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Nada AH, Ibrahim IA, Oteri V, Shalabi L, Asar NK, Aqeilan SR, Hafez W. Safety and efficacy of umbilical cord mesenchymal stem cells in the treatment of type 1 and type 2 diabetes mellitus: a systematic review and meta-analysis. Expert Rev Endocrinol Metab 2025; 20:107-117. [PMID: 39905688 DOI: 10.1080/17446651.2025.2457474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Accepted: 11/22/2024] [Indexed: 02/06/2025]
Abstract
INTRODUCTION Many patients struggle to control glucose without side effects. Due to their immunomodulatory and regenerative properties, mesenchymal stem cells (MSCs) might treat Diabetes Mellitus (DM). The authors employed this meta-analysis to evaluate the efficacy and safety of umbilical cord MSCs (UCMSCs) for DM management. METHODS The PubMed, Cochrane, WOS, Embase, and Scopus databases were searched for randomized controlled trials (RCTs) investigating the effects of UCMSCs on DM (Types 1, 2) till January 2024. Patient demographics, interventions, and outcomes, including glycated hemoglobin (HbA1c%), C-peptide levels, and insulin requirements, were extracted. A comprehensive meta-analysis software was used. RESULTS Eight CTs of 334 patients (172 experimental and 162 controls) were included. UMSCs treatment substantially lowered HbA1c levels (MD = -1.06, 95% CI [-1.27, -0.85], p < 0.00001) with consistent outcomes (i2 = 0%, p = 0.43). Fasting C-peptide levels were heterogeneous but favored placebo (MD = 0.35, 95% CI [0.15, 0.56], p = 0.0007). In T1D patients, daily insulin requirements decreased considerably (MD = -0.24, 95% CI [-0.29, -0.18], p < 0.00001), with heterogeneity addressed by sensitivity analysis. CONCLUSION UMSCs therapy reduced HbA1c and insulin requirements, and increased C-peptide levels. Multicenter clinical trials are required to confirm the long-term efficacy and safety of UMSC therapy.
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Affiliation(s)
| | - Ismail A Ibrahim
- Faculty of Health Sciences, Fenerbahce University, Istanbul, Turkey
| | - Vittorio Oteri
- Endocrine Unit, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, Catania, Italy
| | - Laila Shalabi
- Faculty of Medicine, Gharyan University, Gharyan, Libya
| | | | | | - Wael Hafez
- Medical Research and Clinical Studies Institute, National Research Centre, Cairo, Egypt
- NMC Royal Hospital, Khalifa City, Abu Dhabi, UAE
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AlOraibi S, Taurin S, Alshammary S. Advancements in Umbilical Cord Biobanking: A Comprehensive Review of Current Trends and Future Prospects. Stem Cells Cloning 2024; 17:41-58. [PMID: 39655226 PMCID: PMC11626973 DOI: 10.2147/sccaa.s481072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Accepted: 11/01/2024] [Indexed: 12/12/2024] Open
Abstract
Biobanking has emerged as a transformative concept in advancing the medical field, particularly with the exponential growth of umbilical cord (UC) biobanking in recent decades. UC blood and tissue provide a rich source of primitive hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) for clinical transplantation, offering distinct advantages over alternative adult stem cell sources. However, to fully realize the therapeutic potential of UC-derived stem cells and establish a comprehensive global UC-biobanking network, it is imperative to optimize and standardize UC processing, cryopreservation methods, quality control protocols, and regulatory frameworks, alongside developing effective consent provisions. This review aims to comprehensively explore recent advancements in UC biobanking, focusing on the establishment of rigorous safety and quality control procedures, the standardization of biobanking operations, and the optimization and automation of UC processing and cryopreservation techniques. Additionally, the review examines the expanded clinical applications of UC stem cells, addresses the challenges associated with umbilical cord biobanking and UC-derived stem cell therapies, and discusses the promising role of artificial intelligence (AI) in enhancing various operational aspects of biobanking, streamlining data processing, and improving data analysis accuracy while ensuring compliance with safety and quality standards. By addressing these critical areas, this review seeks to provide insights into the future direction of UC biobanking and its potential to significantly impact regenerative medicine.
