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Zeng J, Wang J, Zhang Y, Wang Z, Zhu Y, Hou Y, Li X, Peng H, Lobie PE, Ma S. Mesenchymal stem cells attenuate diabetic vascular complication by reducing irregular extracellular matrix production in human blood vessel organoids. LAB ON A CHIP 2025. [PMID: 40341804 DOI: 10.1039/d5lc00107b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/11/2025]
Abstract
Mesenchymal stem cells (MSCs) hold potential for treating diabetic vascular complications, but current models fail to adequately replicate the complexities of diabetic vascular disease, limiting our ability to accurately assess their therapeutic effects. To this end, we developed a co-culture system using a combination of human embryonic stem cell-derived blood vessel organoids (BVOs) and MSCs. This system could accurately replicate key aspects of diabetic pathology, including basement membrane thickening and excessive extracellular matrix (ECM) deposition. The results showed that MSCs were effective in attenuating basement membrane thickening and reducing ECM deposition in BVOs under diabetic conditions. Subsequent transcriptomics demonstrated that the MSC-treated group exhibited a notable normalization of ECM-related gene expression, particularly in collagen IV levels. Furthermore, the inhibition of the NF-κB signaling pathway was identified as a crucial mechanism underlying the therapeutic efficacy of MSCs. This study demonstrates the potential of MSCs to counteract diabetic vascular complications and emphasizes the co-culture system as a more physiologically relevant model to investigate the preventive and therapeutic potential of MSCs in diabetic pathology.
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Affiliation(s)
- Junhong Zeng
- Tsinghua Shenzhen International Graduate School (SIGS), Tsinghua University, Shenzhen 518055, China.
| | - Jiaqi Wang
- Tsinghua Shenzhen International Graduate School (SIGS), Tsinghua University, Shenzhen 518055, China.
| | - Yu Zhang
- Tsinghua Shenzhen International Graduate School (SIGS), Tsinghua University, Shenzhen 518055, China.
| | - Zitian Wang
- Tsinghua Shenzhen International Graduate School (SIGS), Tsinghua University, Shenzhen 518055, China.
- Key Lab of Industrial Biocatalysis Ministry of Education, Tsinghua University, Beijing 100084, China
| | - Yu Zhu
- Tsinghua Shenzhen International Graduate School (SIGS), Tsinghua University, Shenzhen 518055, China.
| | - Yibo Hou
- Tsinghua Shenzhen International Graduate School (SIGS), Tsinghua University, Shenzhen 518055, China.
| | - Xiangsai Li
- Tsinghua Shenzhen International Graduate School (SIGS), Tsinghua University, Shenzhen 518055, China.
| | - Haiying Peng
- General Hospital of the Southern Theater Command of the Chinese People's Liberation Army, Guangzhou 510010, China
| | - Peter E Lobie
- Tsinghua Shenzhen International Graduate School (SIGS), Tsinghua University, Shenzhen 518055, China.
- Key Lab of Industrial Biocatalysis Ministry of Education, Tsinghua University, Beijing 100084, China
| | - Shaohua Ma
- Tsinghua Shenzhen International Graduate School (SIGS), Tsinghua University, Shenzhen 518055, China.
- Key Lab of Industrial Biocatalysis Ministry of Education, Tsinghua University, Beijing 100084, China
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Hoang VT, Nguyen QT, Phan TTK, Pham TH, Dinh NTH, Anh LPH, Dao LTM, Bui VD, Dao H, Le DS, Ngo ATL, Le Q, Nguyen Thanh L. Tissue Engineering and Regenerative Medicine: Perspectives and Challenges. MedComm (Beijing) 2025; 6:e70192. [PMID: 40290901 PMCID: PMC12022429 DOI: 10.1002/mco2.70192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Revised: 12/30/2024] [Accepted: 03/04/2025] [Indexed: 04/30/2025] Open
Abstract
From the pioneering days of cell therapy to the achievement of bioprinting organs, tissue engineering, and regenerative medicine have seen tremendous technological advancements, offering solutions for restoring damaged tissues and organs. However, only a few products and technologies have received United States Food and Drug Administration approval. This review highlights significant progress in cell therapy, extracellular vesicle-based therapy, and tissue engineering. Hematopoietic stem cell transplantation is a powerful tool for treating many diseases, especially hematological malignancies. Mesenchymal stem cells have been extensively studied. The discovery of induced pluripotent stem cells has revolutionized disease modeling and regenerative applications, paving the way for personalized medicine. Gene therapy represents an innovative approach to the treatment of genetic disorders. Additionally, extracellular vesicle-based therapies have emerged as rising stars, offering promising solutions in diagnostics, cell-free therapeutics, drug delivery, and targeted therapy. Advances in tissue engineering enable complex tissue constructs, further transforming the field. Despite these advancements, many technical, ethical, and regulatory challenges remain. This review addresses the current bottlenecks, emphasizing novel technologies and interdisciplinary research to overcome these hurdles. Standardizing practices and conducting clinical trials will balance innovation and regulation, improving patient outcomes and quality of life.
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Affiliation(s)
- Van T. Hoang
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Quyen Thi Nguyen
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Trang Thi Kieu Phan
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Trang H. Pham
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Nhung Thi Hong Dinh
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Le Phuong Hoang Anh
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Lan Thi Mai Dao
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Van Dat Bui
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- School of Chemical EngineeringCollege of EngineeringSungkyunkwan University (SKKU)SuwonRepublic of Korea
| | - Hong‐Nhung Dao
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Duc Son Le
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Anh Thi Lan Ngo
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Quang‐Duong Le
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Liem Nguyen Thanh
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
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Hong J, Kim YH. Cutting-edge biotherapeutics and advanced delivery strategies for the treatment of metabolic dysfunction-associated steatotic liver disease spectrum. J Control Release 2025; 380:433-456. [PMID: 39923856 DOI: 10.1016/j.jconrel.2025.02.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 12/22/2024] [Accepted: 02/04/2025] [Indexed: 02/11/2025]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), a condition with the potential to progress into liver cirrhosis or hepatocellular carcinoma, has become a significant global health concern due to its increasing prevalence alongside obesity and metabolic syndrome. Despite the promise of existing therapies such as thyroid hormone receptor-β (THR-β) agonists, PPAR agonists, FXR agonists, and GLP-1 receptor agonists, their effectiveness is limited by the complexity of the metabolic, inflammatory, and fibrotic pathways that drive MASLD progression, encompassing steatosis, metabolic dysfunction-associated steatohepatitis (MASH), and reversible liver fibrosis. Recent advances in targeted therapeutics, including RNA interference (RNAi), mRNA-based gene therapies, monoclonal antibodies, proteolysis-targeting chimeras (PROTAC), peptide-based strategies, cell-based therapies such as CAR-modified immune cells and stem cells, and extracellular vesicle-based approaches, have emerged as promising interventions. Alongside these developments, innovative drug delivery systems are being actively researched to enhance the stability, precision, and therapeutic efficacy of these biotherapeutics. These delivery strategies aim to optimize biodistribution, improve target-specific action, and reduce systemic exposure, thus addressing critical limitations of existing treatment modalities. This review provides a comprehensive exploration of the underlying biological mechanisms of MASLD and evaluates the potential of these cutting-edge biotherapeutics in synergy with advanced delivery approaches to address unmet clinical needs. By integrating fundamental disease biology with translational advancements, it aims to highlight future directions for the development of effective, targeted treatments for MASLD and its associated complications.
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Affiliation(s)
- Juhyeong Hong
- Department of Bioengineering, Institute for Bioengineering and Biopharmaceutical Research Hanyang University, 04763 Seoul, South Korea; Education and Research Group for Biopharmaceutical Innovation Leader, Hanyang University, 04763 Seoul, South Korea
| | - Yong-Hee Kim
- Department of Bioengineering, Institute for Bioengineering and Biopharmaceutical Research Hanyang University, 04763 Seoul, South Korea; Education and Research Group for Biopharmaceutical Innovation Leader, Hanyang University, 04763 Seoul, South Korea; Cursus Bio Inc., Icure Tower, Gangnam-gu, Seoul 06170, Republic of Korea.
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Ghassemifard L, Hasanlu M, Parsamanesh N, Atkin SL, Almahmeed W, Sahebkar A. Cell Therapies and Gene Therapy for Diabetes: Current Progress. Curr Diabetes Rev 2025; 21:e130524229899. [PMID: 38747221 DOI: 10.2174/0115733998292392240425122326] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Revised: 03/07/2024] [Accepted: 03/21/2024] [Indexed: 04/23/2025]
Abstract
The epidemic of diabetes continues to be an increasing problem, and there is a need for new therapeutic strategies. There are several promising drugs and molecules in synthetic medicinal chemistry that are developing for diabetes. In addition to this approach, extensive studies with gene and cell therapies are being conducted. Gene therapy is an existing approach in treating several diseases, such as cancer, autoimmune diseases, heart disease and diabetes. Several reports have also suggested that stem cells have the differentiation capability to functional pancreatic beta cell development in vitro and in vivo, with the utility to treat diabetes and prevent the progression of diabetes-related complications. In this current review, we have focused on the different types of cell therapies and vector-based gene therapy in treating or preventing diabetes.
