danwantri Dental College and Hospital, Parbhani, 431401 Maharashtra, India
| | - Rupesh K. Srivastava
- Department of Biotechnology, All India Institute of Medical Science, New Delhi 110029, India
| | - Geetanjali B. Tomar
- Institute of Bioinformatics and Biotechnology, Savitribai Phule Pune University, Pune, 411007 Maharashtra, India
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Tan L, Liu X, Dou H, Hou Y. Characteristics and regulation of mesenchymal stem cell plasticity by the microenvironment — specific factors involved in the regulation of MSC plasticity. Genes Dis 2022; 9:296-309. [PMID: 35224147 PMCID: PMC8843883 DOI: 10.1016/j.gendis.2020.10.006] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 10/05/2020] [Accepted: 10/22/2020] [Indexed: 02/07/2023] Open
Abstract
Mesenchymal stem cells (MSCs), multipotent stromal cells, have attracted extensive attention in the field of regenerative medicine and cell therapy due to the capacity of self-renewal, multilineage differentiation, and immune regulation. MSCs have different cellular effects in different diseases, and even have markedly different curative effects with different tissue sources, indicating the plasticity of MSCs. The phenotypes, secreted factors, and proliferative, migratory, differentiating, and immunomodulatory effects of MSCs depend on certain mediators present in their microenvironment. Understanding microenvironmental factors and their internal mechanisms in MSC responses may help in subsequent prediction and improvement of clinical benefits. This review highlighted the recent advances in MSC plasticity in the physiological and pathological microenvironment and multiple microenvironmental factors regulating MSC plasticity. It also highlighted some progress in the underlying molecular mechanisms of MSC remodeling in the microenvironment. It might provide references for the improvement in vitro culture of MSCs, clinical application, and in vivo induction.
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Kim M, Go J, Kwon JH, Jin HJ, Bae YK, Kim EY, Chang EJ, Choi SJ, Kim SW. CD26 Inhibition Potentiates the Therapeutic Effects of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells by Delaying Cellular Senescence. Front Cell Dev Biol 2022; 9:803645. [PMID: 35178399 PMCID: PMC8846329 DOI: 10.3389/fcell.2021.803645] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 12/23/2021] [Indexed: 12/27/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are recognized as potential treatments for multiple degenerative and inflammatory disorders as a number of animal and human studies have indicated their therapeutic effects. There are also several clinically approved medicinal products that are manufactured using these cells. For such large-scale manufacturing requirements, the in vitro expansion of harvested MSCs is essential. Multiple subculturing of MSCs, however, provokes cellular senescence processes which is known to deteriorate the therapeutic efficacy of the cells. Strategies to rejuvenate or selectively remove senescent MSCs are therefore highly desirable for fostering future clinical applications of these cells. In this present study, we investigated gene expression changes related to cellular senescence of MSCs derived from umbilical cord blood and found that CD26, also known as DPP4, is significantly upregulated upon cellular aging. We further observed that the inhibition of CD26 by genetic or pharmacologic means delayed the cellular aging of MSCs with their multiple passaging in culture. Moreover, the sorting and exclusion of CD26-positive MSCs from heterogenous cell population enhanced in vitro cell attachment and reduced senescence-associated cytokine secretion. CD26-negative MSCs also showed superior therapeutic efficacy in mouse lung emphysema model. Our present results collectively suggest CD26 is a potential novel target for the rejuvenation of senescent MSCs for their use in manufacturing MSC-based applications.