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Affiliation(s)
- Sahar AlOraibi
- Molecular Medicine Department, Princess Al Jawhara Center for Molecular Medicine, Genetics, and Hereditary Diseases, College of Medicine and Health Sciences, Arabian Gulf University, Manama, Bahrain
| | - Sebastien Taurin
- Molecular Medicine Department, Princess Al Jawhara Center for Molecular Medicine, Genetics, and Hereditary Diseases, College of Medicine and Health Sciences, Arabian Gulf University, Manama, Bahrain
| | - Sfoug Alshammary
- Molecular Medicine Department, Princess Al Jawhara Center for Molecular Medicine, Genetics, and Hereditary Diseases, College of Medicine and Health Sciences, Arabian Gulf University, Manama, Bahrain
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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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Qi Y, Wang X, Bai Z, Xu Y, Lu T, Zhu H, Zhang S, Wu Z, Liu Z, He Z, Jia W. Enhancement of the function of mesenchymal stem cells by using a GMP-grade three-dimensional hypoxic large-scale production system. Heliyon 2024; 10:e30968. [PMID: 38826705 PMCID: PMC11141262 DOI: 10.1016/j.heliyon.2024.e30968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Revised: 05/07/2024] [Accepted: 05/08/2024] [Indexed: 06/04/2024] Open
Abstract
Background Efficiently increasing the production of clinical-grade mesenchymal stem cells (MSCs) is crucial for clinical applications. Challenges with the current planar culture methods include scalability issues, labour intensity, concerns related to cell senescence, and heterogeneous responses. This study aimed to establish a large-scale production system for MSC generation. In addition, a comparative analysis of the biological differences between MSCs cultured under various conditions was conducted. Methods and materials We developed a GMP-grade three-dimensional hypoxic large-scale production (TDHLSP) system for MSCs using self-fabricated glass microcarriers and a multifunctional bioreactor. Different parameters, including cell viability, cell diameter, immunophenotype, morphology, karyotype, and tumourigenicity were assessed in MSCs cultured using different methods. Single-cell RNA sequencing (scRNA-seq) revealed pathways and genes associated with the enhanced functionality of MSCs cultured in three dimensions under hypoxic conditions (3D_Hypo MSCs). Moreover, CD142 knockdown in 3D_Hypo MSCs confirmed its in vitro functions. Results Inoculating 2 × 108 MSCs into a 2.6 L bioreactor in the TDHLSP system resulted in a final scale of 4.6 × 109 3D_Hypo MSCs by day 10. The 3D_Hypo MSCs retained characteristics of the 2D MSCs, demonstrating their genomic stability and non-tumourigenicity. Interestingly, the subpopulations of 3D_Hypo MSCs exhibited a more uniform distribution and a closer relationship than those of 2D MSCs. The heterogeneity of MSCs was strongly correlated with 'cell cycle' and 'stroma/mesenchyme', with 3D_Hypo MSCs expressing higher levels of activated stroma genes. Compared to 2D MSCs, 3D_Hypo MSCs demonstrated enhanced capabilities in blood vessel formation, TGF-β1 secretion, and inhibition of BV2 proliferation, with maintenance of Senescence-Associated β-Galactosidase (SA-β-gal) negativity. However, the enhanced functions of 3D_Hypo MSCs decreased upon the downregulation of CD142 expression. Conclusion The TDHLSP system led to a high overall production of MSCs and promoted uniform distribution of MSC clusters. This cultivation method also enhanced key cellular properties, such as angiogenesis, immunosuppression, and anti-aging. These functionally improved and uniform MSC subpopulations provide a solid basis for the clinical application of stem cell therapies.
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Affiliation(s)
- Yiyao Qi
- Institute for Regenerative Medicine, School of Life Sciences and Technology, School of Medicine, Tongji University, Shanghai, 200123, China
- National Stem Cell Translational Resource Center, Shanghai East Hospital, Tongji University, Shanghai, 200123, China
| | - Xicheng Wang
- Institute for Regenerative Medicine, School of Life Sciences and Technology, School of Medicine, Tongji University, Shanghai, 200123, China
- National Stem Cell Translational Resource Center, Shanghai East Hospital, Tongji University, Shanghai, 200123, China
| | - Zhihui Bai
- Institute for Regenerative Medicine, School of Life Sciences and Technology, School of Medicine, Tongji University, Shanghai, 200123, China
- National Stem Cell Translational Resource Center, Shanghai East Hospital, Tongji University, Shanghai, 200123, China
| | - Ying Xu
- Institute for Regenerative Medicine, School of Life Sciences and Technology, School of Medicine, Tongji University, Shanghai, 200123, China
- National Stem Cell Translational Resource Center, Shanghai East Hospital, Tongji University, Shanghai, 200123, China
| | - Tingting Lu
- Institute for Regenerative Medicine, School of Life Sciences and Technology, School of Medicine, Tongji University, Shanghai, 200123, China
- National Stem Cell Translational Resource Center, Shanghai East Hospital, Tongji University, Shanghai, 200123, China
| | - Hanyu Zhu
- Institute for Regenerative Medicine, School of Life Sciences and Technology, School of Medicine, Tongji University, Shanghai, 200123, China
- National Stem Cell Translational Resource Center, Shanghai East Hospital, Tongji University, Shanghai, 200123, China
| | - Shoumei Zhang
- Institute for Regenerative Medicine, School of Life Sciences and Technology, School of Medicine, Tongji University, Shanghai, 200123, China
- National Stem Cell Translational Resource Center, Shanghai East Hospital, Tongji University, Shanghai, 200123, China
| | - Zhihong Wu
- School of Materials Science and Engineering, University of Shanghai for Science and Technology, Shanghai, 200093, China
| | - Zhongmin Liu
- Institute for Regenerative Medicine, School of Life Sciences and Technology, School of Medicine, Tongji University, Shanghai, 200123, China
- National Stem Cell Translational Resource Center, Shanghai East Hospital, Tongji University, Shanghai, 200123, China
| | - Zhiying He
- Institute for Regenerative Medicine, School of Life Sciences and Technology, School of Medicine, Tongji University, Shanghai, 200123, China
- National Stem Cell Translational Resource Center, Shanghai East Hospital, Tongji University, Shanghai, 200123, China
| | - Wenwen Jia
- Institute for Regenerative Medicine, School of Life Sciences and Technology, School of Medicine, Tongji University, Shanghai, 200123, China
- National Stem Cell Translational Resource Center, Shanghai East Hospital, Tongji University, Shanghai, 200123, China
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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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Arte PA, Tungare K, Bhori M, Jobby R, Aich J. Treatment of type 2 diabetes mellitus with stem cells and antidiabetic drugs: a dualistic and future-focused approach. Hum Cell 2024; 37:54-84. [PMID: 38038863 DOI: 10.1007/s13577-023-01007-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Accepted: 10/31/2023] [Indexed: 12/02/2023]
Abstract
Type 2 Diabetes Mellitus (T2DM) accounts for more than 90% of total diabetes mellitus cases all over the world. Obesity and lack of balance between energy intake and energy expenditure are closely linked to T2DM. Initial pharmaceutical treatment and lifestyle interventions can at times lead to remission but usually help alleviate it to a certain extent and the condition remains, thus, recurrent with the patient being permanently pharmaco-dependent. Mesenchymal stromal cells (MSCs) are multipotent, self-renewing cells with the ability to secrete a variety of biological factors that can help restore and repair injured tissues. MSC-derived exosomes possess these properties of the original stem cells and are potentially able to confer superior effects due to advanced cell-to-cell signaling and the presence of stem cell-specific miRNAs. On the other hand, the repository of antidiabetic agents is constantly updated with novel T2DM disease-modifying drugs, with higher efficacy and increasingly convenient delivery protocols. Delving deeply, this review details the latest progress and ongoing studies related to the amalgamation of stem cells and antidiabetic drugs, establishing how this harmonized approach can exert superior effects in the management and potential reversal of T2DM.