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Affiliation(s)
- Leila Ghassemifard
- Department of Physiology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
- Department of Persian Medicine, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Masumeh Hasanlu
- Department of Internal Medicine, Vali-e-Asr Hospital, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Negin Parsamanesh
- Metabolic Diseases Research Center, Zanjan University of Medical Sciences, Zanjan, Iran
- Department of Genetics and Molecular Medicine, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Stephen L Atkin
- Research Department, Royal College of Surgeons in Ireland Bahrain, Adliya, Bahrain
| | - Wael Almahmeed
- Heart and Vascular Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Amirhossein Sahebkar
- Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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Toledano A, Rodríguez-Casado A, Älvarez MI, Toledano-Díaz A. Alzheimer's Disease, Obesity, and Type 2 Diabetes: Focus on Common Neuroglial Dysfunctions (Critical Review and New Data on Human Brain and Models). Brain Sci 2024; 14:1101. [PMID: 39595866 PMCID: PMC11591712 DOI: 10.3390/brainsci14111101] [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: 09/19/2024] [Revised: 10/17/2024] [Accepted: 10/24/2024] [Indexed: 11/28/2024] Open
Abstract
BACKGROUND/OBJECTIVES Obesity, type 2 diabetes (T2D), and Alzheimer's disease (AD) are pathologies that affect millions of people worldwide. They have no effective therapy and are difficult to prevent and control when they develop. It has been known for many years that these diseases have many pathogenic aspects in common. We highlight in this review that neuroglial cells (astroglia, oligodendroglia, and microglia) play a vital role in the origin, clinical-pathological development, and course of brain neurodegeneration. Moreover, we include the new results of a T2D-AD mouse model (APP+PS1 mice on a high-calorie diet) that we are investigating. METHODS Critical bibliographic revision and biochemical neuropathological study of neuroglia in a T2D-AD model. RESULTS T2D and AD are not only "connected" by producing complex pathologies in the same individual (obesity, T2D, and AD), but they also have many common pathogenic mechanisms. These include insulin resistance, hyperinsulinemia, hyperglycemia, oxidative stress, mitochondrial dysfunction, and inflammation (both peripheral and central-or neuroinflammation). Cognitive impairment and AD are the maximum exponents of brain neurodegeneration in these pathological processes. both due to the dysfunctions induced by metabolic changes in peripheral tissues and inadequate neurotoxic responses to changes in the brain. In this review, we first analyze the common pathogenic mechanisms of obesity, T2D, and AD (and/or cerebral vascular dementia) that induce transcendental changes and responses in neuroglia. The relationships between T2D and AD discussed mainly focus on neuroglial responses. Next, we present neuroglial changes within their neuropathological context in diverse scenarios: (a) aging involution and neurodegenerative disorders, (b) human obesity and diabetes and obesity/diabetes models, (c) human AD and in AD models, and (d) human AD-T2D and AD-T2D models. An important part of the data presented comes from our own studies on humans and experimental models over the past few years. In the T2D-AD section, we included the results of a T2D-AD mouse model (APP+PS1 mice on a high-calorie diet) that we investigated, which showed that neuroglial dysfunctions (astrocytosis and microgliosis) manifest before the appearance of amyloid neuropathology, and that the amyloid pathology is greater than that presented by mice fed a normal, non-high-caloric diet A broad review is finally included on pharmacological, cellular, genic, and non-pharmacological (especially diet and lifestyle) neuroglial-related treatments, as well as clinical trials in a comparative way between T2D and AD. These neuroglial treatments need to be included in the multimodal/integral treatments of T2D and AD to achieve greater therapeutic efficacy in many millions of patients. CONCLUSIONS Neuroglial alterations (especially in astroglia and microglia, cornerstones of neuroinflammation) are markedly defining brain neurodegeneration in T2D and A, although there are some not significant differences between each of the studied pathologies. Neuroglial therapies are a very important and p. promising tool that are being developed to prevent and/or treat brain dysfunction in T2D-AD. The need for further research in two very different directions is evident: (a) characterization of the phenotypic changes of astrocytes and microglial cells in each region of the brain and in each phase of development of each isolated and associated pathology (single-cell studies are mandatory) to better understand the pathologies and define new therapeutic targets; (b) studying new therapeutic avenues to normalize the function of neuroglial cells (preventing neurotoxic responses and/or reversing them) in these pathologies, as well as the phenotypic characteristics in each moment of the course and place of the neurodegenerative process.
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Affiliation(s)
- Adolfo Toledano
- Instituto Cajal, CSIC, 28002 Madrid, Spain; (A.R.-C.); (M.I.Ä.)
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Zeinhom A, Fadallah SA, Mahmoud M. Human mesenchymal stem/stromal cell based-therapy in diabetes mellitus: experimental and clinical perspectives. Stem Cell Res Ther 2024; 15:384. [PMID: 39468609 PMCID: PMC11520428 DOI: 10.1186/s13287-024-03974-z] [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: 09/02/2024] [Accepted: 10/04/2024] [Indexed: 10/30/2024] Open
Abstract
Diabetes mellitus (DM), a chronic metabolic disease, poses a significant global health challenge, with current treatments often fail to prevent the long-term disease complications. Mesenchymal stem/stromal cells (MSCs) are, adult progenitors, able to repair injured tissues, exhibiting regenerative effects and immunoregulatory and anti-inflammatory responses, so they have been emerged as a promising therapeutic approach in many immune-related and inflammatory diseases. This review summarizes the therapeutic mechanisms and outcomes of MSCs, derived from different human tissue sources (hMSCs), in the context of DM type 1 and type 2. Animal model studies and clinical trials indicate that hMSCs can facilitate pleiotropic actions in the diabetic milieu for improved metabolic indices. In addition to modulating abnormally active immune system, hMSCs can ameliorate peripheral insulin resistance, halt beta-cell destruction, preserve residual beta-cell mass, promote beta-cell regeneration and insulin production, support islet grafts, and correct lipid metabolism. Moreover, hMSC-free derivatives, importantly extracellular vesicles, have shown potent experimental anti-diabetic efficacy. Moreover, the review discusses the diverse priming strategies that are introduced to enhance the preclinical anti-diabetic actions of hMSCs. Such strategies are recommended to restore the characteristics and functions of MSCs isolated from patients with DM for autologous implications. Finally, limitations and merits for the wide spread clinical applications of MSCs in DM such as the challenge of autologous versus allogeneic MSCs, the optimal MSC tissue source and administration route, the necessity of larger clinical trials for longer evaluation duration to assess safety concerns, are briefly presented.
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Affiliation(s)
- Alaa Zeinhom
- Biotechnology Department, Faculty of Science, Cairo University, Cairo Governorate, 12316, Egypt
| | - Sahar A Fadallah
- Biotechnology Department, Faculty of Science, Cairo University, Cairo Governorate, 12316, Egypt
| | - Marwa Mahmoud
- Human Medical Molecular Genetics Department, Human Genetics and Genome Research Institute, National Research Centre (NRC), Cairo, 12622, Egypt.
- Stem Cell Research Unit, Medical Research Centre of Excellence, NRC, Cairo, Egypt.
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Petropavlovskaia M, Assouline-Thomas B, Cuerquis J, Zhao J, Violette-Deslauriers S, Nano E, Eliopoulos N, Rosenberg L. Characterization of MSCs expressing islet neogenesis associated protein (INGAP): INGAP secretion and cell survival in vitro and in vivo. Heliyon 2024; 10:e35372. [PMID: 39170459 PMCID: PMC11336584 DOI: 10.1016/j.heliyon.2024.e35372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 07/25/2024] [Accepted: 07/26/2024] [Indexed: 08/23/2024] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are emerging as a new therapy for diabetes. Here we investigate the properties of MSCs engineered to express Islet Neogenesis Associated Protein (INGAP) previously shown to reverse diabetes in animal models and evaluate their potential for anti-diabetic applications in mice. Mouse bone marrow-derived MSCs retrovirally transduced to co-express INGAP, Firefly Luciferase and EGFP (INGAP-MSCs), were characterized in vitro and implanted intraperitoneally (IP) into non-diabetic and diabetic C57BL/6 mice (Streptozotocin model) and tracked by live bioluminescence imaging (BLI). Distribution and survival of IP injected INGAP-MSCs differed between diabetic and non-diabetic mice, with a rapid clearance of cells in the latter, and a stronger retention (up to 4 weeks) in diabetic mice concurring with homing towards the pancreas. Interestingly, INGAP-MSCs inhibited the progression of hyperglycemia starting at day 3 and lasting for the entire 6 weeks of the study. Pursuing greater retention, we investigated the survival of INGAP-MSCs in hydrogel matrices. When mixed with Matrigel™ and injected subcutaneously into non-diabetic mice, INGAP-MSCs remained in the implant up to 16 weeks. In vitro tests in three matrices (Matrigel™, Type I Collagen and VitroGel®-MSC) demonstrated that INGAP-MSCs survive and secrete INGAP, with best results at the density of 1-2 x 106 cells/mL. However, all matrices induced spontaneous adipogenic differentiation of INGAP-MSCs in vitro and in vivo, which requires further investigation of its potential impact on MSC therapeutic properties. In summary, based on their ability to stop the rise in hyperglycemia in STZ-treated mice, INGAP-MSCs are a promising therapeutic tool against diabetes but require further research to improve cell delivery and survival.