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Affiliation(s)
- Miyeon Kim
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam, South Korea
| | - Jinyoung Go
- Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Ji Hye Kwon
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam, South Korea
| | - Hye Jin Jin
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam, South Korea
| | - Yun Kyung Bae
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam, South Korea
| | - Eun-Young Kim
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Eun-Ju Chang
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Soo Jin Choi
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam, South Korea
| | - Seong Who Kim
- Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
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Selle M, Koch JD, Ongsiek A, Ulbrich L, Ye W, Jiang Z, Krettek C, Neunaber C, Noack S. Influence of age on stem cells depends on the sex of the bone marrow donor. J Cell Mol Med 2022; 26:1594-1605. [PMID: 35088539 PMCID: PMC8899192 DOI: 10.1111/jcmm.17201] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 12/05/2021] [Accepted: 01/05/2022] [Indexed: 11/28/2022] Open
Abstract
Ageing is often accompanied by an increase in bone marrow fat together with reduced bone volume and diseases of the bone such as osteoporosis. As mesenchymal stem cells (MSCs) are capable of forming bone, cartilage and fat tissue, studying these cells is of great importance to understand the underlying mechanisms behind age‐related bone diseases. However, inter‐donor variation has been found when handling MSCs. Therefore, the aim of this study was to investigate the effects of donor age and sex by comparing in vitro characteristics of human bone marrow‐derived MSCs (hBMSCs) from a large donor cohort (n = 175). For this, hBMSCs were analysed for CFU‐F capacity, proliferation, differentiation capacity and surface antigen expression under standardized culture conditions. The results demonstrated a significantly reduced CFU‐F number for hBMSCs of female compared to male donors. Furthermore, there was a significant decrease in the proliferation rate, adipogenic differentiation potential and cell surface expression of SSEA‐4, CD146 and CD274 of hBMSCs with an increase in donor age. Interestingly, all these findings were exclusive to hBMSCs from female donors. Further research should focus on postmenopausal‐related effects on hBMSCs, as the results imply a functional loss and immunophenotypic change of hBMSCs particularly in aged women.
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Affiliation(s)
- Michael Selle
- Trauma Department, Hannover Medical School, Hannover, Germany
| | | | - Alina Ongsiek
- Trauma Department, Hannover Medical School, Hannover, Germany
| | - Linnea Ulbrich
- Trauma Department, Hannover Medical School, Hannover, Germany
| | - Weikang Ye
- Trauma Department, Hannover Medical School, Hannover, Germany
| | - Zhida Jiang
- Trauma Department, Hannover Medical School, Hannover, Germany
| | | | | | - Sandra Noack
- Trauma Department, Hannover Medical School, Hannover, Germany
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Iwasaki K, Peng Y, Kanda R, Umeda M, Ishikawa I. Stem Cell Transplantation and Cell-Free Treatment for Periodontal Regeneration. Int J Mol Sci 2022; 23:ijms23031011. [PMID: 35162935 PMCID: PMC8835344 DOI: 10.3390/ijms23031011] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 01/12/2022] [Accepted: 01/13/2022] [Indexed: 02/04/2023] Open
Abstract
Increasing attention has been paid to cell-based medicines. Many in vivo and in vitro studies have demonstrated the efficacy of stem cell transplantation for the regeneration of periodontal tissues over the past 20 years. Although positive evidence has accumulated regarding periodontal regeneration using stem cells, the exact mechanism of tissue regeneration is still largely unknown. This review outlines the practicality and emerging problems of stem cell transplantation therapy for periodontal regeneration. In addition, possible solutions to these problems and cell-free treatment are discussed.
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Affiliation(s)
- Kengo Iwasaki
- Institute of Dental Research, Osaka Dental University, Osaka 573-1121, Japan;
- Correspondence: ; Tel.: +81-72-864-3125
| | - Yihao Peng
- Department of Periodontology, Osaka Dental University, Osaka 573-1121, Japan; (Y.P.); (M.U.)
| | - Ryuhei Kanda
- Institute of Dental Research, Osaka Dental University, Osaka 573-1121, Japan;
| | - Makoto Umeda
- Department of Periodontology, Osaka Dental University, Osaka 573-1121, Japan; (Y.P.); (M.U.)