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Affiliation(s)
- Priyamvada Amol Arte
- School of Biotechnology and Bioinformatics, DY Patil Deemed to Be University, CBD Belapur, Navi Mumbai, Maharashtra, 400614, India.
- Anatek Services PVT LTD, Sai Chamber, 10, Near Santacruz Railway Bridge, Sen Nagar, Santacruz East, Mumbai, Maharashtra, 400055, India.
| | - Kanchanlata Tungare
- School of Biotechnology and Bioinformatics, DY Patil Deemed to Be University, CBD Belapur, Navi Mumbai, Maharashtra, 400614, India
| | - Mustansir Bhori
- Inveniolife Technology PVT LTD, Office No.118, Grow More Tower, Plot No.5, Sector 2, Kharghar, Navi Mumbai, Maharashtra, 410210, India
| | - Renitta Jobby
- Amity Institute of Biotechnology, Amity University Maharashtra, Mumbai-Pune Expressway, Bhatan, Panvel, Navi Mumbai, Maharashtra, 410206, India
- Amity Centre of Excellence in Astrobiology, Amity University Maharashtra, Mumbai-Pune Expressway, Bhatan, Panvel, Navi Mumbai, Maharashtra, 410206, India
| | - Jyotirmoi Aich
- School of Biotechnology and Bioinformatics, DY Patil Deemed to Be University, CBD Belapur, Navi Mumbai, Maharashtra, 400614, India
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Lian XF, Lu DH, Liu HL, Liu YJ, Yang Y, Lin Y, Xie F, Huang CH, Wu HM, Long AM, Hui CJ, Shi Y, Chen Y, Gao YF, Zhang F. Safety evaluation of human umbilical cord-mesenchymal stem cells in type 2 diabetes mellitus treatment: A phase 2 clinical trial. World J Clin Cases 2023; 11:5083-5096. [PMID: 37583846 PMCID: PMC10424020 DOI: 10.12998/wjcc.v11.i21.5083] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 05/23/2023] [Accepted: 06/16/2023] [Indexed: 07/26/2023] Open
Abstract
BACKGROUND Progressive pancreatic β cell dysfunction is a fundamental aspect of the pathology underlying type 2 diabetes mellitus (T2DM). Recently, mesenchymal stem cell (MSC) transplantation has emerged as a new therapeutic method due to its ability to promote the regeneration of pancreatic β cells. However, current studies have focused on its efficacy, and there are few clinical studies on its safety. AIM To evaluate the safety of human umbilical cord (hUC)-MSC infusion in T2DM treatment. METHODS An open-label and randomized phase 2 clinical trial was designed to evaluate the safety of hUC-MSC transplantation in T2DM in a Class A hospital. Ten patients in the placebo group received acellular saline intravenously once per week for 3 wk. Twenty-four patients in the hUC-MSC group received hUC-MSCs (1 × 106 cells/kg) intravenously once per week for 3 wk. Diabetic clinical symptoms and signs, laboratory findings, and imaging findings were evaluated weekly for the 1st mo and then at weeks 12 and 24 post-treatment. RESULTS No serious adverse events were observed during the 24-wk follow-up. Four patients (16.7%) in the hUC-MSC group experienced transient fever, which occurred within 24 h after the second or third infusion; this did not occur in any patients in the placebo group. One patient from the hUC-MSC group experienced hypoglycemic attacks within 1 mo after transplantation. Significantly lower lymphocyte levels (weeks 2 and 3) and thrombin coagulation time (week 2) were observed in the hUC-MSC group compared to those in the placebo group (all P < 0.05). Significantly higher platelet levels (week 3), immunoglobulin levels (weeks 1, 2, 3, and 4), fibrinogen levels (weeks 2 and 3), D-dimer levels (weeks 1, 2, 3, 4, 12, and 24), and neutrophil-to-lymphocyte ratios (weeks 2 and 3) were observed in the hUC-MSC group compared to those in the placebo group (all P < 0.05). There were no significant differences between the two groups for tumor markers (alpha-fetoprotein, carcinoembryonic antigen, and carbohydrate antigen 199) or blood fat. No liver damage or other side effects were observed on chest X-ray. CONCLUSION Our study suggested that hUC-MSC transplantation has good tolerance and high safety in the treatment of T2DM. It can improve human immunity and inhibit lymphocytes. Coagulation function should be monitored vigilantly for abnormalities.
