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Verma E, Gupta M, Sierhuis R, Dhingra S. Scientometric analysis of evolution in sex-specific MSC therapy for cardiovascular diseases. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167878. [PMID: 40311883 DOI: 10.1016/j.bbadis.2025.167878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Revised: 04/15/2025] [Accepted: 04/28/2025] [Indexed: 05/03/2025]
Abstract
BACKGROUND Mesenchymal stem cell (MSC) therapy for cardiovascular diseases has shown promise; however, sex-specific differences remain understudied. This scientometric analysis provides the first comprehensive overview of sex-specific differences in mesenchymal stem cell (MSC) therapy for cardiovascular diseases, spanning from 1947 to 2024. METHODS We analyzed 61,029 publications using advanced bibliometric tools to identify research hotspots, publication trends, and collaborative networks. RESULTS A significant shift in research focus has been observed in the field of mesenchymal stem cell (MSC) therapy for cardiovascular diseases, transitioning from broad cardiovascular concepts in the 20th century to specialized sex-specific considerations in the 21st century. Furthermore, in the 21st-century research landscape, the formation of two distinct clusters for "male" and "female" in VOSviewer-generated network visualizations is highly important, emphasizing the growing recognition of sex-specific differences in MSC therapy responses and outcomes. This shift was accompanied by a marked increase in terminology related to sex-specific differences, with keywords like "genetic association" and "body mass index" forming distinct clusters in recent years. CONCLUSIONS This analysis underscores the critical need for sex-specific considerations in MSC therapy for cardiovascular disease. The emergence of distinct male and female clusters in research networks emphasizes the importance of tailoring approaches based on sex differences. Key areas identified for future investigation include the role of epigenetics in mediating sex-specific effects and the potential of sex-matched MSC-derived exosomes. These findings pave the way for more effective and personalized approaches in cardiovascular regenerative medicine, potentially leading to improved outcomes through sex-specific therapeutic strategies.
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Affiliation(s)
- Elika Verma
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre Regenerative Medicine Program, Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, Biomedical Engineering Program, University of Manitoba, Winnipeg, Manitoba R2H2A6, Canada
| | - Mehak Gupta
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre Regenerative Medicine Program, Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, Biomedical Engineering Program, University of Manitoba, Winnipeg, Manitoba R2H2A6, Canada
| | - Riley Sierhuis
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre Regenerative Medicine Program, Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, Biomedical Engineering Program, University of Manitoba, Winnipeg, Manitoba R2H2A6, Canada
| | - Sanjiv Dhingra
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre Regenerative Medicine Program, Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, Biomedical Engineering Program, University of Manitoba, Winnipeg, Manitoba R2H2A6, Canada.
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Nallakumarasamy A, Shrivastava S, Rangarajan RV, Jeyaraman N, Devadas AG, Ramasubramanian S, Jeyaraman M. Optimizing bone marrow harvesting sites for enhanced mesenchymal stem cell yield and efficacy in knee osteoarthritis treatment. World J Methodol 2025; 15:101458. [DOI: 10.5662/wjm.v15.i2.101458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Revised: 11/07/2024] [Accepted: 11/20/2024] [Indexed: 11/27/2024] Open
Abstract
Knee osteoarthritis (OA) is a debilitating condition with limited long-term treatment options. The therapeutic potential of mesenchymal stem cells (MSCs), particularly those derived from bone marrow aspirate concentrate, has garnered attention for cartilage repair in OA. While the iliac crest is the traditional site for bone marrow harvesting (BMH), associated morbidity has prompted the exploration of alternative sites such as the proximal tibia, distal femur, and proximal humerus. This paper reviews the impact of different harvesting sites on mesenchymal stem cell (MSC) yield, viability, and regenerative potential, emphasizing their relevance in knee OA treatment. The iliac crest consistently offers the highest MSC yield, but alternative sites within the surgical field of knee procedures offer comparable MSC characteristics with reduced morbidity. The integration of harvesting techniques into existing knee surgeries, such as total knee arthroplasty, provides a less invasive approach while maintaining therapeutic efficacy. However, variability in MSC yield from these alternative sites underscores the need for further research to standardize techniques and optimize clinical outcomes. Future directions include large-scale comparative studies, advanced characterization of MSCs, and the development of personalized harvesting strategies. Ultimately, the findings suggest that optimizing the site of BMH can significantly influence the quality of MSC-based therapies for knee OA, enhancing their clinical utility and patient outcomes.