| | - Isao Ishikawa
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University, Tokyo 162-8666, Japan;
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Biological characteristics of dental pulp stem cells and their potential use in regenerative medicine. J Oral Biosci 2022; 64:26-36. [PMID: 35031479 DOI: 10.1016/j.job.2022.01.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 12/30/2021] [Accepted: 01/06/2022] [Indexed: 11/20/2022]
Abstract
BACKGROUND Regenerative medicine has emerged as a multidisciplinary field with the promising potential of renewing tissues and organs. The main types of adult stem cells used in clinical trials are hematopoietic and mesenchymal stem cells (MSCs). Stem cells are defined as self-renewing clonogenic progenitor cells that can generate one or more types of specialized cells. HIGHLIGHT MSCs form adipose, cartilage, and bone tissue. Their protective and regenerative effects, such as mitogenic, anti-apoptotic, anti-inflammatory, and angiogenic effects, are mediated through paracrine and endocrine mechanisms. Dental pulp is a valuable source of stem cells because the collection of dental pulp for stem cell isolation is non-invasive, in contrast to conventional sources, such as bone marrow and adipose tissue. Teeth are an excellent source of dental pulp stem cells (DPSCs) for therapeutic procedures and they can be easily obtained after tooth extraction or the shedding of deciduous teeth. Thus, there is increased interest in optimizing and establishing standard procedures for obtaining DPSCs; preserving well-defined DPSC cultures for specific applications; and increasing the efficiency, reproducibility, and safety of the clinical use of DPSCs. CONCLUSION This review comprehensively describes the biological characteristics and origins of DPSCs, their identification and harvesting, key aspects related to their characterization, their multilineage differentiation potential, current clinical applications, and their potential use in regenerative medicine for future dental and medical applications.
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Weng Z, Wang Y, Ouchi T, Liu H, Qiao X, Wu C, Zhao Z, Li L, Li B. OUP accepted manuscript. Stem Cells Transl Med 2022; 11:356-371. [PMID: 35485439 PMCID: PMC9052415 DOI: 10.1093/stcltm/szac004] [Citation(s) in RCA: 126] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 12/19/2021] [Indexed: 11/14/2022] Open
Affiliation(s)
| | | | - Takehito Ouchi
- Department of Physiology, Tokyo Dental College, Tokyo, Japan
| | - Hanghang Liu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People’s Republic of China
| | - Xianghe Qiao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People’s Republic of China
| | - Chenzhou Wu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People’s Republic of China
| | - Zhihe Zhao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People’s Republic of China
| | - Longjiang Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People’s Republic of China
| | - Bo Li
- Corresponding author: Bo Li, DDS, PhD, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, No.14, 3rd Section of Ren Min Nan Rd. Chengdu, Sichuan 610041, People’s Republic of China.
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Barilani M, Lovejoy C, Piras R, Abramov AY, Lazzari L, Angelova PR. Age-related changes in the energy of human mesenchymal stem cells. J Cell Physiol 2021; 237:1753-1767. [PMID: 34791648 DOI: 10.1002/jcp.30638] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 11/04/2021] [Accepted: 11/08/2021] [Indexed: 01/06/2023]
Abstract
Aging is a physiological process that leads to a higher risk for the most devastating diseases. There are a number of theories of human aging proposed, and many of them are directly or indirectly linked to mitochondria. Here, we used mesenchymal stem cells (MSCs) from young and older donors to study age-related changes in mitochondrial metabolism. We have found that aging in MSCs is associated with a decrease in mitochondrial membrane potential and lower NADH levels in mitochondria. Mitochondrial DNA content is higher in aged MSCs, but the overall mitochondrial mass is decreased due to increased rates of mitophagy. Despite the higher level of ATP in aged cells, a higher rate of ATP consumption renders them more vulnerable to energy deprivation compared to younger cells. Changes in mitochondrial metabolism in aged MSCs activate the overproduction of reactive oxygen species in mitochondria which is compensated by a higher level of the endogenous antioxidant glutathione. Thus, energy metabolism and redox state are the drivers for the aging of MSCs/mesenchymal stromal cells.