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Affiliation(s)
- Xiao-Fen Lian
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Dong-Hui Lu
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Hong-Li Liu
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Yan-Jing Liu
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Yang Yang
- Department of Endocrinology, Huizhou Central People’s Hospital, Huizhou 516000, Guangdong Province, China
| | - Yuan Lin
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Feng Xie
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Cai-Hao Huang
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Hong-Mei Wu
- Department of Endocrinology, Longgang District Central Hospital of Shenzhen, Shenzhen 518000, Guangdong Province, China
| | - Ai-Mei Long
- Department of Endocrinology, Longgang District Central Hospital of Shenzhen, Shenzhen 518000, Guangdong Province, China
| | - Chen-Jun Hui
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Yu Shi
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Yun Chen
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Yun-Feng Gao
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Fan Zhang
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
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Mikłosz A, Chabowski A. Adipose-derived Mesenchymal Stem Cells Therapy as a new Treatment Option for Diabetes Mellitus. J Clin Endocrinol Metab 2023; 108:1889-1897. [PMID: 36916961 PMCID: PMC10348459 DOI: 10.1210/clinem/dgad142] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 01/01/2023] [Accepted: 03/06/2023] [Indexed: 03/16/2023]
Abstract
The worldwide increase in the prevalence of diabetes mellitus has raised the demand for new therapeutic strategies targeting diabetic symptoms and its chronic complications. Among different treatment options for diabetes, adipose-derived mesenchymal stem cells (ADMSCs) therapy attract the most attention. The therapeutic effects of ADMSCs are based primarily on their paracrine release of immunomodulatory, anti-inflammatory, and trophic factors. Animal models of diabetes as well as human clinical trials have shown that ADMSCs can effectively facilitate endogenous β cell regeneration, preserve residual β cell mass, reduce islet graft rejection, regulate the immune system, and ultimately improve insulin sensitivity or ameliorate insulin resistance in peripheral tissues. Nevertheless, transplantation of mesenchymal stem cells is associated with certain risks; therefore recently much attention has been devoted to ADMSCs derivatives, such as exosomes or conditioned media, as therapeutic agents for the treatment of diabetes. Compared to ADMSCs, cell-free therapy has even better therapeutic potential. This narrative review summarizes recent outcomes and molecular mechanisms of ADMSCs action in the treatment for both type 1 DM and type 2 DM, as well as shows their feasibility, benefits, and current limitations.
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Affiliation(s)
- Agnieszka Mikłosz
- Department of Physiology, Medical University of Bialystok, 15-222 Bialystok, Poland
| | - Adrian Chabowski
- Department of Physiology, Medical University of Bialystok, 15-222 Bialystok, Poland
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Chen W, Lv L, Chen N, Cui E. Immunogenicity of mesenchymal stromal/stem cells. Scand J Immunol 2023; 97:e13267. [PMID: 39007962 DOI: 10.1111/sji.13267] [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: 08/29/2022] [Revised: 03/06/2023] [Accepted: 03/17/2023] [Indexed: 04/07/2023]
Abstract
Mesenchymal stromal/stem cells (MSCs) possess the ability to self-renew and differentiate into other cell types. Because of their anti-inflammatory and immunomodulatory abilities, as well as their more ready availability compared to other stem cell sources, MSCs hold great promise for the treatment of many diseases, such as haematological defects, acute respiratory distress syndrome, autoimmunity, cardiovascular diseases, etc. However, immune rejection remains an important problem. MSCs are considered to have low immunogenicity, but they do not have full immunological privilege. This review analyzes and discusses the safety of MSCs from the perspective of their immunogenicity, with the aim of providing a reference for future research and clinical application.
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Affiliation(s)
- Wenyan Chen
- Department of Respiratory and Critical Care Medicine, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, 313000, Zhejiang, No. 1558, Third Ring North Road, Huzhou, China
| | - Lu Lv
- Department of Respiratory and Critical Care Medicine, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, 313000, Zhejiang, No. 1558, Third Ring North Road, Huzhou, China
| | - Na Chen
- Department of Respiratory and Critical Care Medicine, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, 313000, Zhejiang, No. 1558, Third Ring North Road, Huzhou, China
| | - Enhai Cui
- Department of Respiratory and Critical Care Medicine, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, 313000, Zhejiang, No. 1558, Third Ring North Road, Huzhou, China
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Li H, Zhirong Z, Shibo Z, Lichen Z, Ming S, Hua J, Zheng T, Ruiwu D. The Effects of Umbilical Cord Mesenchymal Stem Cells on Traumatic Pancreatitis in Rats. Dig Dis Sci 2023; 68:147-154. [PMID: 35430701 DOI: 10.1007/s10620-022-07493-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 03/17/2022] [Indexed: 02/01/2023]
Abstract
OBJECTIVE This study explored the therapeutic and protective effects of umbilical cord mesenchymal stem cells (ucMSCs) on traumatic pancreatitis (TP) to provide a theoretical basis for TP treatment with MCSs by establishing a TP rat model. METHODS We used 60 healthy adult male Sprague Dawley (SD) rats to create four experimental groups: sham, ucMSC control, TP, and ucMSC treatment. We observed ucMSC homing in the rats by fluorescence microscopy and assessed the degree of pancreatic tissue injury by hematoxylin and eosin (HE) staining on days 1, 3, and 7 after transplantation. Furthermore, we used an in vivo imaging system to evaluate the localization of cell membrane-stained ucMSCs in rats with TP. Finally, we measured the serum levels of amylase, lipase, pro-and anti-inflammatory factors, and oxidative stress factors by enzyme-linked immunosorbent assay (ELISA). RESULTS The pancreatic histopathological score and the serum amylase and lipase levels were lower in the ucMSC treatment group than in the TP group (P < 0.05). Interleukin (IL)-6, tumor necrosis factor-α (TNF-α), and oxidase malondialdehyde (MOD) levels were significantly higher in the ucMSC treatment group than in the TP group. However, IL-10, transforming growth factor-β, and superoxide dismutase (an antioxidant enzyme, SOD) levels were significantly higher in the ucMSC treatment group than in the TP group (P < 0.05). CONCLUSION ucMSCs can migrate and implant in injured areas of the pancreas in rats. Furthermore, they participate in pancreatic tissue repair and regulate immunity by inhibiting the systemic inflammatory response and oxidative stress.