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Affiliation(s)
- Maria Petropavlovskaia
- Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, Montreal, QC, Canada
- Department of Surgery, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada
| | | | - Jessica Cuerquis
- Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, Montreal, QC, Canada
| | - Jing Zhao
- Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, Montreal, QC, Canada
| | - Shaun Violette-Deslauriers
- Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, Montreal, QC, Canada
- Department of Surgery, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada
| | - Eni Nano
- Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, Montreal, QC, Canada
- Department of Surgery, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada
| | - Nicoletta Eliopoulos
- Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, Montreal, QC, Canada
- Department of Surgery, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada
| | - Lawrence Rosenberg
- Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, Montreal, QC, Canada
- Department of Surgery, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada
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Chandrasekara CMN, Gemikonakli G, Mach J, Sang R, Anwer AG, Agha A, Goldys EM, Hilmer SN, Campbell JM. Ageing and Polypharmacy in Mesenchymal Stromal Cells: Metabolic Impact Assessed by Hyperspectral Imaging of Autofluorescence. Int J Mol Sci 2024; 25:5830. [PMID: 38892017 PMCID: PMC11171960 DOI: 10.3390/ijms25115830] [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: 04/22/2024] [Revised: 05/20/2024] [Accepted: 05/23/2024] [Indexed: 06/21/2024] Open
Abstract
The impact of age on mesenchymal stromal cell (MSC) characteristics has been well researched. However, increased age is concomitant with increased prevalence of polypharmacy. This adjustable factor may have further implications for the functionality of MSCs and the effectiveness of autologous MSC procedures. We applied hyperspectral microscopy of cell autofluorescence-a non-invasive imaging technique used to characterise cytometabolic heterogeneity-to identify changes in the autofluorescence signals of MSCs from (1) young mice, (2) old mice, (3) young mice randomised to receive polypharmacy (9-10 weeks of oral therapeutic doses of simvastatin, metoprolol, oxycodone, oxybutynin and citalopram), and (4) old mice randomised to receive polypharmacy. Principal Component Analysis and Logistic Regression Analysis were used to assess alterations in spectral and associated metabolic characteristics. Modelling demonstrated that cells from young mice receiving polypharmacy had less NAD(P)H and increased porphyrin relative to cells from old control mice, allowing for effective separation of the two groups (AUC of ROC curve > 0.94). Similarly, cells from old polypharmacy mice were accurately separated from those from young controls due to lower levels of NAD(P)H (p < 0.001) and higher porphyrin (p < 0.001), allowing for an extremely accurate logistic regression (AUC of ROC curve = 0.99). This polypharmacy regimen may have a more profound impact on MSCs than ageing, and can simultaneously reduce optical redox ratio (ORR) and increase porphyrin levels. This has implications for the use of autologous MSCs for older patients with chronic disease.
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Affiliation(s)
- Chandrasekara M. N. Chandrasekara
- Graduate School of Biomedical Engineering, Faculty of Engineering, University of New South Wales, Sydney, NSW 2052, Australia; (C.M.N.C.); (R.S.); (A.G.A.); (A.A.); (E.M.G.)
| | - Gizem Gemikonakli
- Laboratory of Ageing and Pharmacology, Kolling Institute, Northern Sydney Local Health District and Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia; (G.G.); (J.M.); (S.N.H.)
| | - John Mach
- Laboratory of Ageing and Pharmacology, Kolling Institute, Northern Sydney Local Health District and Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia; (G.G.); (J.M.); (S.N.H.)
| | - Rui Sang
- Graduate School of Biomedical Engineering, Faculty of Engineering, University of New South Wales, Sydney, NSW 2052, Australia; (C.M.N.C.); (R.S.); (A.G.A.); (A.A.); (E.M.G.)
| | - Ayad G. Anwer
- Graduate School of Biomedical Engineering, Faculty of Engineering, University of New South Wales, Sydney, NSW 2052, Australia; (C.M.N.C.); (R.S.); (A.G.A.); (A.A.); (E.M.G.)
| | - Adnan Agha
- Graduate School of Biomedical Engineering, Faculty of Engineering, University of New South Wales, Sydney, NSW 2052, Australia; (C.M.N.C.); (R.S.); (A.G.A.); (A.A.); (E.M.G.)
| | - Ewa M. Goldys
- Graduate School of Biomedical Engineering, Faculty of Engineering, University of New South Wales, Sydney, NSW 2052, Australia; (C.M.N.C.); (R.S.); (A.G.A.); (A.A.); (E.M.G.)
| | - Sarah N. Hilmer
- Laboratory of Ageing and Pharmacology, Kolling Institute, Northern Sydney Local Health District and Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia; (G.G.); (J.M.); (S.N.H.)
| | - Jared M. Campbell
- Graduate School of Biomedical Engineering, Faculty of Engineering, University of New South Wales, Sydney, NSW 2052, Australia; (C.M.N.C.); (R.S.); (A.G.A.); (A.A.); (E.M.G.)
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Habiba UE, Khan N, Greene DL, Ahmad K, Shamim S, Umer A. Meta-analysis shows that mesenchymal stem cell therapy can be a possible treatment for diabetes. Front Endocrinol (Lausanne) 2024; 15:1380443. [PMID: 38800472 PMCID: PMC11116613 DOI: 10.3389/fendo.2024.1380443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 04/09/2024] [Indexed: 05/29/2024] Open
Abstract
Objective This meta-analysis includes the systematic literature review and meta-analysis involving clinical trials to assess the efficacy and safety of mesenchymal stem cell (MSC) transplantation for treating T1DM and T2DM. Methods We searched PubMed, ScienceDirect, Web of Science, clinicaltrials.gov, and Cochrane Library for "published" research from their inception until November 2023. Two researchers independently reviewed the studies' inclusion and exclusion criteria. Our meta-analysis included 13 studies on MSC treatment for diabetes. Results The MSC-treated group had a significantly lower HbA1c at the last follow-up compared to the baseline (MD: 0.95, 95% CI: 0.33 to 1.57, P-value: 0.003< 0.05), their insulin requirement was significantly lower (MD: 0.19, 95% CI: 0.07 to 0.31, P-value: 0.002< 0.05), the level of FBG with MSC transplantation significantly dropped compared to baseline (MD: 1.78, 95% CI: -1.02 to 4.58, P-value: 0.212), the FPG level of the MSC-treated group was significantly lower (MD: -0.77, 95% CI: -2.36 to 0.81, P-value: 0.339 > 0.05), and the fasting C-peptide level of the MSC-treated group was slightly high (MD: -0.02, 95% CI: -0.07 to 0.02, P-value: 0.231 > 0.05). Conclusion The transplantation of MSCs has been found to positively impact both types of diabetes mellitus without signs of apparent adverse effects.
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Affiliation(s)
- Umm E. Habiba
- Research and Development (R&D) Department, R3 Medical Research LLC, Scottsdale, AZ, United States
- Research and Development (R&D) Department, Pak-American Hospital Pvt. Ltd., Islamabad, Pakistan
- Research and Development (R&D) Department, R3 Stem Cell LLC, Scottsdale, AZ, United States
| | - Nasar Khan
- Research and Development (R&D) Department, R3 Medical Research LLC, Scottsdale, AZ, United States
- Research and Development (R&D) Department, Pak-American Hospital Pvt. Ltd., Islamabad, Pakistan
- Research and Development (R&D) Department, R3 Stem Cell LLC, Scottsdale, AZ, United States
- Research and Development (R&D) Department, Bello Bio Labs and Therapeutics Pvt. Ltd., Islamabad, Pakistan
| | - David Lawrence Greene
- Research and Development (R&D) Department, R3 Medical Research LLC, Scottsdale, AZ, United States
- Research and Development (R&D) Department, Pak-American Hospital Pvt. Ltd., Islamabad, Pakistan
- Research and Development (R&D) Department, R3 Stem Cell LLC, Scottsdale, AZ, United States
- Research and Development (R&D) Department, Bello Bio Labs and Therapeutics Pvt. Ltd., Islamabad, Pakistan
| | - Khalil Ahmad
- Department of Statistics, Quaid-i-Azam University, Islamabad, Pakistan
| | - Sabiha Shamim
- Research and Development (R&D) Department, R3 Medical Research LLC, Scottsdale, AZ, United States
- Research and Development (R&D) Department, Pak-American Hospital Pvt. Ltd., Islamabad, Pakistan
- Research and Development (R&D) Department, R3 Stem Cell LLC, Scottsdale, AZ, United States
| | - Amna Umer
- Research and Development (R&D) Department, R3 Medical Research LLC, Scottsdale, AZ, United States
- Research and Development (R&D) Department, Pak-American Hospital Pvt. Ltd., Islamabad, Pakistan
- Research and Development (R&D) Department, R3 Stem Cell LLC, Scottsdale, AZ, United States
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10
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Kamal MM, Ammar RA, Kassem DH. Silencing of forkhead box protein O-1 (FOXO-1) enhances insulin-producing cell generation from adipose mesenchymal stem cells for diabetes therapy. Life Sci 2024; 344:122579. [PMID: 38518842 DOI: 10.1016/j.lfs.2024.122579] [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: 01/07/2024] [Revised: 03/09/2024] [Accepted: 03/18/2024] [Indexed: 03/24/2024]
Abstract
AIMS Generation of mature β-cells from MSCs has been a challenge in the field of stem cell therapy of diabetes. Adipose tissue-derived mesenchymal stem cells (Ad-MSCs) have made their mark in regenerative medicine, and provide several advantages compared to other MSCs sources. Forkhead box protein O-1 (FOXO-1) is an important transcription factor for normal development of β-cells, yet its over expression in β-cells may cause glucose intolerance. In this study, we isolated, characterized Ad-MSCs from rat epididymal fat pads, differentiated these MSCs into insulin producing cells (IPCs) and studied the role of FOXO-1 in such differentiation. MATERIALS AND METHODS We examined the expression of FOXO-1 and its nuclear cytoplasmic localization in the generated IPCs. Afterwards we knocked down FOXO-1 using siRNA targeting FOXO-1 (siFOXO-1). The differentiated siFOXO-1 IPCs were compared to non-targeting siRNA (siNT) IPCs regarding expression of β-cell markers by qRT-PCR and western blotting, dithizone (DTZ) staining and glucose stimulated insulin secretion (GSIS). KEY FINDINGS Isolated Ad-MSCs exhibited all characteristics of MSCs and can generate IPCs. FOXO-1 was initially elevated during differentiation followed by a decline towards end of differentiation. FOXO-1 was dephosphorylated and localized to the nucleus upon differentiation into IPCs. Knock down of FOXO-1 improved the expression of β-cell markers in final differentiated IPCs, improved DTZ uptake and showed increased insulin secretion upon challenging with increased glucose concentration. SIGNIFICANCE These results portray FOXO-1 as a hindering factor of generation of IPCs whose down-regulation can generate more mature IPCs for MSCs therapy of diabetes mellitus.