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Affiliation(s)
- Mario Barilani
- Department of Transfusion Medicine and Hematology, Laboratory of Regenerative Medicine - Cell Factory, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Christopher Lovejoy
- Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK
| | - Roberta Piras
- Department of Transfusion Medicine and Hematology, Laboratory of Regenerative Medicine - Cell Factory, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Andrey Y Abramov
- Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK
| | - Lorenza Lazzari
- Department of Transfusion Medicine and Hematology, Laboratory of Regenerative Medicine - Cell Factory, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Plamena R Angelova
- Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK
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Secretome Analysis of Rabbit and Human Mesenchymal Stem and Endothelial Progenitor Cells: A Comparative Study. Int J Mol Sci 2021; 22:ijms222212283. [PMID: 34830165 PMCID: PMC8625496 DOI: 10.3390/ijms222212283] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 11/05/2021] [Accepted: 11/10/2021] [Indexed: 12/19/2022] Open
Abstract
Human adipose tissue-derived mesenchymal stem cells (AT-MSCs) have been studied several years for their immunomodulatory effect through the paracrine mechanism and cytokine secretion. In combination with endothelial progenitor cells (EPCs), MSCs have great therapeutical potential for the repair of endothelium and wound healing. However, little is known about the cytokine profile of rabbit AT-MSCs or even EPCs. The aim of this study was to analyze the secretomes of these rabbit stem/progenitor cells. A large-scale human cytokine array (up to 80 cytokines) was used to identify and compare cytokines secreted into conditioned media of human and rabbit AT-MSCs as well as HUVECs and rabbit EPCs. Few cytokines were highly expressed by human AT-MSCs (TIMP-2, TIMP-1), HUVECs (MCP-1, TIMP-2, GRO, Angiogenin, IL-8, TIMP-1), or by rabbit EPCs (TIMP-2). Several cytokines have moderate expression by human (MCP-1, GRO, Angiogenin, TGF-β 2, IL-8, LIF, IL-6, Osteopontin, Osteoprotegerin) and rabbit AT-MSCs (TIMP-2, TGF-β 2, LIF, Osteopontin, IL-8, IL-5, IL-3) or by HUVECs (IL-6, MIF, TGF-β 2, GCP-2, IGFBP-2, Osteoprotegerin, EGF, LIF, PDGF-BB, MCP-3, Osteopontin, Leptin, IL-5, ENA-78, TNF-β) and rabbit EPCs (TGF-β 2, Osteopontin, GRO, LIF, IL-8, IL-5, IL-3). In conclusion, the proposed method seems to be useful for the secretome analysis of rabbit stem/progenitor cells.
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Muthu S, Jeyaraman M, Jeyaraman N, Rajendran RL, Gangadaran P. Where Do We Stand in Stem Cell Therapy for the Management of Diabetes Mellitus?-A Scientometric Research Trend Analysis from 1990 to 2020. Bioengineering (Basel) 2021; 8:159. [PMID: 34821725 PMCID: PMC8615097 DOI: 10.3390/bioengineering8110159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 10/19/2021] [Accepted: 10/24/2021] [Indexed: 02/05/2023] Open
Abstract
Stem cell therapy has been considered a promising strategy in the management of both type I and type II diabetes mellitus (DM) because of its immunomodulatory and regenerative capability to restore the beta cell number and function. Various modalities of cellular therapy like transplantation of pancreatic islet cells, transplantation of pancreatic ductal stem cells, and mesenchymal stromal cell transplantation have been tried, and the modality is undergoing rapid advancements that may become the reality in the near future. In the course of its evolution, it is essential to have a comprehensive summary of the progress for a greater capacity to refine our future directives. With technological developments like data mining, graphic drawing, and information analytics combined with computational statistics, visualization of scientific metrology has become a reality. With a newer perspective, we intend to use scientometric tools including text mining, co-word analysis, word frequency analysis, co-citation analysis, cluster network analysis, to perform a systematic and comprehensive analysis of the research trend in stem cell therapy in the management of DM over the past three decades (1990-2020) and to identify the future research hotspots.