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Affiliation(s)
- Han Li
- College of Medicine, Southwest Jiaotong University, Chengdu, 610031, Sichuan Province, China
| | - Zhao Zhirong
- College of Medicine, Southwest Jiaotong University, Chengdu, 610031, Sichuan Province, China
- General Surgery Center, General Hospital of Western Theater Command, Chengdu, 610083, China
| | - Zhou Shibo
- General Surgery Center, General Hospital of Western Theater Command, Chengdu, 610083, China
- College of Clinical Medicine Southwest, Medical University, Luzhou, 646000, Sichuan Province, China
| | - Zhou Lichen
- General Surgery Center, General Hospital of Western Theater Command, Chengdu, 610083, China
- College of Clinical Medicine Southwest, Medical University, Luzhou, 646000, Sichuan Province, China
| | - Shi Ming
- General Surgery Center, General Hospital of Western Theater Command, Chengdu, 610083, China
- College of Clinical Medicine Southwest, Medical University, Luzhou, 646000, Sichuan Province, China
| | - Ji Hua
- General Surgery Center, General Hospital of Western Theater Command, Chengdu, 610083, China
- College of Clinical Medicine Southwest, Medical University, Luzhou, 646000, Sichuan Province, China
| | - Tang Zheng
- General Surgery Center, General Hospital of Western Theater Command, Chengdu, 610083, China
- College of Clinical Medicine Southwest, Medical University, Luzhou, 646000, Sichuan Province, China
| | - Dai Ruiwu
- College of Medicine, Southwest Jiaotong University, Chengdu, 610031, Sichuan Province, China.
- General Surgery Center, General Hospital of Western Theater Command, Chengdu, 610083, China.
- College of Clinical Medicine Southwest, Medical University, Luzhou, 646000, Sichuan Province, China.
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Rodríguez-Eguren A, Gómez-Álvarez M, Francés-Herrero E, Romeu M, Ferrero H, Seli E, Cervelló I. Human Umbilical Cord-Based Therapeutics: Stem Cells and Blood Derivatives for Female Reproductive Medicine. Int J Mol Sci 2022; 23:ijms232415942. [PMID: 36555583 PMCID: PMC9785531 DOI: 10.3390/ijms232415942] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 12/04/2022] [Accepted: 12/08/2022] [Indexed: 12/23/2022] Open
Abstract
There are several conditions that lead to female infertility, where traditional or conventional treatments have limited efficacy. In these challenging scenarios, stem cell (SC) therapies have been investigated as alternative treatment strategies. Human umbilical cord (hUC) mesenchymal stem cells (hUC-MSC), along with their secreted paracrine factors, extracts, and biomolecules, have emerged as promising therapeutic alternatives in regenerative medicine, due to their remarkable potential to promote anti-inflammatory and regenerative processes more efficiently than other autologous treatments. Similarly, hUC blood derivatives, such as platelet-rich plasma (PRP), or isolated plasma elements, such as growth factors, have also demonstrated potential. This literature review aims to summarize the recent therapeutic advances based on hUC-MSCs, hUC blood, and/or other plasma derivatives (e.g., extracellular vesicles, hUC-PRP, and growth factors) in the context of female reproductive medicine. We present an in-depth analysis of the principal molecules mediating tissue regeneration, compiling the application of these therapies in preclinical and clinical studies, within the context of the human reproductive tract. Despite the recent advances in bioengineering strategies that sustain delivery and amplify the scope of the therapeutic benefits, further clinical trials are required prior to the wide implementation of these alternative therapies in reproductive medicine.
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Affiliation(s)
- Adolfo Rodríguez-Eguren
- IVI Foundation, Health Research Institute La Fe, 46026 Valencia, Spain
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT 05610, USA
| | | | - Emilio Francés-Herrero
- IVI Foundation, Health Research Institute La Fe, 46026 Valencia, Spain
- Department of Pediatrics, Obstetrics and Gynecology, School of Medicine, University of Valencia, 46010 Valencia, Spain
| | - Mónica Romeu
- Gynecological Service, Consortium General University Hospital of Valencia, 46014 Valencia, Spain
| | - Hortensia Ferrero
- IVI Foundation, Health Research Institute La Fe, 46026 Valencia, Spain
| | - Emre Seli
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT 05610, USA
- IVIRMA New Jersey, Basking Ridge, NJ 07920, USA
| | - Irene Cervelló
- IVI Foundation, Health Research Institute La Fe, 46026 Valencia, Spain
- Correspondence: or
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Pires IGS, Silva e Souza JA, de Melo Bisneto AV, Passos XS, Carneiro CC. Clinical efficacy of stem-cell therapy on diabetes mellitus: A systematic review and meta-analysis. Transpl Immunol 2022; 75:101740. [DOI: 10.1016/j.trim.2022.101740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 09/12/2022] [Accepted: 11/05/2022] [Indexed: 11/13/2022]
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Lian XF, Lu DH, Liu HL, Liu YJ, Han XQ, Yang Y, Lin Y, Zeng QX, Huang ZJ, Xie F, Huang CH, Wu HM, Long AM, Deng LP, Zhang F. Effectiveness and safety of human umbilical cord-mesenchymal stem cells for treating type 2 diabetes mellitus. World J Diabetes 2022; 13:877-887. [PMID: 36312002 PMCID: PMC9606793 DOI: 10.4239/wjd.v13.i10.877] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 08/19/2022] [Accepted: 09/07/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Progressive pancreatic β-cell dysfunction is a fundamental part of the pathology of type 2 diabetes mellitus (T2DM). Cellular therapies offer novel opportunities for the treatment of T2DM to improve the function of islet β-cells.