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Affiliation(s)
- Arulkumar Nallakumarasamy
- Department of Orthopaedics, Datta Meghe Institute of Higher Education and Research, Wardha 442004, Maharashtra, India
- Department of Regenerative Medicine, Mother Cell Regenerative Centre, Tiruchirappalli 620017, Tamil Nadu, India
| | - Sandeep Shrivastava
- Department of Orthopaedics, Datta Meghe Institute of Higher Education and Research, Wardha 442004, Maharashtra, India
| | - Ravi Velamoor Rangarajan
- Department of Regenerative Medicine, Mother Cell Regenerative Centre, Tiruchirappalli 620017, Tamil Nadu, India
| | - Naveen Jeyaraman
- Department of Orthopaedics, Datta Meghe Institute of Higher Education and Research, Wardha 442004, Maharashtra, India
- Department of Regenerative Medicine, Mother Cell Regenerative Centre, Tiruchirappalli 620017, Tamil Nadu, India
| | - Avinash Gandi Devadas
- Department of Regenerative Medicine, Mother Cell Regenerative Centre, Tiruchirappalli 620017, Tamil Nadu, India
| | - Swaminathan Ramasubramanian
- Department of Orthopaedics, Government Medical College, Omandurar Government Estate, Chennai 600002, Tamil Nadu, India
| | - Madhan Jeyaraman
- Department of Regenerative Medicine, Mother Cell Regenerative Centre, Tiruchirappalli 620017, Tamil Nadu, India
- Department of Orthopaedics, ACS Medical College and Hospital, Dr MGR Educational and Research Institute, Chennai 600077, Tamil Nadu, India
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Riazuelo L, Planat-Bénard V, Vinel A, Laurencin S, Casteilla L, Kémoun P, Marty M, Monsarrat P. Acceptability of Allogeneic Mesenchymal Stromal Cell-Based Tissue Engineering for the Treatment of Periodontitis: A Qualitative Study in France. Int Dent J 2025; 75:840-848. [PMID: 39245621 PMCID: PMC11976543 DOI: 10.1016/j.identj.2024.07.1208] [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: 05/27/2024] [Revised: 07/15/2024] [Accepted: 07/20/2024] [Indexed: 09/10/2024] Open
Abstract
INTRODUCTION AND AIMS Periodontitis, the main cause of tooth loss in adults, is a public health concern; its incidence increases with age, and its prevalence increases with increasing life expectancy of the population. Innovative therapies such as cell therapy represent promising future solutions for guided tissue regeneration. However, these therapies may be associated with fears and mistrust from the general public. The aim of this study was to estimate the acceptability of an advanced therapy medicinal product combining allogeneic mesenchymal stromal cells from adipose tissue with a natural fibrin hydrogel in the treatment of periodontitis. METHODS The methodology was based on a qualitative study conducted through semi-structured interviews with patients followed for periodontitis in the Oral Medicine Department of the Toulouse University Hospital, Toulouse, France. Qualitative studies are essential methodologies to understand the patterns of health behaviours, describe illness experiences, and design health interventions in a humanistic and person-centred way of discovering. RESULTS Eleven interviews (with 4 men and 7 women) were required to reach thematic saturation. Analysis allowed 4 main themes to emerge: (1) perception of new treatments, science, and caregivers; (2) conditions that the treatment must meet; (3) patient perception of the disease; and (4) factors related to the content of the treatment. CONCLUSIONS Patients find cell therapy for periodontitis to be acceptable. If they express a need to be informed about the benefit/risk ratio, they are not particularly worried about side effects of the treatment, for either allogeneic or blood-derived products. Periodontitis is a prototypical model of chronic inflammatory pathology and is multitissular, with hard- and soft-tissue lesions. In a patient-centred approach, the success of cell therapy will require a bilateral, informed decision, taking into account potential therapeutic effectiveness and patient expectations for regeneration.
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Affiliation(s)
- Lucas Riazuelo
- Oral Medicine Department and CHU de Toulouse, Toulouse Institute of Oral Medicine and Science, Toulouse, France
| | - Valérie Planat-Bénard
- RESTORE Research Center, Université de Toulouse, INSERM, CNRS, EFS, ENVT, Université P. Sabatier, Toulouse, France
| | - Alexia Vinel
- Oral Medicine Department and CHU de Toulouse, Toulouse Institute of Oral Medicine and Science, Toulouse, France; I2MC, INSERM UMR 1297, University of Toulouse III, Toulouse, France
| | - Sara Laurencin
- Oral Medicine Department and CHU de Toulouse, Toulouse Institute of Oral Medicine and Science, Toulouse, France; Center for Epidemiology and Research in POPulation Health (CERPOP), UMR 1295, Paul Sabatier University, Toulouse, France
| | - Louis Casteilla
- RESTORE Research Center, Université de Toulouse, INSERM, CNRS, EFS, ENVT, Université P. Sabatier, Toulouse, France
| | - Philippe Kémoun
- Oral Medicine Department and CHU de Toulouse, Toulouse Institute of Oral Medicine and Science, Toulouse, France; RESTORE Research Center, Université de Toulouse, INSERM, CNRS, EFS, ENVT, Université P. Sabatier, Toulouse, France
| | - Mathieu Marty
- Oral Medicine Department and CHU de Toulouse, Toulouse Institute of Oral Medicine and Science, Toulouse, France; LIRDEF, Faculty of Educational Sciences, Paul Valery University, Montpellier, France
| | - Paul Monsarrat
- Oral Medicine Department and CHU de Toulouse, Toulouse Institute of Oral Medicine and Science, Toulouse, France; RESTORE Research Center, Université de Toulouse, INSERM, CNRS, EFS, ENVT, Université P. Sabatier, Toulouse, France; Artificial and Natural Intelligence Toulouse Institute ANITI, Toulouse, France.