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Affiliation(s)
- Sathish Muthu
- Department of Orthopaedics, Government Medical College and Hospital, Dindigul 624001, Tamil Nadu, India;
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida 201310, Uttar Pradesh, India
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow 226010, Uttar Pradesh, India;
| | - Madhan Jeyaraman
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida 201310, Uttar Pradesh, India
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow 226010, Uttar Pradesh, India;
- Department of Orthopedics, School of Medical Sciences and Research, Sharda University, Greater Noida 201310, Uttar Pradesh, India
| | - Naveen Jeyaraman
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow 226010, Uttar Pradesh, India;
- Department of Orthopedics, School of Medical Sciences and Research, Sharda University, Greater Noida 201310, Uttar Pradesh, India
| | - Ramya Lakshmi Rajendran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Korea;
| | - Prakash Gangadaran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Korea;
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Sciences, School of Medicine, Kyungpook National University, Daegu 41944, Korea
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Carvalho MS, Alves L, Bogalho I, Cabral JMS, da Silva CL. Impact of Donor Age on the Osteogenic Supportive Capacity of Mesenchymal Stromal Cell-Derived Extracellular Matrix. Front Cell Dev Biol 2021; 9:747521. [PMID: 34676216 PMCID: PMC8523799 DOI: 10.3389/fcell.2021.747521] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 09/10/2021] [Indexed: 12/27/2022] Open
Abstract
Mesenchymal stromal cells (MSC) have been proposed as an emerging cell-based therapeutic option for regenerative medicine applications as these cells can promote tissue and organ repair. In particular, MSC have been applied for the treatment of bone fractures. However, the healing capacity of these fractures is often compromised by patient's age. Therefore, considering the use of autologous MSC, we evaluated the impact of donor age on the osteogenic potential of bone marrow (BM)-derived MSC. MSC from older patients (60 and 80 years old) demonstrated impaired proliferative and osteogenic capacities compared to MSC isolated from younger patients (30 and 45 years old), suggesting that aging potentially changes the quantity and quality of MSC. Moreover, in this study, we investigated the capacity of the microenvironment [i.e., extracellular matrix (ECM)] to rescue the impaired proliferative and osteogenic potential of aged MSC. In this context, we aimed to understand if BM MSC features could be modulated by exposure to an ECM derived from cells obtained from young or old donors. When aged MSC were cultured on decellularized ECM derived from young MSC, their in vitro proliferative and osteogenic capacities were enhanced, which did not happen when cultured on old ECM. Our results suggest that the microenvironment, specifically the ECM, plays a crucial role in the quality (assessed in terms of osteogenic differentiation capacity) and quantity of MSC. Specifically, the aging of ECM is determinant of osteogenic differentiation of MSC. In fact, old MSC maintained on a young ECM produced higher amounts of extracellularly deposited calcium (9.10 ± 0.22 vs. 4.69 ± 1.41 μg.μl-1.10-7 cells for young ECM and old ECM, respectively) and up-regulated the expression of osteogenic gene markers such as Runx2 and OPN. Cell rejuvenation by exposure to a functional ECM might be a valuable clinical strategy to overcome the age-related decline in the osteogenic potential of MSC by recapitulating a younger microenvironment, attenuating the effects of aging on the stem cell niche. Overall, this study provides new insights on the osteogenic potential of MSC during aging and opens new possibilities for developing clinical strategies for elderly patients with limited bone formation capacity who currently lack effective treatments.