AIM To evaluate the effectiveness and safety of human umbilical cord-mesenchymal stem cell (hUC-MSC) infusion in T2DM treatment.
METHODS Sixteen patients were enrolled and received 1 × 106 cells/kg per week for 3 wk as intravenous hUC-MSC infusion. The effectiveness was evaluated by assessing fasting blood glucose, C-peptide, normal glycosylated hemoglobin A1c (HbA1c), insulin resistance index (homeostatic model assessment for insulin resistance), and islet β-cell function (homeostasis model assessment of β-cell function). The dosage of hypoglycemic agents and safety were evaluated by monitoring the occurrence of any adverse events (AEs).
RESULTS During the entire intervention period, the fasting plasma glucose level was significantly reduced [baseline: 9.3400 (8.3575, 11.7725), day 14 ± 3: 6.5200 (5.2200, 8.6900); P < 0.01]. The HbA1c level was significantly reduced on day 84 ± 3 [baseline: 7.8000 (7.5250, 8.6750), day 84 ± 3: 7.150 (6.600, 7.925); P < 0.01]. The patients’ islet β-cell function was significantly improved on day 28 ± 3 of intervention [baseline: 29.90 (16.43, 37.40), day 28 ± 3: 40.97 (19.27, 56.36); P < 0.01]. The dosage of hypoglycemic agents was reduced in all patients, of whom 6 (50%) had a decrement of more than 50% and 1 (6.25%) discontinued the hypoglycemic agents. Four patients had transient fever, which occurred within 24 h after the second or third infusion. One patient (2.08%) had asymptomatic nocturnal hypoglycemia after infusion on day 28 ± 3. No liver damage or other side effects were reported.
CONCLUSION The results of this study suggest that hUC-MSC infusion can improve glycemia, restore islet β-cell function, and reduce the dosage of hypoglycemic agents without serious AEs. Thus, hUC-MSC infusion may be a novel option for the treatment of T2DM.
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Affiliation(s)
- Xiao-Fen Lian
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Dong-Hui Lu
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Hong-Li Liu
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Yan-Jing Liu
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Xiu-Qun Han
- Department of Research & Development, Zhejiang MaiDa Gene Tech Co. Ltd, Zhoushan 316000, Zhejiang Province, China
| | - Yang Yang
- Department of Endocrinology, Huizhou Central People's Hospital, Huizhou 516000, Guangdong Province, China
| | - Yuan Lin
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Qing-Xiang Zeng
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Zheng-Jie Huang
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Feng Xie
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Cai-Hao Huang
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Hong-Mei Wu
- Department of Endocrinology, Longgang District Central Hospital of Shenzhen, Shenzhen 518000, Guangdong Province, China
| | - Ai-Mei Long
- Department of Endocrinology, Longgang District Central Hospital of Shenzhen, Shenzhen 518000, Guangdong Province, China
| | - Ling-Ping Deng
- Department of Endocrinology, Longgang District Central Hospital of Shenzhen, Shenzhen 518000, Guangdong Province, China
| | - Fan Zhang
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
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Zhang C, Huang L, Wang X, Zhou X, Zhang X, Li L, Wu J, Kou M, Cai C, Lian Q, Zhou X. Topical and intravenous administration of human umbilical cord mesenchymal stem cells in patients with diabetic foot ulcer and peripheral arterial disease: a phase I pilot study with a 3-year follow-up. Stem Cell Res Ther 2022; 13:451. [PMID: 36064461 PMCID: PMC9446755 DOI: 10.1186/s13287-022-03143-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 08/16/2022] [Indexed: 12/26/2022] Open
Abstract
Background Diabetic foot ulcer (DFU) is a serious chronic complication of diabetes mellitus that contributes to 85% of nontraumatic lower extremity amputations in diabetic patients. Preliminary clinical benefits have been shown in treatments based on mesenchymal stem cells for patients with DFU or peripheral arterial disease (PAD). However, the long-term safety and benefits are unclear for patients with both DFU and PAD who are not amenable to surgical revascularization. Methods In this phase I pilot study, 14 patients with PAD and incurable DFU were enrolled to assess the safety and efficacy of human umbilical cord mesenchymal stem cell (hUC-MSC) administration based on conservative treatments. All patients received topical and intravenous administrations of hUC-MSCs at a dosage of 2 × 105 cells/kg with an upper limit of 1 × 107 cells for each dose. The adverse events during treatment and follow-up were documented for safety assessments. The therapeutic efficacy was assessed by ulcer healing status, recurrence rate, and 3-year amputation-free rate in the follow-up phase. Results The safety profiles were favorable. Only 2 cases of transient fever were observed within 3 days after transfusion and considered possibly related to hUC-MSC administration intravenously. Ulcer disclosure was achieved for more than 95% of the lesion area for all patients within 1.5 months after treatment. The symptoms of chronic limb ischaemia were alleviated along with a decrease in Wagner scores, Rutherford grades, and visual analogue scale scores. No direct evidence was observed to indicate the alleviation of the obstruction in the main vessels of target limbs based on computed tomography angiography. The duration of rehospitalization for DFU was 2.0 ± 0.6 years. All of the patients survived without amputation due to the recurrence of DFU within 3 years after treatments. Conclusions Based on the current pilot study, the preliminary clinical benefits of hUC-MSCs on DFU healing were shown, including good tolerance, a shortened healing time to 1.5 months and a favorable 3-year amputation-free survival rate. The clinical evidence in the current study suggested a further phase I/II study with a larger patient population and a more rigorous design to explore the efficacy and mechanism of hUC-MSCs on DFU healing. Trial registration: The current study was registered retrospectively on 22 Jan 2022 with the Chinese Clinical Trial Registry (ChiCTR2200055885), http://www.chictr.org.cn/showproj.aspx?proj=135888 Graphical Abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-03143-0.