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Zhou W, Lin J, Hay DC, Yao X, Ouyang H. Combining transcriptomic and metabolomic insights to guide the clinical application of adipose- and bone marrow-derived mesenchymal stem cells. MEDICAL REVIEW (2021) 2025; 5:76-82. [PMID: 39974562 PMCID: PMC11834745 DOI: 10.1515/mr-2024-0056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 08/09/2024] [Indexed: 02/21/2025]
Abstract
Adipose-derived mesenchymal stem cells (ADSCs) and bone marrow-derived mesenchymal stem cells (BMSCs) have shown great potential in clinical applications. However, the similarities and differences between these two cell types have not been fully elucidated. Recent advances in transcriptomic and metabolomic research have provided valuable insight into the characteristics and functions of ADSCs and BMSCs. In this perspective article, we review the key findings from these studies, including cellular heterogeneity as well as differences in metabolic and secretory properties. We discuss how these insights can help guide the selection of the most suitable cell source for the clinic, and the optimization of preconditioning strategies prior to clinical deployment. Furthermore, we analyze the current landscape of products and clinical trials involving ADSCs and BMSCs, highlighting their therapeutic potential. We propose that the integration of multi-omics datasets will be crucial for establishing a comprehensive understanding of ADSC and BMSC identity and potency, and the provision of quality-assured stem cell-derived products for the clinic.
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Affiliation(s)
- Wenyan Zhou
- School of Medicine, Taizhou University, Taizhou, Zhejiang, China
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang UniversitySchool of Medicine, Hangzhou, Zhejiang, China
| | - Junxin Lin
- School of Medicine, Taizhou University, Taizhou, Zhejiang, China
| | - David C. Hay
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Xudong Yao
- International School of Medicine, International Institutes of Medicine, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang, China
| | - Hongwei Ouyang
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang UniversitySchool of Medicine, Hangzhou, Zhejiang, China
- Department of Sports Medicine of the Second Affiliated Hospital, and Liangzhu Laboratory, Zhejiang UniversitySchool of Medicine, Hangzhou, China
- China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, China
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Garmany A, Terzic A. Artificial intelligence powers regenerative medicine into predictive realm. Regen Med 2024; 19:611-616. [PMID: 39660914 PMCID: PMC11703382 DOI: 10.1080/17460751.2024.2437281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 11/29/2024] [Indexed: 12/12/2024] Open
Abstract
The expanding regenerative medicine toolkit is reaching a record number of lives. There is a pressing need to enhance the precision, efficiency, and effectiveness of regenerative approaches and achieve reliable outcomes. While regenerative medicine has relied on an empiric paradigm, availability of big data along with advances in informatics and artificial intelligence offer the opportunity to inform the next generation of regenerative sciences along the discovery, translation, and application pathway. Artificial intelligence can streamline discovery and development of optimized biotherapeutics by aiding in the interpretation of readouts associated with optimal repair outcomes. In advanced biomanufacturing, artificial intelligence holds potential in ensuring quality control and assuring scalability through automated monitoring of process-critical variables mandatory for product consistency. In practice application, artificial intelligence can guide clinical trial design, patient selection, delivery strategies, and outcome assessment. As artificial intelligence transforms the regenerative horizon, caution is necessary to reduce bias, ensure generalizability, and mitigate ethical concerns with the goal of equitable access for patients and populations.
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Affiliation(s)
- Armin Garmany
- Marriott Heart Disease Research Program, Department of Cardiovascular Medicine, Department of Molecular Pharmacology & Experimental Therapeutics, Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA
- Mayo Clinic Alix School of Medicine, Regenerative Sciences Track, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN, USA
| | - Andre Terzic
- Marriott Heart Disease Research Program, Department of Cardiovascular Medicine, Department of Molecular Pharmacology & Experimental Therapeutics, Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA
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Silva-Sousa T, Usuda JN, Al-Arawe N, Frias F, Hinterseher I, Catar R, Luecht C, Riesner K, Hackel A, Schimke LF, Dias HD, Filgueiras IS, Nakaya HI, Camara NOS, Fischer S, Riemekasten G, Ringdén O, Penack O, Winkler T, Duda G, Fonseca DLM, Cabral-Marques O, Moll G. The global evolution and impact of systems biology and artificial intelligence in stem cell research and therapeutics development: a scoping review. Stem Cells 2024; 42:929-944. [PMID: 39230167 DOI: 10.1093/stmcls/sxae054] [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: 06/13/2024] [Accepted: 08/07/2024] [Indexed: 09/05/2024]
Abstract
Advanced bioinformatics analysis, such as systems biology (SysBio) and artificial intelligence (AI) approaches, including machine learning (ML) and deep learning (DL), is increasingly present in stem cell (SC) research. An approximate timeline on these developments and their global impact is still lacking. We conducted a scoping review on the contribution of SysBio and AI analysis to SC research and therapy development based on literature published in PubMed between 2000 and 2024. We identified an 8 to 10-fold increase in research output related to all 3 search terms between 2000 and 2021, with a 10-fold increase in AI-related production since 2010. Use of SysBio and AI still predominates in preclinical basic research with increasing use in clinically oriented translational medicine since 2010. SysBio- and AI-related research was found all over the globe, with SysBio output led by the (US, n = 1487), (UK, n = 1094), Germany (n = 355), The Netherlands (n = 339), Russia (n = 215), and France (n = 149), while for AI-related research the US (n = 853) and UK (n = 258) take a strong lead, followed by Switzerland (n = 69), The Netherlands (n = 37), and Germany (n = 19). The US and UK are most active in SCs publications related to AI/ML and AI/DL. The prominent use of SysBio in ESC research was recently overtaken by prominent use of AI in iPSC and MSC research. This study reveals the global evolution and growing intersection among AI, SysBio, and SC research over the past 2 decades, with substantial growth in all 3 fields and exponential increases in AI-related research in the past decade.