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Affiliation(s)
- Mohamed M Kamal
- Pharmacology and Biochemistry Department, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt; Health Research Center of Excellence, Drug Research and Development Group, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt.
| | - Reham A Ammar
- Pharmacology and Biochemistry Department, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; Health Research Center of Excellence, Drug Research and Development Group, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt
| | - Dina H Kassem
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
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11
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Wang Y, Chen H, Li Y, Hao H, Liu J, Chen Y, Meng J, Zhang S, Gu W, Lyu Z, Zang L, Mu Y. Predictive factors that influence the clinical efficacy of umbilical cord-derived mesenchymal stromal cells in the treatment of type 2 diabetes mellitus. Cytotherapy 2024; 26:311-316. [PMID: 38219142 DOI: 10.1016/j.jcyt.2023.12.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Revised: 11/20/2023] [Accepted: 12/26/2023] [Indexed: 01/15/2024]
Abstract
BACKGROUND Our previous single-center, randomized, double-blinded, placebo-controlled phase 2 study evaluated the safety and effectiveness of human umbilical cord mesenchymal stromal cell (UC-MSC) transfusion for treating patients with type 2 diabetes mellitus (T2DM). Indeed, this potential treatment strategy was able to reduce insulin use by half in a considerable number of patients. However, many other patients' responses to UC-MSC transfusion were insignificant. The selection of patients who might benefit from UC-MSC treatment is crucial from a clinical standpoint. METHODS In this post hoc analysis, 37 patients who received UC-MSC transfusions were divided into two groups based on whether their glycated hemoglobin (hemoglobin A1c, or HbA1c) level was less than 7% after receiving UC-MSC treatment. The baseline differences between the two groups were summarized, and potential factors influencing efficacy of UC-MSCs for T2DM were analyzed by univariate and multivariate logistic regression. The correlations between the relevant hormone levels and the treatment effect were further analyzed. RESULTS At the 9-week follow-up, 59.5% of patients achieved their targeted HbA1c level. Male patients with lower baseline HbA1c and greater C-peptide area under the curve (AUCC-pep) values responded favorably to UC-MSC transfusion, according to multivariate analysis. The effectiveness of UC-MSCs transfusion was predicted by AUCC-pep (cutoff value: 14.22 ng/h/mL). Further investigation revealed that AUCC-pep was increased in male patients with greater baseline testosterone levels. CONCLUSIONS Male patients with T2DM with greater AUCC-pep may be more likely to respond clinically to UC-MSC therapy, and further large-scale multi-ethnic clinical studies should be performed to confirm the conclusion.
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Affiliation(s)
- Yuepeng Wang
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, China; School of Medicine, Nankai University, Tianjin, China
| | - Haixu Chen
- Institute of Geriatrics & National Clinical Research Center of Geriatrics Disease, The Second Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yijun Li
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Haojie Hao
- Department of Biotherapy, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Jiejie Liu
- Department of Biotherapy, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yulong Chen
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Junhua Meng
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Saichun Zhang
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Weijun Gu
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Zhaohui Lyu
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Li Zang
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, China.
| | - Yiming Mu
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, China.
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12
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Mei L, Yuwei Y, Weiping L, Zhiran X, Bingzheng F, Jibing C, Hongjun G. Strategy for Clinical Setting of Co-transplantation of Mesenchymal Stem Cells and Pancreatic Islets. Cell Transplant 2024; 33:9636897241259433. [PMID: 38877672 PMCID: PMC11179456 DOI: 10.1177/09636897241259433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 04/29/2024] [Accepted: 05/06/2024] [Indexed: 06/16/2024] Open
Abstract
Islet transplantation may be the most efficient therapeutic technique for patients with type 1 diabetes mellitus (T1DM). However, the clinical application of this method is faced with numerous limitations, including isolated islet apoptosis, recipient rejection, and graft vascular reconstruction. Mesenchymal stem cells (MSCs) possess anti-apoptotic, immunomodulatory, and angiogenic properties. Here, we review recent studies on co-culture and co-transplantation of islets with MSCs. We have summarized the methods of preparation of co-transplantation, especially the merits of co-culture, and the effects of co-transplantation. Accumulating experimental evidence shows that co-culture of islets with MSCs promotes islet survival, enhances islet secretory function, and prevascularizes islets through various pretransplant preparations. This review is expected to provide a reference for exploring the use of MSCs for clinical islet co-transplantation.
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Affiliation(s)
- Liang Mei
- Graduate School, Guangxi University of Chinese Medicine, Nanning, China
| | - Yang Yuwei
- Ruikang Hospital affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - Liang Weiping
- Ruikang Hospital affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - Xu Zhiran
- Ruikang Hospital affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - Feng Bingzheng
- Ruikang Hospital affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - Chen Jibing
- Ruikang Hospital affiliated to Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Clinical Research Center for Kidney Diseases of Integrated Traditional Chinese and Western Medicine, Nanning, China
| | - Gao Hongjun
- Ruikang Hospital affiliated to Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Clinical Research Center for Kidney Diseases of Integrated Traditional Chinese and Western Medicine, Nanning, China
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13
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Abu-El-Rub E, Almahasneh F, Khasawneh RR, Alzu'bi A, Ghorab D, Almazari R, Magableh H, Sanajleh A, Shlool H, Mazari M, Bader NS, Al-Momani J. Human mesenchymal stem cells exhibit altered mitochondrial dynamics and poor survival in high glucose microenvironment. World J Stem Cells 2023; 15:1093-1103. [PMID: 38179215 PMCID: PMC10762524 DOI: 10.4252/wjsc.v15.i12.1093] [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: 09/28/2023] [Revised: 11/11/2023] [Accepted: 11/24/2023] [Indexed: 12/26/2023] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) are a type of stem cells that possess relevant regenerative abilities and can be used to treat many chronic diseases. Diabetes mellitus (DM) is a frequently diagnosed chronic disease characterized by hyperglycemia which initiates many multisystem complications in the long-run. DM patients can benefit from MSCs transplantation to curb down the pathological consequences associated with hyperglycemia persistence and restore the function of damaged tissues. MSCs therapeutic outcomes are found to last for short period of time and ultimately these regenerative cells are eradicated and died in DM disease model. AIM To investigate the impact of high glucose or hyperglycemia on the cellular and molecular characteristics of MSCs. METHODS Human adipose tissue-derived MSCs (hAD-MSCs) were seeded in low (5.6 mmol/L of glucose) and high glucose (25 mmol/L of glucose) for 7 d. Cytotoxicity, viability, mitochondrial dynamics, and apoptosis were deplored using specific kits. Western blotting was performed to measure the protein expression of phosphatidylinositol 3-kinase (PI3K), TSC1, and mammalian target of rapamycin (mTOR) in these cells. RESULTS hAD-MSCs cultured in high glucose for 7 d demonstrated marked decrease in their viability, as shown by a significant increase in lactate dehydrogenase (P < 0.01) and a significant decrease in Trypan blue (P < 0.05) in these cells compared to low glucose control. Mitochondrial membrane potential, indicated by tetramethylrhodamine ethyl ester (TMRE) fluorescence intensity, and nicotinamide adenine dinucleotide (NAD+)/NADH ratio were significantly dropped (P < 0.05 for TMRE and P < 0.01 for NAD+/NADH) in high glucose exposed hAD-MSCs, indicating disturbed mitochondrial function. PI3K protein expression significantly decreased in high glucose culture MSCs (P < 0.05 compared to low glucose) and it was coupled with significant upregulation in TSC1 (P < 0.05) and downregulation in mTOR protein expression (P < 0.05). Mitochondrial complexes I, IV, and V were downregulated profoundly in high glucose (P < 0.05 compared to low glucose). Apoptosis was induced as a result of mitochondrial impairment and explained the poor survival of MSCs in high glucose. CONCLUSION High glucose impaired the mitochondrial dynamics and regulatory proteins in hAD-MSCs ensuing their poor survival and high apoptosis rate in hyperglycemic microenvironment.
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Affiliation(s)
- Ejlal Abu-El-Rub
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid 21163, Jordan.
| | - Fatimah Almahasneh
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid 21163, Jordan
| | - Ramada R Khasawneh
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid 21163, Jordan
| | - Ayman Alzu'bi
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid 21163, Jordan
| | - Doaa Ghorab
- Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Rawan Almazari
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid 21163, Jordan
| | - Huthaifa Magableh
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid 21163, Jordan
| | - Ahmad Sanajleh
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid 21163, Jordan
| | - Haitham Shlool
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid 21163, Jordan
| | - Mohammad Mazari
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid 21163, Jordan
| | - Noor S Bader
- Department of Basic Medical Sciences, Yarmouk University, Irbid 21163, Jordan
| | - Joud Al-Momani
- Department of Basic Medical Sciences, Yarmouk University, Irbid 21163, Jordan
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14
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Wang X, Tian H, Yang X, Zhao H, Liang X, Li Y. Mesenchymal Stem Cells‐Derived Extracellular Vesicles in Orthopedic Diseases: Recent Advances and Therapeutic Potential. ADVANCED THERAPEUTICS 2023; 6. [DOI: 10.1002/adtp.202300193] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Indexed: 01/06/2025]
Abstract
AbstractEver since the first application of mesenchymal stem cell (MSC) transplantation treating human hematologic malignancies in 1995, MSC‐based treatments have demonstrated great therapeutic potential in clinical settings. However, only a few MSC‐based cell therapy products have been clinically approved. Accumulating evidence suggests that the beneficial effects of MSCs are mainly attributed to the release of paracrine factors or extracellular vesicles (EVs) rather than their mesodermal differentiation potential. Therefore, MSC‐derived EVs (MSC‐EVs), such as exosomes and microvesicles, have merged as promising alternatives to traditional cell‐based therapeutics in clinical practice. They offer several advantages such as better safety, lower immunogenicity, protection of cargoes from degradation, and the ability to overcome biological barriers. Moreover, there have been multiple clinical studies exploring the potential of MSC‐EVs for treating various diseases, including orthopedic disorders. However, there is no definitive “cure” for conditions such as osteoporosis and other bone disorders, but MSC‐EVs have displayed significant therapeutic potential for these orthopedic ailments. Therefore, the objective of this study is to conduct a systematic review of current knowledge related to MSC‐EVs and emphasize their potential application in treating orthopedic diseases, such as bone defects, osteoarthritis, osteoporosis, intervertebral disc degeneration, osteosarcoma, and osteoradionecrosis.