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Affiliation(s)
- Che Zhang
- Department of Pediatrics, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 West Yanta Road, Xi'an, 710061, Shaanxi, China.,Clinical Research Centre, Affiliated Taihe Hospital of Hubei University of Medicine, Shiyan, China
| | - Li Huang
- Clinical Research Centre, Affiliated Taihe Hospital of Hubei University of Medicine, Shiyan, China.,Guangzhou Cord Blood Bank, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China
| | - Xiaofen Wang
- Department of Endocrinology, Affiliated Taihe Hospital of Hubei University of Medicine, Shiyan, China
| | - Xiaoya Zhou
- Guangzhou Cord Blood Bank, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China
| | - Xiaoxian Zhang
- Guangzhou Cord Blood Bank, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China
| | - Ling Li
- Clinical Data Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Jieying Wu
- Guangzhou Cord Blood Bank, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China
| | - Meng Kou
- Guangzhou Cord Blood Bank, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China
| | - Cheguo Cai
- Shenzhen Beike Biotechnology Co., Ltd., Shenzhen, China
| | - Qizhou Lian
- Guangzhou Cord Blood Bank, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China. .,Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
| | - Xihui Zhou
- Department of Pediatrics, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 West Yanta Road, Xi'an, 710061, Shaanxi, China.
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15
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Linkova DD, Rubtsova YP, Egorikhina MN. Cryostorage of Mesenchymal Stem Cells and Biomedical Cell-Based Products. Cells 2022; 11:cells11172691. [PMID: 36078098 PMCID: PMC9454587 DOI: 10.3390/cells11172691] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 08/15/2022] [Accepted: 08/24/2022] [Indexed: 11/16/2022] Open
Abstract
Mesenchymal stem cells (MSCs) manifest vast opportunities for clinical use due both to their ability for self-renewal and for effecting paracrine therapeutic benefits. At the same time, difficulties with non-recurrent generation of large numbers of cells due to the necessity for long-term MSC expansion ex vivo, or the requirement for repeated sampling of biological material from a patient significantly limits the current use of MSCs in clinical practice. One solution to these problems entails the creation of a biobank using cell cryopreservation technology. This review is aimed at analyzing and classifying literature data related to the development of protocols for the cryopreservation of various types of MSCs and tissue-engineered structures. The materials in the review show that the existing techniques and protocols for MSC cryopreservation are very diverse, which significantly complicates standardization of the entire process. Here, the selection of cryoprotectors and of cryoprotective media shows the greatest variability. Currently, it is the cryopreservation of cell suspensions that has been studied most extensively, whereas there are very few studies in the literature on the freezing of intact tissues or of tissue-engineered structures. However, even now it is possible to develop general recommendations to optimize the cryopreservation process, making it less traumatic for cells.
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16
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Zang L, Li Y, Hao H, Liu J, Cheng Y, Li B, Yin Y, Zhang Q, Gao F, Wang H, Gu S, Li J, Lin F, Zhu Y, Tian G, Chen Y, Gu W, Du J, Chen K, Guo Q, Yang G, Pei Y, Yan W, Wang X, Meng J, Zhang S, Ba J, Lyu Z, Dou J, Han W, Mu Y. Efficacy and safety of umbilical cord-derived mesenchymal stem cells in Chinese adults with type 2 diabetes: a single-center, double-blinded, randomized, placebo-controlled phase II trial. Stem Cell Res Ther 2022; 13:180. [PMID: 35505375 PMCID: PMC9066971 DOI: 10.1186/s13287-022-02848-6] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 04/14/2022] [Indexed: 12/26/2022] Open
Abstract
Background To determine the efficacy and safety of umbilical cord-derived mesenchymal stem cells (UC-MSCs) in Chinese adults with type 2 diabetes mellitus (T2DM). Methods In this single-center, double-blinded, randomized, placebo-controlled phase II trial, 91 patients were randomly assigned to receive intravenous infusion of UC-MSCs (n = 45) or placebo (n = 46) three times with 4-week intervals and followed up for 48 weeks from October 2015 to December 2018. The primary endpoint was the percentage of patients with glycated hemoglobin (HbA1c) levels of < 7.0% and daily insulin reduction of ≥ 50% at 48 weeks. Additional endpoints were changes of metabolic control, islet β-cell function, insulin resistance, and safety. Results At 48 weeks, 20% of the patients in the UC-MSCs group and 4.55% in the placebo group reached the primary endpoint (p < 0.05, 95% confidence interval (CI) 2.25–28.66%). The percentage of insulin reduction of the UC-MSCs group was significantly higher than that of the placebo group (27.78% versus 15.62%, p < 0.05). The levels of HbA1c decreased 1.31% (9.02 ± 1.27% to 7.52 ± 1.07%, p < 0.01) in the UC-MSCs group, and only 0.63% in the placebo group (8.89 ± 1.11% to 8.19 ± 1.02%, p˃0.05; p = 0.0081 between both groups). The glucose infusion rate (GIR) increased significantly in the UC-MSCs group (from 3.12 to 4.76 mg/min/kg, p < 0.01), whereas no significant change was observed in the placebo group (from 3.26 to 3.60 mg/min/kg, p ˃ 0.05; p < 0.01 between both groups). There was no improvement in islet β-cell function in both groups. No major UC-MSCs transplantation-related adverse events occurred. Conclusions UC-MSCs transplantation could be a potential therapeutic approach for Chinese adults with T2DM. Trial registration This study was registered on ClinicalTrials.gov (identifier: NCT02302599). Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02848-6.