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Affiliation(s)
- Marta S. Carvalho
- Department of Bioengineering and IBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
| | - Laura Alves
- Department of Bioengineering and IBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
| | - Isabel Bogalho
- Department of Bioengineering and IBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
| | - Joaquim M. S. Cabral
- Department of Bioengineering and IBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
| | - Cláudia L. da Silva
- Department of Bioengineering and IBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
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Strategies to Improve the Efficiency of Transplantation with Mesenchymal Stem Cells for the Treatment of Ischemic Stroke: A Review of Recent Progress. Stem Cells Int 2021; 2021:9929128. [PMID: 34490053 PMCID: PMC8418553 DOI: 10.1155/2021/9929128] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 08/10/2021] [Accepted: 08/12/2021] [Indexed: 12/11/2022] Open
Abstract
Cerebral ischemia is a common global disease that is characterized by a loss of neurological function and a poor prognosis in many patients. However, only a limited number of treatments are available for this condition at present. Given that the efficacies of these treatments tend to be poor, cerebral ischemia can create a significant burden on patients, families, and society. Mesenchymal stem cell (MSC) transplantation treatment has shown significant potential in animal models of ischemic stroke; however, the specific mechanisms underlying this effect have yet to be elucidated. Furthermore, clinical trials have yet to yield promising results. Consequently, there is an urgent need to identify new methods to improve the efficiency of MSC transplantation as an optimal treatment for ischemic stroke. In this review, we provide an overview of recent scientific reports concerning novel strategies that promote MSC transplantation as an effective therapeutic approach, including physical approaches, chemical agents, traditional Chinese medicines and extracts, and genetic modification. Our analyses showed that two key factors need to be considered if we are to improve the efficacy of MSC transplantation treatments: survival ability and homing ability. We also highlight the importance of other significant mechanisms, including the enhanced activation of MSCs to promote neurogenesis and angiogenesis, and the regulation of permeability in the blood-brain barrier. Further in-depth investigations of the specific mechanisms underlying MSC transplantation treatment will help us to identify effective methods that improve the efficiency of MSC transplantation for ischemic stroke. The development of safer and more effective methods will facilitate the application of MSC transplantation as a promising adjuvant therapy for the treatment of poststroke brain damage.
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Mantripragada VP, Boehm C, Bova W, Briskin I, Piuzzi NS, Muschler GF. Patient Age and Cell Concentration Influence Prevalence and Concentration of Progenitors in Bone Marrow Aspirates: An Analysis of 436 Patients. J Bone Joint Surg Am 2021; 103:1628-1636. [PMID: 33844657 DOI: 10.2106/jbjs.20.02055] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
BACKGROUND Connective tissue progenitors (CTPs) resident in native tissues serve as biological building blocks in tissue repair and remodeling processes. Methods for analysis and reporting on CTP quantity and quality are essential for defining optimal cell sources and donor characteristics and the impact of cell processing methods for cell therapy applications. The present study examines the influence of donor characteristics and cell concentration (nucleated cells/mL) on CTP prevalence (CTPs/million nucleated cells) and CTP concentration (CTPs/mL) in bone marrow aspirates (BMAs). METHODS Iliac crest bone marrow was aspirated from 436 patients during elective total knee or hip arthroplasty. Bone marrow-derived nucleated cells were plated at a density of 1.19 × 105 cells/cm2. Colony-forming unit analysis was performed on day 6. RESULTS Large variation was seen between donors. Age (p < 0.05) and cell concentration (p < 0.001) significantly influenced CTP prevalence and CTP concentration. For every 1-year increase in age, the odds of having at least an average CTP prevalence and CTP concentration decreased by 1.5% and 1.6%, respectively. For every 1 million cells/mL increase in cell concentration, the odds of having at least an average CTP prevalence and CTP concentration increased by 2.2% and 7.9%, respectively. Sex, race, body mass index (BMI), and the presence of osteoporosis did not influence CTP prevalence or CTP concentration. CONCLUSIONS BMA-derived CTPs were obtained from all patient groups. CTP prevalence and CTP concentration decreased with age. Cell concentration decreased with age and positively correlated with total CTP prevalence and CTP concentration. The mean CTP concentration in patients >60 years of age was a third of the CTP concentration in patients <30 years of age. CLINICAL RELEVANCE Proper BMA techniques are necessary to obtain a high-quality yield and composition of cells and CTPs. The reduced CTP concentration and CTP prevalence in the elderly may be mitigated by the use of cell processing methods that increase CTP concentration and CTP prevalence (e.g., by removing red blood cells, serum, and non-CTPs or by increasing aspirate volumes). Cell concentration in the BMA can be measured at the point of care and is an appropriate initial assessment of the quality of BMA.
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Affiliation(s)
- Venkata P Mantripragada
- Department of Biomedical Engineering, Lerner Research Institute (V.P.M., C.B., W.B., and G.F.M), Department of Health Science (I.B.), and Department of Orthopedic Surgery (N.S.P. and G.F.M.), Cleveland Clinic, Cleveland, Ohio
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