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Affiliation(s)
- Xinwen Wang
- Department of Foot and Ankle Surgery, Honghui Hospital Xi'an Jiaotong University Xi'an Shaanxi Province 710054 P. R. China
| | - Haodong Tian
- Department of Foot and Ankle Surgery, Honghui Hospital Xi'an Jiaotong University Xi'an Shaanxi Province 710054 P. R. China
| | - Xinquan Yang
- Department of Foot and Ankle Surgery, Honghui Hospital Xi'an Jiaotong University Xi'an Shaanxi Province 710054 P. R. China
| | - Hongmou Zhao
- Department of Foot and Ankle Surgery, Honghui Hospital Xi'an Jiaotong University Xi'an Shaanxi Province 710054 P. R. China
| | - Xiaojun Liang
- Department of Foot and Ankle Surgery, Honghui Hospital Xi'an Jiaotong University Xi'an Shaanxi Province 710054 P. R. China
| | - Yi Li
- Department of Foot and Ankle Surgery, Honghui Hospital Xi'an Jiaotong University Xi'an Shaanxi Province 710054 P. R. China
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15
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Jia Z, Zhang S, Li W. Harnessing Stem Cell-Derived Extracellular Vesicles for the Regeneration of Degenerative Bone Conditions. Int J Nanomedicine 2023; 18:5561-5578. [PMID: 37795043 PMCID: PMC10546935 DOI: 10.2147/ijn.s424731] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 09/23/2023] [Indexed: 10/06/2023] Open
Abstract
Degenerative bone disorders such as intervertebral disc degeneration (IVDD), osteoarthritis (OA), and osteoporosis (OP) pose significant health challenges for aging populations and lack effective treatment options. The field of regenerative medicine holds promise in addressing these disorders, with a focus on utilizing extracellular vesicles (EVs) derived from stem cells as an innovative therapeutic approach. EVs have shown great potential in stimulating biological responses, making them an attractive candidate for rejuvenating degenerative bone disorders. However, a comprehensive review summarizing the current state of this field and providing a clear assessment of EV-based therapies in degenerative bone disorders is currently deficient. In this review, we aim to fill the existing gap by outlining the current knowledge on the role of EVs derived from different types of stem cells, such as mesenchymal stem cells, embryonic stem cells, and induced pluripotent stem cells, in bone regeneration. Furthermore, we discuss the therapeutic potential of EV-based treatments for IVDD, OA, and OP. By substantiating the use of stem cell-derived EVs, we highlight their promising potential as a cell-free strategy to improve degenerative bone disorders.
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Affiliation(s)
- Zhiwei Jia
- Department of Orthopedics, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 101100, People’s Republic of China
| | - Shunxin Zhang
- Department of Ultrasound, 2nd Medical Center of PLA General Hospital, Beijing, 100853, People’s Republic of China
| | - Wei Li
- Department of Sports Medicine, Fourth Medical Center of PLA General Hospital, Beijing, 100048, People’s Republic of China
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16
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Kashani SA, Navabi R, Amini A, Hajinasrollah M, Jenab Y, Rabbani S, Nazari A, Pakzad M, Moazenchi M, Atrabi MJ, Samsonchi Z, Hezavehei M, Hosseini-Beheshti E, Shekari F, Hajizadeh-Saffar E, Baharvand H. Immunomodulatory potential of human clonal mesenchymal stem cells and their extracellular vesicle subpopulations in an inflammatory-mediated diabetic Rhesus monkey model. Life Sci 2023; 329:121950. [PMID: 37473804 DOI: 10.1016/j.lfs.2023.121950] [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: 01/25/2023] [Revised: 07/05/2023] [Accepted: 07/14/2023] [Indexed: 07/22/2023]
Abstract
AIMS This study aimed to investigate the therapeutic potential of a homogenous clonal population of mesenchymal stem cells (cMSC) and their extracellular vesicles (cMSC-EV) subpopulations on isolated rat islets in vitro and in inflammatory-mediated type 1 diabetes (T1D) non-human primate models. MAIN METHODS EV subpopulations were isolated from human bone marrow-derived cMSC supernatant by low- and high-speed ultracentrifuge (EV-20K and EV-U110K) and sucrose density gradient (EV-S110K). The EVs were characterized generally and for the level of albumin, acetylcholinesterase (AChE) activity, co-isolate apoptotic markers, and expression of CD63+/annexin V+. Rat islet-derived single cells (iSCs) proliferation was measured using a Ki-67 proliferation assay. Diabetes was induced by multiple low-dose administrations of streptozotocin in rhesus monkeys. The diabetic monkeys were divided into three groups: the cMSC group, received two injections of 1.5 × 106 cMSC/kg body weight; the EV group received two injections of EVs isolated from 1.5 × 106 cMSC/kg, and the vehicle group received phosphate-buffered saline. KEY FINDINGS EV-S110K showed higher AChE activity, lower expression of CD63+/annexin V+, and lower apoptotic co-isolates. EV-S110K induced β-cell proliferation in vitro in a dose-dependent manner. The administration of EV-S110K and/or cMSC in diabetic monkeys demonstrated no significant changes in general diabetic indices and β-cell mass in the pancreas of the monkeys. Both treatments demonstrated a lowering trend in blood glucose levels and reduced pro-inflammatory cytokines. In contrast, regulatory T cells and anti-inflammatory cytokines were increased. SIGNIFICANCE cMSC and cMSC-EV provided initial evidence to attenuate clinical symptoms in inflammatory-mediated T1D non-human primates through immunomodulation.
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Affiliation(s)
- Sara Assar Kashani
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Roghayeh Navabi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Azadeh Amini
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Mostafa Hajinasrollah
- Animal Core Facility, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Yaser Jenab
- Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Shahram Rabbani
- Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Abdoreza Nazari
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran; Advanced Therapy Medicinal Product Technology Development Center, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Mohammad Pakzad
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Maedeh Moazenchi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran; Advanced Therapy Medicinal Product Technology Development Center, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Mohammad Jafari Atrabi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Zakieh Samsonchi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Maryam Hezavehei
- Department of Embryology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Elham Hosseini-Beheshti
- School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2006, Australia; Sydney Nano Institute, The University of Sydney, Camperdown, NSW 2006, Australia
| | - Faezeh Shekari
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran; Advanced Therapy Medicinal Product Technology Development Center, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Ensiyeh Hajizadeh-Saffar
- Advanced Therapy Medicinal Product Technology Development Center, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran; Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
| | - Hossein Baharvand
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran; Department of Developmental Biology, School of Basic Sciences and Advanced Technologies in Biology, University of Science and Culture, Tehran, Iran.
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17
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Zhoujun Z, Bingzheng F, Yuwei Y, Yingying Z, Zhiran X, Chunhua H, Jing L, Haibo T, Wanli L, Ting Z, Fujun L, Jibing C, Hongjun G. Transplantation of insulin-producing cells derived from human MSCs to treat diabetes in a non-human primate model. Artif Organs 2023; 47:1298-1308. [PMID: 37032529 DOI: 10.1111/aor.14538] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 01/05/2023] [Accepted: 01/24/2023] [Indexed: 04/11/2023]
Abstract
BACKGROUND Islet cell transplantation is an emerging therapy in the treatment of diabetes mellitus. Differentiation of islet cells from mesenchymal stem cells (MSCs) is a potential solution to the challenge of insufficient donor sources. This study investigated whether human umbilical cord-derived MSCs could effectively differentiate into insulin-producing cells (IPCs) and evaluated the therapeutic efficacy of IPCs in treating diabetes. METHODS IPCs were induced from MSCs by a two-step protocol. IPC expression products were evaluated by western blot and real-time PCR. IPC insulin secretion was evaluated by ELISA. The viability of IPCs was measured by FDA/PI and dithizone staining. The non-human primate tree shrew was used as a diabetes model. After a single STZ induction into a diabetes model, a single intraportal transplantation of IPCs, MSCs, or normal saline was performed (n = 6 per group). Blood glucose was monitored for 3 weeks, then the animals were euthanized and the distribution of IPCs in the liver was examined pathologically. RESULTS After about 3 weeks of in vitro induction, IPCs formed microspheres of 100-200 μm, with >95% viable cells that were dithizone stain positive. IPCs expressed islet-related genes and proteins and secreted high levels of insulin whether stimulated by low or high levels of glucose. After transplantation of IPCs into diabetic tree shrews, blood glucose levels decreased rapidly to near normal and were significantly lower than the MSC or saline groups for 3 weeks thereafter. CONCLUSION We present the novel discovery that IPCs derived from human umbilical cord MSCs exert a therapeutic effect in a non-human primate model of diabetes. This study provides a preliminary experimental basis for the use of autologous MSC-derived IPCs in the treatment of human diabetes.