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Affiliation(s)
- Thayna Silva-Sousa
- BIH Center for Regenerative Therapies (BCRT), Charité Universitätzsmedizin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health (BIH), 10117 Berlin, Germany
- Julius Wolff Institute (JWI), Charité Universitätzsmedizin, 10117 Berlin, Germany
- Department of Vascular Surgery, Universitätsklinikum Ruppin-Brandenburg, Medizinische Hochschule Branderburg Theodor Fontane, 16816 Neuruppin, Germany
- Fakultät für Gesundheitswissenschaften Brandenburg, Gemeinsame Fakultät der Universität Potsdam, der Medizinischen Hochschule Brandenburg Theodor Fontane, und der Brandenburgischen Technischen Universität Cottbus-Senftenberg, 14476 Potsdam, Germany
| | - Júlia Nakanishi Usuda
- BIH Center for Regenerative Therapies (BCRT), Charité Universitätzsmedizin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health (BIH), 10117 Berlin, Germany
- Julius Wolff Institute (JWI), Charité Universitätzsmedizin, 10117 Berlin, Germany
- Department of Vascular Surgery, Universitätsklinikum Ruppin-Brandenburg, Medizinische Hochschule Branderburg Theodor Fontane, 16816 Neuruppin, Germany
- Fakultät für Gesundheitswissenschaften Brandenburg, Gemeinsame Fakultät der Universität Potsdam, der Medizinischen Hochschule Brandenburg Theodor Fontane, und der Brandenburgischen Technischen Universität Cottbus-Senftenberg, 14476 Potsdam, Germany
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo (USP), São Paulo (SP), Brazil
| | - Nada Al-Arawe
- BIH Center for Regenerative Therapies (BCRT), Charité Universitätzsmedizin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health (BIH), 10117 Berlin, Germany
- Julius Wolff Institute (JWI), Charité Universitätzsmedizin, 10117 Berlin, Germany
- Department of Vascular Surgery, Universitätsklinikum Ruppin-Brandenburg, Medizinische Hochschule Branderburg Theodor Fontane, 16816 Neuruppin, Germany
- Fakultät für Gesundheitswissenschaften Brandenburg, Gemeinsame Fakultät der Universität Potsdam, der Medizinischen Hochschule Brandenburg Theodor Fontane, und der Brandenburgischen Technischen Universität Cottbus-Senftenberg, 14476 Potsdam, Germany
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätzsmedizin, 10117 Berlin, Germany
- Department of Hematology, Oncology, and Tumorimmunology, Charité Universitätzsmedizin, 10117 Berlin, Germany
| | - Francisca Frias
- BIH Center for Regenerative Therapies (BCRT), Charité Universitätzsmedizin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health (BIH), 10117 Berlin, Germany
- Julius Wolff Institute (JWI), Charité Universitätzsmedizin, 10117 Berlin, Germany
- Department of Vascular Surgery, Universitätsklinikum Ruppin-Brandenburg, Medizinische Hochschule Branderburg Theodor Fontane, 16816 Neuruppin, Germany
- Fakultät für Gesundheitswissenschaften Brandenburg, Gemeinsame Fakultät der Universität Potsdam, der Medizinischen Hochschule Brandenburg Theodor Fontane, und der Brandenburgischen Technischen Universität Cottbus-Senftenberg, 14476 Potsdam, Germany
| | - Irene Hinterseher
- Department of Vascular Surgery, Universitätsklinikum Ruppin-Brandenburg, Medizinische Hochschule Branderburg Theodor Fontane, 16816 Neuruppin, Germany
- Fakultät für Gesundheitswissenschaften Brandenburg, Gemeinsame Fakultät der Universität Potsdam, der Medizinischen Hochschule Brandenburg Theodor Fontane, und der Brandenburgischen Technischen Universität Cottbus-Senftenberg, 14476 Potsdam, Germany
- Vascular Surgery, Charité Universitätzsmedizin, 10117 Berlin, Germany
| | - Rusan Catar
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätzsmedizin, 10117 Berlin, Germany
| | - Christian Luecht
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätzsmedizin, 10117 Berlin, Germany
| | - Katarina Riesner
- Department of Hematology, Oncology, and Tumorimmunology, Charité Universitätzsmedizin, 10117 Berlin, Germany
| | - Alexander Hackel
- Clinic for Rheumatology and Clinical Immunology, University Medical Center Schleswig Holstein Campus Lübeck, 23538 Lübeck, Germany
| | - Lena F Schimke
- Department of Immunology, Institute of Biomedical Sciences, USP, SP, Brazil
| | - Haroldo Dutra Dias
- Interunit Postgraduate Program on Bioinformatics, Institute of Mathematics and Statistics (IME), USP, SP, Brazil
| | | | - Helder I Nakaya
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo (USP), São Paulo (SP), Brazil
- Department of Medicine, Division of Molecular Medicine, Laboratory of Medical Investigation 29, USP School of Medicine (USPM), São Paulo (SP), Brazil
| | - Niels Olsen Saraiva Camara
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo (USP), São Paulo (SP), Brazil