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Affiliation(s)
- Zhu Zhoujun
- Ruikang Hospital affiliated to Guangxi University of Chinese Medicine, Nanning, China
- Sixth Hospital affiliated to Xinjiang Medical University, Xinjiang, China
| | - Feng Bingzheng
- Ruikang Hospital affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - Yang Yuwei
- Guangxi University of Chinese Medicine, Nanning, China
| | | | - Xu Zhiran
- Ruikang Hospital affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - He Chunhua
- Sixth Hospital affiliated to Xinjiang Medical University, Xinjiang, China
| | - Leng Jing
- Guangxi Key Laboratory of High Incidence Infectious Diseases for Integrated Traditional Chinese and Western Medicine & Translational Medicine, Nanning, China
| | - Tang Haibo
- Guangxi Key Laboratory of High Incidence Infectious Diseases for Integrated Traditional Chinese and Western Medicine & Translational Medicine, Nanning, China
| | - Li Wanli
- Guangxi University of Chinese Medicine, Nanning, China
| | - Zhang Ting
- Ruikang Hospital affiliated to Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Clinical Research Center for Kidney Diseases of Integrated Traditional Chinese and Western Medicine, Nanning, China
| | - Li Fujun
- Ruikang Hospital affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - Chen Jibing
- Ruikang Hospital affiliated to Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Clinical Research Center for Kidney Diseases of Integrated Traditional Chinese and Western Medicine, Nanning, China
| | - Gao Hongjun
- Ruikang Hospital affiliated to Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Clinical Research Center for Kidney Diseases of Integrated Traditional Chinese and Western Medicine, Nanning, China
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18
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Arshad M, Jalil F, Jaleel H, Ghafoor F. Bone marrow derived mesenchymal stem cells therapy for rheumatoid arthritis - a concise review of past ten years. Mol Biol Rep 2023; 50:4619-4629. [PMID: 36929285 DOI: 10.1007/s11033-023-08277-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 01/11/2023] [Indexed: 03/18/2023]
Abstract
Rheumatoid arthritis is an autoimmune disorder characterized by swelling in synovial joints and erosion of bones. The disease is normally treated with conventional drugs which provide only temporary relief to the symptoms. Over the past few years, mesenchymal stromal cells have become the center of attention for treating this disease due to their immuno-modulatory and anti-inflammatory characteristics. Various studies on treatment of rheumatoid arthritis by using these cells have shown positive outcomes in terms of reduction in the level of pain as well as improvement of the function and structure of joints. Mesenchymal stromal cells can be derived from multiple sources, however, the ones derived from bone marrow are considered most beneficial for treating several disorders including rheumatoid arthritis on account of being safer and more effective. This review summarizes all the preclinical and clinical studies which were conducted over the last ten years for therapy of rheumatoid arthritis utilizing these cells. The literature was reviewed using the terms "mesenchymal stem/stromal cells and rheumatoid arthritis'' and "bone marrow derived mesenchymal stromal cells and therapy of rheumatoid arthritis''. Data was extracted to enable the readers to have access to the most relevant information regarding advancement in therapeutic potential of these stromal cells. Additionally, this review will also help in fulfilling any gap in current knowledge of readers about the outcome of using these cells in animal models, cell line and in patients suffering from rheumatoid arthritis and other autoimmune disorders as well.
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Affiliation(s)
- Maria Arshad
- Department of Research & Innovation, Shalamar Institute of Health Sciences, Lahore, Pakistan.
| | - Fazal Jalil
- Department of Biotechnology, Abdul Wali Khan University, Mardan, Pakistan
| | - Hadiqa Jaleel
- Department of Research & Innovation, Shalamar Institute of Health Sciences, Lahore, Pakistan
| | - Farkhanda Ghafoor
- Department of Research & Innovation, Shalamar Institute of Health Sciences, Lahore, Pakistan
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Dayal D, Gupta BM, Mamdapur GM, Rohilla L, Nanda PM. Stem cell therapy for type 1 diabetes: a scientometric assessment of global research during the twenty-first century. J Diabetes Metab Disord 2022; 21:1679-1687. [PMID: 36404818 PMCID: PMC9672280 DOI: 10.1007/s40200-022-01120-1] [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: 07/19/2021] [Accepted: 09/01/2022] [Indexed: 10/14/2022]
Abstract
Purpose We aimed to provide a scientometric assessment of global research in stem cell therapy (SCT) for type 1 diabetes (T1D) during 1999-2020. Methods The published data on SCT in T1D were retrieved from Elsevier's Scopus database and analyzed using select bibliometric tools. We used VOSviewer software and the Biblioshiny app to construct and visualize bibliometric networks. Results The global yield totaled 1806 publications in the 22-year study period, registering a 17.7% annual growth peaking at 196.9% in the last 11 years. The average citations per publication (CPP) decreased from 62.0 during 1999-2009 to 24.3 during 2010-2020. The funded publications were 727 (40.2%). Randomized controlled trials (RCTs) were only 2.4% (45). Amongst 70 participating countries, the USA led with a 38.6% share. Of the 388 global organizations, Harvard Medical School, USA, San Raffaele Scientific Institute, Italy, and the University of Florida, USA were the topmost contributors. Florina, Couri, and Trucco were the top productive authors, whereas Melton, Abdi, and Simoes were the most impactful. Only 129 (3.1%) publications were highly-cited; their total and average CPP were 31,228 and 214.0 (range 101-1841), respectively. Conclusions The quantity of research in SCT for T1D has increased during the last two decades while the quality has dipped. The research landscape is dominated by high-income North-American and Western-European countries. There is a need for conducting large-scale RCTs and promoting research collaborations between high- and low-income countries for long-term sustainability and global impact.
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Affiliation(s)
- Devi Dayal
- Endocrinology and Diabetes Unit, Department of Pediatrics, Advanced Pediatrics Center, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India
| | - Brij Mohan Gupta
- CSIR-National Institute of Science, Technology and Development Studies, New Delhi, India
| | - Ghouse Modin Mamdapur
- Information & Documentation, Synthite Industries (Pvt.) Ltd, Kolenchery, Kerala India
| | - Latika Rohilla
- Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Pamali Mahasweta Nanda
- Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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Perinatal Stem Cell Therapy to Treat Type 1 Diabetes Mellitus: A Never-Say-Die Story of Differentiation and Immunomodulation. Int J Mol Sci 2022; 23:ijms232314597. [PMID: 36498923 PMCID: PMC9738084 DOI: 10.3390/ijms232314597] [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: 10/13/2022] [Revised: 11/14/2022] [Accepted: 11/18/2022] [Indexed: 11/24/2022] Open
Abstract
Human term placenta and other postpartum-derived biological tissues are promising sources of perinatal cells with unique stem cell properties. Among the massive current research on stem cells, one medical focus on easily available stem cells is to exploit them in the design of immunotherapy protocols, in particular for the treatment of chronic non-curable human diseases. Type 1 diabetes is characterized by autoimmune destruction of pancreatic beta cells and perinatal cells can be harnessed both to generate insulin-producing cells for beta cell replenishment and to regulate autoimmune mechanisms via immunomodulation capacity. In this study, the strong points of cells derived from amniotic epithelial cells and from umbilical cord matrix are outlined and their potential for supporting cell therapy development. From a basic research and expert stem cell point of view, the aim of this review is to summarize information regarding the regenerative medicine field, as well as describe the state of the art on possible cell therapy approaches for diabetes.
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Zhang W, Ling Q, Wang B, Wang K, Pang J, Lu J, Bi Y, Zhu D. Comparison of therapeutic effects of mesenchymal stem cells from umbilical cord and bone marrow in the treatment of type 1 diabetes. Stem Cell Res Ther 2022; 13:406. [PMID: 35941696 PMCID: PMC9358877 DOI: 10.1186/s13287-022-02974-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 06/13/2022] [Indexed: 11/17/2022] Open
Abstract
Background The therapeutic potential of mesenchymal stem cells (MSCs) in type 1 diabetes (T1D) has been demonstrated in both preclinical and clinical studies. MSCs that have been used in research on T1D are derived from various tissue sources, with bone marrow (BM) and umbilical cord (UC) tissues being the most commonly used. However, the influence of tissue origin on the functional properties and therapeutic effects of MSCs in T1D remains unclear. This study aimed to compare the therapeutic efficacy of UC-MSCs and BM-MSCs in a mouse model of T1D as well as in patients with T1D. Methods In non-obese diabetic (NOD) mice, the development of diabetes was accelerated by streptozotocin injections. Thereafter, diabetic mice were randomized and treated intravenously with UC-MSCs, BM-MSCs or phosphate-buffered saline as a control. Blood glucose and serum insulin were measured longitudinally after transplantation. At 14 days post-transplantation, pancreatic tissues were collected to assess insulitis and the β-cell mass. Flow cytometry was performed to evaluate the composition of T lymphocytes in the spleen and pancreatic lymph nodes of the NOD mice. In our retrospective study of patients with T1D, 28 recipients who received insulin therapy alone or a single transplantation of UC-MSCs or BM-MSCs were enrolled. The glycaemic control and β-cell function of the patients during the first year of follow-up were compared. Results In NOD mice, UC-MSC and BM-MSC transplantation showed similar effects on decreasing blood glucose levels and preserving β cells. The regulation of islet autoimmunity was examined, and no significant difference between UC-MSCs and BM-MSCs was observed in the attenuation of insulitis, the decrease in T helper 17 cells or the increase in regulatory T cells. In patients with T1D, MSC transplantation markedly lowered haemoglobin A1c (HbA1c) levels and reduced insulin doses compared to conventional insulin therapy. However, the therapeutic effects were comparable between UC-MSCs and BM-MSCs, and they also exerted similar effects on the endogenous β-cell function in the patients. Conclusion In conclusion, both UC-MSCs and BM-MSCs exhibited comparable therapeutic effects on improving glycaemic control and preserving β-cell function in T1D. Considering their abundance and higher cell yields, UC-MSCs appear to be more promising than BM-MSCs in clinical applications. Trial registration NCT02763423. Registered on May 5, 2016—Retrospectively registered, https://www.clinicaltrials.gov/.