| | - Stefan Fischer
- Clinic for Rheumatology and Clinical Immunology, University Medical Center Schleswig Holstein Campus Lübeck, 23538 Lübeck, Germany
| | - Gabriela Riemekasten
- Clinic for Rheumatology and Clinical Immunology, University Medical Center Schleswig Holstein Campus Lübeck, 23538 Lübeck, Germany
| | - Olle Ringdén
- Division of Pediatrics, Department of CLINTEC, Karolinska Institutet, Stockholm, Sweden
| | - Olaf Penack
- Department of Hematology, Oncology, and Tumorimmunology, Charité Universitätzsmedizin, 10117 Berlin, Germany
| | - Tobias Winkler
- BIH Center for Regenerative Therapies (BCRT), Charité Universitätzsmedizin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health (BIH), 10117 Berlin, Germany
- Julius Wolff Institute (JWI), Charité Universitätzsmedizin, 10117 Berlin, Germany
| | - Georg Duda
- BIH Center for Regenerative Therapies (BCRT), Charité Universitätzsmedizin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health (BIH), 10117 Berlin, Germany
- Julius Wolff Institute (JWI), Charité Universitätzsmedizin, 10117 Berlin, Germany
| | - Dennyson Leandro M Fonseca
- BIH Center for Regenerative Therapies (BCRT), Charité Universitätzsmedizin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health (BIH), 10117 Berlin, Germany
- Julius Wolff Institute (JWI), Charité Universitätzsmedizin, 10117 Berlin, Germany
- Interunit Postgraduate Program on Bioinformatics, Institute of Mathematics and Statistics (IME), USP, SP, Brazil
| | - Otávio Cabral-Marques
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo (USP), São Paulo (SP), Brazil
- Department of Immunology, Institute of Biomedical Sciences, USP, SP, Brazil
- Interunit Postgraduate Program on Bioinformatics, Institute of Mathematics and Statistics (IME), USP, SP, Brazil
- Department of Medicine, Division of Molecular Medicine, Laboratory of Medical Investigation 29, USP School of Medicine (USPM), São Paulo (SP), Brazil
- D'OR Institute Research and Education, SP, Brazil
| | - Guido Moll
- BIH Center for Regenerative Therapies (BCRT), Charité Universitätzsmedizin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health (BIH), 10117 Berlin, Germany
- Julius Wolff Institute (JWI), Charité Universitätzsmedizin, 10117 Berlin, Germany
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätzsmedizin, 10117 Berlin, Germany
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7
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Vaishya R, Dhall S, Vaish A. Artificial Intelligence (AI): A Potential Game Changer in Regenerative Orthopedics-A Scoping Review. Indian J Orthop 2024; 58:1362-1374. [PMID: 39324081 PMCID: PMC11420425 DOI: 10.1007/s43465-024-01189-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Accepted: 05/21/2024] [Indexed: 09/27/2024]
Abstract
Background and Aims Regenerative orthopedics involves approaches like stem cell therapy, platelet-rich plasma (PRP) therapy, the use of biological scaffold implants, tissue engineering, etc. We aim to present a scoping review of the role of artificial intelligence (AI) in different treatment approaches of regenerative orthopedics. Methods Using the PRISMA guidelines, a search for articles for the last ten years (2013-2024) on PubMed was done, using several keywords. We have discussed the state-of-the-art, strengths/benefits, and limitations of the published research, and provide a useful resource for the way ahead in future for researchers working in this area. Results Using the eligibility criteria out of 82 initially screened publications, we included 18 studies for this review. We noticed that the treatment responses to regenerative treatments depend on several factors; hence, to facilitate better comprehensive and patient-specific treatments, AI technology is very useful. Machine learning (ML) and deep learning (DL) are a few of the most frequently used AI techniques. They use a data-driven approach for training models to make human-like decisions. Data are fed to the ML/DL algorithm and the trained model makes classifications or predictions based on its learning. Conclusion The area of regenerative orthopedics is highly sophisticated and significantly aids in providing cost-effective and non-invasive treatments to patients suffering from orthopedic ailments and injuries. Due to its promising future, the use of AI in regenerative orthopedics is an emerging and promising research field; however, its universal clinical applications are associated with some ethical considerations, which need addressing. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1007/s43465-024-01189-1.
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Affiliation(s)
- Raju Vaishya
- Department of Orthopaedics and Joint Replacement Surgery, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi, 110076 India
| | - Sakshi Dhall
- Department of Mathematics, Jamia Millia Islamia, Delhi, 110025 India
| | - Abhishek Vaish
- Department of Orthopaedics and Joint Replacement Surgery, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi, 110076 India
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Yin L, Ye M, Qiao Y, Huang W, Xu X, Xu S, Oh S. Unlocking the full potential of mesenchymal stromal cell therapy for osteoarthritis through machine learning-based in silico trials. Cytotherapy 2024; 26:1252-1263. [PMID: 38904585 DOI: 10.1016/j.jcyt.2024.05.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 05/15/2024] [Accepted: 05/15/2024] [Indexed: 06/22/2024]
Abstract
Despite the potential of mesenchymal stromal cells (MSCs) in osteoarthritis (OA) treatment, the challenge lies in addressing their therapeutic inconsistency. Clinical trials revealed significantly varied therapeutic outcomes among patients receiving the same allogenic MSCs but different treatment regimens. Therefore, optimizing personalized treatment strategies is crucial to fully unlock MSCs' potential and enhance therapeutic consistency. We employed the XGBoost algorithm to train a self-collected database comprising 37 published clinical reports to create a model capable of predicting the probability of effective pain relief and Western Ontario and McMaster Universities (WOMAC) index improvement in OA patients undergoing MSC therapy. Leveraging this model, extensive in silico simulations were conducted to identify optimal personalized treatment strategies and ideal patient profiles. Our in silico trials predicted that the individually optimized MSC treatment strategies would substantially increase patients' chances of recovery compared to the strategies used in reported clinical trials, thereby potentially benefiting 78.1%, 47.8%, 94.4% and 36.4% of the patients with ineffective short-term pain relief, short-term WOMAC index improvement, long-term pain relief and long-term WOMAC index improvement, respectively. We further recommended guidelines on MSC number, concentration, and the patients' appropriate physical (body mass index, age, etc.) and disease states (Kellgren-Lawrence grade, etc.) for OA treatment. Additionally, we revealed the superior efficacy of MSC in providing short-term pain relief compared to platelet-rich plasma therapy for most OA patients. This study represents the pioneering effort to enhance the efficacy and consistency of MSC therapy through machine learning applied to clinical data. The in silico trial approach holds immense potential for diverse clinical applications.
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Affiliation(s)
- Lu Yin
- Jiangxi Provincial Key Laboratory of Respiratory Diseases, Jiangxi Institute of Respiratory Diseases, Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Jiangxi Clinical Research Center for Respiratory Diseases, Nanchang, Jiangxi, China; Jiangxi Hospital of China-Japan Friendship Hospital, Nanchang, Jiangxi, China; Agency for Science Technology and Research, Bioprocessing Technology Institute, Singapore, Singapore.
| | - Meiwu Ye
- Bio-totem Pte. Ltd., Guangzhou (Nanhai) Biomedical Industrial Park, Foshan, Guangdong, China
| | - Yang Qiao
- Jiangxi Provincial Key Laboratory of Respiratory Diseases, Jiangxi Institute of Respiratory Diseases, Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Jiangxi Clinical Research Center for Respiratory Diseases, Nanchang, Jiangxi, China; Jiangxi Hospital of China-Japan Friendship Hospital, Nanchang, Jiangxi, China
| | - Weilu Huang
- Jiangxi Provincial Key Laboratory of Respiratory Diseases, Jiangxi Institute of Respiratory Diseases, Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Jiangxi Clinical Research Center for Respiratory Diseases, Nanchang, Jiangxi, China; Jiangxi Hospital of China-Japan Friendship Hospital, Nanchang, Jiangxi, China
| | - Xinping Xu
- Jiangxi Provincial Key Laboratory of Respiratory Diseases, Jiangxi Institute of Respiratory Diseases, Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Jiangxi Clinical Research Center for Respiratory Diseases, Nanchang, Jiangxi, China; Jiangxi Hospital of China-Japan Friendship Hospital, Nanchang, Jiangxi, China
| | - Shuoyu Xu
- Bio-totem Pte. Ltd., Guangzhou (Nanhai) Biomedical Industrial Park, Foshan, Guangdong, China.
| | - Steve Oh
- Agency for Science Technology and Research, Bioprocessing Technology Institute, Singapore, Singapore; CellVec Pte. Ltd., Singapore, Singapore.
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Shou Y, Liu L, Liu Q, Le Z, Lee KL, Li H, Li X, Koh DZ, Wang Y, Liu TM, Yang Z, Lim CT, Cheung C, Tay A. Mechano-responsive hydrogel for direct stem cell manufacturing to therapy. Bioact Mater 2023; 24:387-400. [PMID: 36632503 PMCID: PMC9817177 DOI: 10.1016/j.bioactmat.2022.12.019] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 12/05/2022] [Accepted: 12/20/2022] [Indexed: 01/04/2023] Open
Abstract
Bone marrow-derived mesenchymal stem cell (MSC) is one of the most actively studied cell types due to its regenerative potential and immunomodulatory properties. Conventional cell expansion methods using 2D tissue culture plates and 2.5D microcarriers in bioreactors can generate large cell numbers, but they compromise stem cell potency and lack mechanical preconditioning to prepare MSC for physiological loading expected in vivo. To overcome these challenges, in this work, we describe a 3D dynamic hydrogel using magneto-stimulation for direct MSC manufacturing to therapy. With our technology, we found that dynamic mechanical stimulation (DMS) enhanced matrix-integrin β1 interactions which induced MSCs spreading and proliferation. In addition, DMS could modulate MSC biofunctions including directing MSC differentiation into specific lineages and boosting paracrine activities (e.g., growth factor secretion) through YAP nuclear localization and FAK-ERK pathway. With our magnetic hydrogel, complex procedures from MSC manufacturing to final clinical use, can be integrated into one single platform, and we believe this 'all-in-one' technology could offer a paradigm shift to existing standards in MSC therapy.