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Affiliation(s)
- Wei Zhang
- Department of Endocrinology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, No. 321, Zhongshan Road, Nanjing, 210008, Jiangsu, China
| | - Qing Ling
- Department of Endocrinology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, No. 321, Zhongshan Road, Nanjing, 210008, Jiangsu, China
| | - Bin Wang
- Clinical Stem Cell Center, Affiliated Drum Tower Hospital, Medical School of Nanjing University, No. 321, Zhongshan Road, Nanjing, 210008, Jiangsu, China
| | - Kai Wang
- Department of Endocrinology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, No. 321, Zhongshan Road, Nanjing, 210008, Jiangsu, China
| | - Jianbo Pang
- Department of Endocrinology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, No. 321, Zhongshan Road, Nanjing, 210008, Jiangsu, China
| | - Jing Lu
- Department of Endocrinology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, No. 321, Zhongshan Road, Nanjing, 210008, Jiangsu, China.
| | - Yan Bi
- Department of Endocrinology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, No. 321, Zhongshan Road, Nanjing, 210008, Jiangsu, China.
| | - Dalong Zhu
- Department of Endocrinology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, No. 321, Zhongshan Road, Nanjing, 210008, Jiangsu, China.
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Azizi Z, Abbaszadeh R, Sahebnasagh R, Norouzy A, Motevaseli E, Maedler K. Bone marrow mesenchymal stromal cells for diabetes therapy: touch, fuse, and fix? Stem Cell Res Ther 2022; 13:348. [PMID: 35883121 PMCID: PMC9327419 DOI: 10.1186/s13287-022-03028-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 07/04/2022] [Indexed: 12/26/2022] Open
Abstract
Bone marrow mesenchymal stromal cells (BM-MSCs) have anti-inflammatory and pro-survival properties. Naturally, they do not express human leukocyte antigen class II surface antigens and have immunosuppressive capabilities. Together with their relatively easy accessibility and expansion, they are an attractive tool for organ support in transplantation and regenerative therapy. Autologous BM-MSC transplantation alone or together with transplanted islets improves β-cell function, graft survival, and glycemic control in diabetes. Albeit MSCs’ capacity to transdifferentiate into β-cell is limited, their protective effects are mediated mainly by paracrine mechanisms through BM-MSCs circulating through the body. Direct cell–cell contact and spontaneous fusion of BM-MSCs with injured cells, although at a very low rate, are further mechanisms of their supportive effect and for tissue regeneration. Diabetes is a disease of long-term chronic inflammation and cell therapy requires stable, highly functional cells. Several tools and protocols have been developed by mimicking natural fusion events to induce and accelerate fusion in vitro to promote β-cell-specific gene expression in fused cells. BM-MSC-islet fusion before transplantation may be a strategy for long-term islet survival and improved function. This review discusses the cell-protective and anti-inflammatory characteristics of BM-MSCs to boost highly functional insulin-producing cells in vitro and in vivo, and the efficacy of their fusion with β-cells as a path to promote β-cell regeneration.
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Affiliation(s)
- Zahra Azizi
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, No. 88, Italia St, Keshavarz Blvd., Tehran, Iran.
| | - Roya Abbaszadeh
- Department of Biology, Philipps-University Marburg, Marburg, Germany
| | - Roxana Sahebnasagh
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, No. 88, Italia St, Keshavarz Blvd., Tehran, Iran
| | - Amir Norouzy
- Department of Energy & Environmental Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
| | - Elahe Motevaseli
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, No. 88, Italia St, Keshavarz Blvd., Tehran, Iran
| | - Kathrin Maedler
- Islet Biology Laboratory, Centre for Biomolecular Interactions Bremen, University of Bremen,, Leobener Straße 5, NW2, 28359, Bremen, Germany.
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Differentiation of multipotent stem cells to insulin-producing cells for treatment of diabetes mellitus: bone marrow- and adipose tissue-derived cells comparison. Mol Biol Rep 2022; 49:3539-3548. [PMID: 35107740 DOI: 10.1007/s11033-022-07194-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Accepted: 01/25/2022] [Indexed: 10/19/2022]
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) from human adipose tissue and bone marrow have a great potential for use in cell therapy due to their ease of isolation, expansion, and differentiation. Our intention was to isolate and promote in vitro expansion and differentiation of MSCs from human adipose and bone marrow tissue into cells with a pancreatic endocrine phenotype and to compare the potency of these cells together. METHODS AND RESULTS MSCs were pre-induced with nicotinamide, mercaptoethanol, B-27 and b-FGF in L-DMEM for 2 days and re-induced again in supplemented H-DMEM for another 3 days. Expression of five genes in differentiated beta cells was evaluated by Real-time PCR and western blotting and the potency of insulin release in response to glucose stimulation was evaluated by insulin and C-peptide ELISA kit. The differentiated cells were evaluated by immunocytochemistry staining for Insulin and PDX-1. Quantitative RT-PCR results showed up-regulation of four genes in differentiated beta-islet cells (Insulin, Ngn-3, Pax-4 and Pdx-1) compared with the control. Western blot analysis showed that MSCs cells mainly produced proinsulin and insulin after differentiation but nestin was more expressed in pre-differentiated stem cells. Glucose and insulin secretion assay showed that insulin levels and C-peptide secretion were significantly increased in response to 10 mM glucose. CONCLUSIONS Our study showed that both adipose and bone marrow stem cells could differentiate into functional beta-islet cells but it seems that adipose stem cells could be a better choice for treatment of diabetes mellitus according to their higher potency.
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Zeynaloo E, Stone LD, Dikici E, Ricordi C, Deo SK, Bachas LG, Daunert S, Lanzoni G. Delivery of therapeutic agents and cells to pancreatic islets: Towards a new era in the treatment of diabetes. Mol Aspects Med 2022; 83:101063. [PMID: 34961627 PMCID: PMC11328325 DOI: 10.1016/j.mam.2021.101063] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Revised: 12/09/2021] [Accepted: 12/13/2021] [Indexed: 02/07/2023]
Abstract
Pancreatic islet cells, and in particular insulin-producing beta cells, are centrally involved in the pathogenesis of diabetes mellitus. These cells are of paramount importance for the endocrine control of glycemia and glucose metabolism. In Type 1 Diabetes, islet beta cells are lost due to an autoimmune attack. In Type 2 Diabetes, beta cells become dysfunctional and insufficient to counterbalance insulin resistance in peripheral tissues. Therapeutic agents have been developed to support the function of islet cells, as well as to inhibit deleterious immune responses and inflammation. Most of these agents have undesired effects due to systemic administration and off-target effects. Typically, only a small fraction of therapeutic agent reaches the desired niche in the pancreas. Because islets and their beta cells are scattered throughout the pancreas, access to the niche is limited. Targeted delivery to pancreatic islets could dramatically improve the therapeutic effect, lower the dose requirements, and lower the side effects of agents administered systemically. Targeted delivery is especially relevant for those therapeutics for which the manufacturing is difficult and costly, such as cells, exosomes, and microvesicles. Along with therapeutic agents, imaging reagents intended to quantify the beta cell mass could benefit from targeted delivery. Several methods have been developed to improve the delivery of agents to pancreatic islets. Intra-arterial administration in the pancreatic artery is a promising surgical approach, but it has inherent risks. Targeted delivery strategies have been developed based on ligands for cell surface molecules specific to islet cells or inflamed vascular endothelial cells. Delivery methods range from nanocarriers and vectors to deliver pharmacological agents to viral and non-viral vectors for the delivery of genetic constructs. Several strategies demonstrated enhanced therapeutic effects in diabetes with lower amounts of therapeutic agents and lower off-target side effects. Microvesicles, exosomes, polymer-based vectors, and nanocarriers are gaining popularity for targeted delivery. Notably, liposomes, lipid-assisted nanocarriers, and cationic polymers can be bioengineered to be immune-evasive, and their advantages to transport cargos into target cells make them appealing for pancreatic islet-targeted delivery. Viral vectors have become prominent tools for targeted gene delivery. In this review, we discuss the latest strategies for targeted delivery of therapeutic agents and imaging reagents to pancreatic islet cells.
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Affiliation(s)
- Elnaz Zeynaloo
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA; Department of Chemistry, University of Miami, FL, USA.
| | - Logan D Stone
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA; Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.
| | - Emre Dikici
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA; Dr. John T. Macdonald Foundation Biomedical Nanotechnology Institute - BioNIUM at University of Miami, Miami, FL, USA
| | - Camillo Ricordi
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA; Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Sapna K Deo
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA; Dr. John T. Macdonald Foundation Biomedical Nanotechnology Institute - BioNIUM at University of Miami, Miami, FL, USA
| | - Leonidas G Bachas
- Department of Chemistry, University of Miami, FL, USA; Dr. John T. Macdonald Foundation Biomedical Nanotechnology Institute - BioNIUM at University of Miami, Miami, FL, USA
| | - Sylvia Daunert
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA; Dr. John T. Macdonald Foundation Biomedical Nanotechnology Institute - BioNIUM at University of Miami, Miami, FL, USA; Clinical and Translational Science Institute, University of Miami, Miami, FL, USA
| | - Giacomo Lanzoni
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA; Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA; Dr. John T. Macdonald Foundation Biomedical Nanotechnology Institute - BioNIUM at University of Miami, Miami, FL, USA.