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Affiliation(s)
- Yufeng Shou
- Department of Biomedical Engineering, National University of Singapore, 117583, Singapore
- Institute for Health Innovation & Technology, National University of Singapore, 117599, Singapore
| | - Ling Liu
- Institute for Health Innovation & Technology, National University of Singapore, 117599, Singapore
- NUS Tissue Engineering Program, National University of Singapore, 117510, Singapore
| | - Qimin Liu
- School of Civil Engineering and Architecture, Wuhan University of Technology, 430070, Wuhan, China
| | - Zhicheng Le
- Department of Biomedical Engineering, National University of Singapore, 117583, Singapore
- Institute for Health Innovation & Technology, National University of Singapore, 117599, Singapore
| | - Khang Leng Lee
- Lee Kong Chian School of Medicine, Nanyang Technological University, 636921, Singapore
| | - Hua Li
- School of Mechanical and Aerospace Engineering, Nanyang Technological University, 639798, Singapore
| | - Xianlei Li
- Department of Biomedical Engineering, National University of Singapore, 117583, Singapore
- Institute for Health Innovation & Technology, National University of Singapore, 117599, Singapore
| | - Dion Zhanyun Koh
- Department of Biomedical Engineering, National University of Singapore, 117583, Singapore
| | - Yuwen Wang
- Department of Biomedical Engineering, National University of Singapore, 117583, Singapore
| | - Tong Ming Liu
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 138648, Singapore
| | - Zheng Yang
- NUS Tissue Engineering Program, National University of Singapore, 117510, Singapore
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, 119288, Singapore
| | - Chwee Teck Lim
- Department of Biomedical Engineering, National University of Singapore, 117583, Singapore
- Institute for Health Innovation & Technology, National University of Singapore, 117599, Singapore
- Mechanobiology Institute, National University of Singapore, 117411, Singapore
| | - Christine Cheung
- Lee Kong Chian School of Medicine, Nanyang Technological University, 636921, Singapore
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 138648, Singapore
| | - Andy Tay
- Department of Biomedical Engineering, National University of Singapore, 117583, Singapore
- Institute for Health Innovation & Technology, National University of Singapore, 117599, Singapore
- NUS Tissue Engineering Program, National University of Singapore, 117510, Singapore
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Srinivasan A, Sathiyanathan P, Yin L, Liu TM, Lam A, Ravikumar M, Smith RAA, Loh HP, Zhang Y, Ling L, Ng SK, Yang YS, Lezhava A, Hui J, Oh S, Cool SM. Strategies to enhance immunomodulatory properties and reduce heterogeneity in mesenchymal stromal cells during ex vivo expansion. Cytotherapy 2022; 24:456-472. [PMID: 35227601 DOI: 10.1016/j.jcyt.2021.11.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 10/24/2021] [Accepted: 11/08/2021] [Indexed: 02/06/2023]
Abstract
Therapies using mesenchymal stromal cells (MSCs) to treat immune and inflammatory conditions are now at an exciting stage of development, with many MSC-based products progressing to phase II and III clinical trials. However, a major bottleneck in the clinical translation of allogeneic MSC therapies is the variable immunomodulatory properties of MSC products due to differences in their tissue source, donor heterogeneity and processes involved in manufacturing and banking. This variable functionality of MSC products likely contributes to the substantial inconsistency observed in the clinical outcomes of phase III trials of MSC therapies; several trials have failed to reach the primary efficacy endpoint. In this review, we discuss various strategies to consistently maintain or enhance the immunomodulatory potency of MSCs during ex vivo expansion, which will enable the manufacture of allogeneic MSC banks that have high potency and low variability. Biophysical and biochemical priming strategies, the use of culture additives such as heparan sulfates, and genetic modification can substantially enhance the immunomodulatory properties of MSCs during in vitro expansion. Furthermore, robust donor screening, the use of biomarkers to select for potent MSC subpopulations, and rigorous quality testing to improve the release criteria for MSC banks have the potential to reduce batch-to-batch heterogeneity and enhance the clinical efficacy of the final MSC product. Machine learning approaches to develop predictive models of individual patient response can enable personalized therapies and potentially establish correlations between in vitro potency measurements and clinical outcomes in human trials.
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Affiliation(s)
- Akshaya Srinivasan
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | | | - Lu Yin
- Bioprocessing Technology Institute, A*STAR, Singapore
| | - Tong Ming Liu
- Institute of Molecular and Cell Biology, A*STAR, Singapore
| | - Alan Lam
- Bioprocessing Technology Institute, A*STAR, Singapore
| | - Maanasa Ravikumar
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Institute of Molecular and Cell Biology, A*STAR, Singapore
| | | | - Han Ping Loh
- Bioprocessing Technology Institute, A*STAR, Singapore
| | - Ying Zhang
- Institute of Molecular and Cell Biology, A*STAR, Singapore
| | - Ling Ling
- Institute of Molecular and Cell Biology, A*STAR, Singapore
| | - Say Kong Ng
- Bioprocessing Technology Institute, A*STAR, Singapore
| | | | - Alexander Lezhava
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore
| | - James Hui
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Steve Oh
- Bioprocessing Technology Institute, A*STAR, Singapore.
| | - Simon M Cool
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Institute of Molecular and Cell Biology, A*STAR, Singapore.
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Chen T, Weng W, Liu Y, Aspera-Werz RH, Nüssler AK, Xu J. Update on Novel Non-Operative Treatment for Osteoarthritis: Current Status and Future Trends. Front Pharmacol 2021; 12:755230. [PMID: 34603064 PMCID: PMC8481638 DOI: 10.3389/fphar.2021.755230] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Accepted: 09/06/2021] [Indexed: 12/27/2022] Open
Abstract
Osteoarthritis (OA) is a leading cause of pain and disability which results in a reduced quality of life. Due to the avascular nature of cartilage, damaged cartilage has a finite capacity for healing or regeneration. To date, conservative management, including physical measures and pharmacological therapy are still the principal choices offered for OA patients. Joint arthroplasties or total replacement surgeries are served as the ultimate therapeutic option to rehabilitate the joint function of patients who withstand severe OA. However, these approaches are mainly to relieve the symptoms of OA, instead of decelerating or reversing the progress of cartilage damage. Disease-modifying osteoarthritis drugs (DMOADs) aiming to modify key structures within the OA joints are in development. Tissue engineering is a promising strategy for repairing cartilage, in which cells, genes, and biomaterials are encompassed. Here, we review the current status of preclinical investigations and clinical translations of tissue engineering in the non-operative treatment of OA. Furthermore, this review provides our perspective on the challenges and future directions of tissue engineering in cartilage regeneration.
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Affiliation(s)
- Tao Chen
- Department of Orthopedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Trauma and Reconstructive Surgery, BG Trauma Center Tübingen, Siegfried Weller Institute for Trauma Research, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Weidong Weng
- Department of Trauma and Reconstructive Surgery, BG Trauma Center Tübingen, Siegfried Weller Institute for Trauma Research, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Yang Liu
- Department of Clinical Sciences, Orthopedics, Faculty of Medicine, Lund University, Lund, Sweden
| | - Romina H. Aspera-Werz
- Department of Trauma and Reconstructive Surgery, BG Trauma Center Tübingen, Siegfried Weller Institute for Trauma Research, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Andreas K Nüssler
- Department of Trauma and Reconstructive Surgery, BG Trauma Center Tübingen, Siegfried Weller Institute for Trauma Research, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Jianzhong Xu
- Department of Orthopedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Proteomic Analysis of Hypoxia-Induced Senescence of Human Bone Marrow Mesenchymal Stem Cells. Stem Cells Int 2021; 2021:5555590. [PMID: 34484348 PMCID: PMC8416403 DOI: 10.1155/2021/5555590] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 06/29/2021] [Accepted: 07/28/2021] [Indexed: 12/18/2022] Open
Abstract
Methods Hypoxia in hBMSCs was induced for 0, 4, and 12 hours, and cellular senescence was evaluated by senescence-associated β-galactosidase (SA-β-gal) staining. Tandem mass tag (TMT) labeling was combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) for differential proteomic analysis of hypoxia in hBMSCs. Parallel reaction monitoring (PRM) analysis was used to validate the candidate proteins. Verifications of signaling pathways were evaluated by western blotting. Cell apoptosis was evaluated using Annexin V/7-AAD staining by flow cytometry. The production of reactive oxygen species (ROS) was detected by the fluorescent probe 2,7-dichlorodihydrofluorescein diacetate (DCFH-DA). Results Cell senescence detected by SA-β-gal activity was higher in the 12-hour hypoxia-induced group. TMT analysis of 12-hour hypoxia-induced cells identified over 6000 proteins, including 686 differentially expressed proteins. Based on biological pathway analysis, we found that the senescence-associated proteins were predominantly enriched in the cancer pathways, PI3K-Akt pathway, and cellular senescence signaling pathways. CDK1, CDK2, and CCND1 were important nodes in PPI analyses. Moreover, the CCND1, UQCRH, and COX7C expressions were verified by PRM. Hypoxia induction for 12 hours in hBMSCs reduced CCND1 expression but promoted ROS production and cell apoptosis. Such effects were markedly reduced by the PI3K agonist, 740 Y-P, and attenuated by LY294002. Conclusions Hypoxia of hBMSCs inhibited CCND1 expression but promoted ROS production and cell apoptosis through activating the PI3K-dependent signaling pathway. These findings provided a detailed characterization of the proteomic profiles related to hypoxia-induced senescence of hBMSCs and facilitated our understanding of the molecular mechanisms leading to stem cell senescence.
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Mukherjee S, Yadav G, Kumar R. Recent trends in stem cell-based therapies and applications of artificial intelligence in regenerative medicine. World J Stem Cells 2021; 13:521-541. [PMID: 34249226 PMCID: PMC8246250 DOI: 10.4252/wjsc.v13.i6.521] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/22/2021] [Accepted: 05/20/2021] [Indexed: 02/06/2023] Open
Abstract
Stem cells are undifferentiated cells that can self-renew and differentiate into diverse types of mature and functional cells while maintaining their original identity. This profound potential of stem cells has been thoroughly investigated for its significance in regenerative medicine and has laid the foundation for cell-based therapies. Regenerative medicine is rapidly progressing in healthcare with the prospect of repair and restoration of specific organs or tissue injuries or chronic disease conditions where the body’s regenerative process is not sufficient to heal. In this review, the recent advances in stem cell-based therapies in regenerative medicine are discussed, emphasizing mesenchymal stem cell-based therapies as these cells have been extensively studied for clinical use. Recent applications of artificial intelligence algorithms in stem cell-based therapies, their limitation, and future prospects are highlighted.
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Affiliation(s)
- Sayali Mukherjee
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow 226028, Uttar Pradesh, India
| | - Garima Yadav
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow 226028, Uttar Pradesh, India
| | - Rajnish Kumar
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow 226028, Uttar Pradesh, India
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