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Sun YL, Shang LR, Liu RH, Li XY, Zhang SH, Ren YK, Fu K, Cheng HB, Yahaya BH, Liu YL, Lin JT. Therapeutic effects of menstrual blood-derived endometrial stem cells on mouse models of streptozotocin-induced type 1 diabetes. World J Stem Cells 2022; 14:104-116. [PMID: 35126831 PMCID: PMC8788184 DOI: 10.4252/wjsc.v14.i1.104] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 07/20/2021] [Accepted: 12/25/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Type 1 diabetes (T1D), a chronic metabolic and autoimmune disease, seriously endangers human health. In recent years, mesenchymal stem cell (MSC) transplantation has become an effective treatment for diabetes. Menstrual blood-derived endometrial stem cells (MenSC), a novel MSC type derived from the decidual endometrium during menstruation, are expected to become promising seeding cells for diabetes treatment because of their noninvasive collection procedure, high proliferation rate and high immunomodulation capacity.
AIM To comprehensively compare the effects of MenSC and umbilical cord-derived MSC (UcMSC) transplantation on T1D treatment, to further explore the potential mechanism of MSC-based therapies in T1D, and to provide support for the clinical application of MSC in diabetes treatment.
METHODS A conventional streptozotocin-induced T1D mouse model was established, and the effects of MenSC and UcMSC transplantation on their blood glucose and serum insulin levels were detected. The morphological and functional changes in the pancreas, liver, kidney, and spleen were analyzed by routine histological and immunohistochemical examinations. Changes in the serum cytokine levels in the model mice were assessed by protein arrays. The expression of target proteins related to pancreatic regeneration and apoptosis was examined by western blot.
RESULTS MenSC and UcMSC transplantation significantly improved the blood glucose and serum insulin levels in T1D model mice. Immunofluorescence analysis revealed that the numbers of insulin+ and CD31+ cells in the pancreas were significantly increased in MSC-treated mice compared with control mice. Subsequent western blot analysis also showed that vascular endothelial growth factor (VEGF), Bcl2, Bcl-xL and Proliferating cell nuclear antigen in pancreatic tissue was significantly upregulated in MSC-treated mice compared with control mice. Additionally, protein arrays indicated that MenSC and UcMSC transplantation significantly downregulated the serum levels of interferon γ and tumor necrosis factor α and upregulated the serum levels of interleukin-6 and VEGF in the model mice. Additionally, histological and immunohistochemical analyses revealed that MSC transplantation systematically improved the morphologies and functions of the liver, kidney, and spleen in T1D model mice.
CONCLUSION MenSC transplantation significantly improves the symptoms in T1D model mice and exerts protective effects on their main organs. Moreover, MSC-mediated angiogenesis, antiapoptotic effects and immunomodulation likely contribute to the above improvements. Thus, MenSC are expected to become promising seeding cells for clinical diabetes treatment due to their advantages mentioned above.
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Affiliation(s)
- Yu-Liang Sun
- Stem Cell and Biotherapy Technology Research Center, Xinxiang Medical University, Xinxiang 453000, Henan Province, China
- Regenerative Medicine Cluster, Advanced Medical and Dental Institute (IPPT), Universiti Sains Malaysia, Kepala Batas 13200, Penang, Malaysia
| | - Ling-Rui Shang
- Stem Cell and Biotherapy Technology Research Center, Xinxiang Medical University, Xinxiang 453000, Henan Province, China
| | - Rui-Hong Liu
- College of Biomedical Engineering, Xinxiang Medical University, Xinxiang 453000, Henan Province, China
| | - Xin-Yi Li
- Stem Cell and Biotherapy Technology Research Center, Xinxiang Medical University, Xinxiang 453000, Henan Province, China
| | - Sheng-Hui Zhang
- The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang Medical University, Xinxiang 453000, Henan Province, China
| | - Ya-Kun Ren
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang 453000, Henan Province, China
| | - Kang Fu
- Department of Technical, Henan Intercell Biotechnology co. LTD, Xinxiang 453000, Henan Province, China
| | - Hong-Bin Cheng
- College of Biomedical Engineering, Xinxiang Medical University, Xinxiang 453000, Henan Province, China
| | - Badrul Hisham Yahaya
- Regenerative Medicine Cluster, Advanced Medical and Dental Institute (IPPT), Universiti Sains Malaysia, Kepala Batas 13200, Penang, Malaysia
| | - Yan-Li Liu
- Stem Cell and Biotherapy Technology Research Center, Xinxiang Medical University, Xinxiang 453000, Henan Province, China
| | - Jun-Tang Lin
- Stem Cell and Biotherapy Technology Research Center, Xinxiang Medical University, Xinxiang 453000, Henan Province, China
- College of Biomedical Engineering, Xinxiang Medical University, Xinxiang 453000, Henan Province, China
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Li Y, Bian W, Jiang Y, Liu D, Shen L. hMSCs Migrate under the Chemotaxis of CXCL-13 and Enhance Islet B Cell Activity through p-AKT Signaling Pathway in High-Glucose Environment. JOURNAL OF HEALTHCARE ENGINEERING 2022; 2022:5430175. [PMID: 35035844 PMCID: PMC8759880 DOI: 10.1155/2022/5430175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 12/06/2021] [Accepted: 12/09/2021] [Indexed: 11/24/2022]
Abstract
As a common clinical chronic disease, the incidence of diabetes is increasing year by year. According to the latest statistics from the International Diabetes Federation, as of 2019, the global prevalence of diabetes has reached 8.3%. This study aims to investigate the effect of CXCL-13 on the migration ability of human mesenchymal stem cells (hMSCs) and to clarify the specific molecular mechanism of the protective effect of hMSCs on islet B cells. The hMSCs were cultured in high-glucose environment, and the effect of CXCL-13 on the migration ability of hMSCs was determined by Transwell experiment. After coculture of hMSCs and islet B cells, the activity of cells was detected by CCK8 assay, the expression of Ki-67 in cells was detected by RT-PCR, and the expression of P53 was detected by Western blot to investigate the effect of hMSCs on the proliferation and apoptosis of islet B cells. The effect of hMSCs on the function of islet B cells was determined by glucose stimulated insulin secretion experiment. Transwell experiment results showed that CXCL-13 could promote the migration of hMSCs to islet B cells in high-glucose environment. The results of CCK-8 showed that the cell activity in the coculture group was significantly higher than that of the other groups, and RT-PCR showed that the expression of Ki-67 was significantly increased in the coculture group of hMSCs and islet B cells. The results of Western blot showed that the expression of P53 was significantly decreased in the coculture group, and the glucose stimulated insulin secretion test showed that insulin secretion was significantly increased. It was found that after the inhibition of ATK, cell activity was significantly reduced, and apoptosis was significantly increased. Meanwhile, the expression of Ki-67 was inhibited, the expression of P-53 was significantly increased, and insulin secretion was significantly reduced. To sum up, in a high-glucose environment, CXCL-13 effectively promoted the migration of hMSCs, and hMSCs protected the activity and function of islet B cells through Akt signaling pathway.
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Affiliation(s)
- Yongtao Li
- Department of Anatomy, Basic Medical College, Qiqihar Medical University, Qiqihar 161006, Heilongjiang, China
| | - Wenshan Bian
- Department of Anatomy, Basic Medical College, Qiqihar Medical University, Qiqihar 161006, Heilongjiang, China
| | - Yang Jiang
- Department of Anatomy, Basic Medical College, Qiqihar Medical University, Qiqihar 161006, Heilongjiang, China
| | - Danyang Liu
- Department of Histology and Embryolog, Basic Medical College, Qiqihar Medical University, Qiqihar 161006, Heilongjiang, China
| | - Lei Shen
- Department of Anatomy, Basic Medical College, Qiqihar Medical University, Qiqihar 161006, Heilongjiang, China
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Yang Q, Liu Y, Chen G, Zhang W, Tang S, Zhou T. An Overview of the Safety, Efficiency, and Signal Pathways of Stem Cell Therapy for Systemic Lupus Erythematosus. Stem Cells Int 2021; 2021:2168595. [PMID: 34434237 PMCID: PMC8382560 DOI: 10.1155/2021/2168595] [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: 04/15/2021] [Accepted: 07/28/2021] [Indexed: 02/05/2023] Open
Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease that affects multiple organs and tissues. Mesenchymal stem cells (MSCs) are considered a good source for autoimmune disease and hematological disease therapy. This review will summarize the efficacy, safety, and mechanisms of MSC therapy for SLE. MSC therapy can reduce anti-dsDNA, antinuclear antigen (ANA), proteinuria, and serum creatinine in SLE patients. In animal models of SLE, MSC therapy also indicates that it could reduce anti-dsDNA, ANA, proteinuria, and serum creatinine and ameliorate renal pathology. There are no serious adverse events, treatment-related mortality, or tumor-related events in SLE patients after stem cell treatment. MSCs can inhibit inflammatory factors, such as MCP-1 and HMGB-1, and inhibit inflammation-related signaling pathways, such as the NF-κB, JAK/STAT, and Akt/GSK3β signaling pathways, to alleviate the lesions in SLE.
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Affiliation(s)
- Qian Yang
- Department of Nephrology, Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, China
| | - Yiping Liu
- Department of Nephrology, Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, China
| | - Guangyong Chen
- Department of Nephrology, Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, China
| | - Wancong Zhang
- Department of Plastic Surgery and Burn Center, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, China
- Plastic Surgery Institute of Shantou University Medical College, China
| | - Shijie Tang
- Department of Plastic Surgery and Burn Center, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, China
- Plastic Surgery Institute of Shantou University Medical College, China
| | - Tianbiao Zhou
- Department of Nephrology, Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, China
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