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Affiliation(s)
- Li Zang
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Yijun Li
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Haojie Hao
- Department of Biotherapy, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Jiejie Liu
- Department of Biotherapy, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Yu Cheng
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Bing Li
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Yaqi Yin
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Qian Zhang
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Fei Gao
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Haibin Wang
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Shi Gu
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Jia Li
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Fengxiang Lin
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Yingfei Zhu
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Guanglei Tian
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Yulong Chen
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Weijun Gu
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Jin Du
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Kang Chen
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Qinghua Guo
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Guoqing Yang
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Yu Pei
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Wenhua Yan
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Xianling Wang
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Junhua Meng
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Saichun Zhang
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Jianming Ba
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Zhaohui Lyu
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Jingtao Dou
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China
| | - Weidong Han
- Department of Biotherapy, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China.
| | - Yiming Mu
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China.
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Kaffash Farkhad N, Mahmoudi A, Mahdipour E. Regenerative therapy by using Mesenchymal Stem Cells-derived exosomes in COVID-19 treatment. The potential role and underlying mechanisms. Regen Ther 2022; 20:61-71. [PMID: 35340407 PMCID: PMC8938276 DOI: 10.1016/j.reth.2022.03.006] [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: 12/03/2021] [Revised: 03/04/2022] [Accepted: 03/13/2022] [Indexed: 12/03/2022] Open
Abstract
COVID-19 disease caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), started in December 2019 in Wuhan, China, and quickly became the global pandemic. The high spread rate, relatively high mortality rate, and the lack of specific medicine have led researchers and clinicians worldwide to find new treatment strategies. Unfortunately, evidence shows that the virus-specific receptor Angiotensin-Converting Enzyme 2 (ACE-2) is present on the surface of most cells in the body, leading to immune system dysfunction and multi-organ failure in critically ill patients. In this context, the use of Mesenchymal Stem Cells (MSCs) and their secret has opened new therapeutic horizons for patients due to the lack of ACE2 receptor expression. MSCs exert their beneficial therapeutic actions, particularly anti-inflammatory and immunomodulatory properties, mainly through paracrine effects which are mediated by exosomes. Exosomes are bilayer nanovesicles that carry a unique cargo of proteins, lipids and functional nucleic acids based on their cell origin. This review article aims to investigate the possible role of exosomes and the underlying mechanism involved in treating COVID-19 disease based on recent findings.
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Affiliation(s)
- Najmeh Kaffash Farkhad
- Immunology Research Center, Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Mahmoudi
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Elahe Mahdipour
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Corresponding author. Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, University campus. Azadi Sq, Mashhad. Iran.
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Li B, Cheng X, Aierken A, Du J, He W, Zhang M, Tan N, Kou Z, Peng S, Jia W, Tang H, Hua J. Melatonin Promotes the Therapeutic Effect of Mesenchymal Stem Cells on Type 2 Diabetes Mellitus by Regulating TGF-β Pathway. Front Cell Dev Biol 2021; 9:722365. [PMID: 34722505 PMCID: PMC8554153 DOI: 10.3389/fcell.2021.722365] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 09/27/2021] [Indexed: 12/26/2022] Open
Abstract
Abundant evidence proves the therapeutic effect of adipose-derived mesenchymal stem cells (ADMSCs) in the treatment of diabetes mellitus. However, the problems have not been solved that viability of ADMSCs were inconsistent and the cells quickly undergo senescence after in vitro cell culture. In addition, the therapeutic effect of ADMSCs is still not satisfactory. In this study, melatonin (MLT) was added to canine ADMSC culture medium, and the treated cells were used to treat type 2 diabetes mellitus (T2DM). Our research reveals that adding MLT to ADMSC culture medium can promote the viability of ADMSCs. This effect depends on the binding of MLT and MLT receptors, which activates the transforming growth factor β (TGF-β) pathway and then changes the cell cycle of ADMSCs and improves the viability of ADMSCs. Since ADMSCs were found to be used to treat T2DM by anti-inflammatory and anti-endoplasmic reticulum (ER) stress capabilities, our data demonstrate that MLT augment several effects of ADMSCs in remission hyperglycemia, insulin resistance, and liver glycogen metabolism in T2DM patients. This suggest that ADMSCs and MLT-ADMSCs is safe and vabulable for pet clinic.
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Affiliation(s)
- Balun Li
- Shaanxi Centre of Stem Cells Engineering and Technology, College of Veterinary Medicine, Northwest A&F University, Xianyang, China
| | - Xuedi Cheng
- Shaanxi Centre of Stem Cells Engineering and Technology, College of Veterinary Medicine, Northwest A&F University, Xianyang, China
| | - Aili Aierken
- Shaanxi Centre of Stem Cells Engineering and Technology, College of Veterinary Medicine, Northwest A&F University, Xianyang, China
| | - Jiaxin Du
- Department of Animal Engineering, Yangling Vocational and Technical College, Xianyang, China.,Department of Veterinary Medicine, College of Animal Sciences, Institute of Preventive Veterinary Sciences, Zhejiang University, Hangzhou, China
| | - Wenlai He
- Shaanxi Centre of Stem Cells Engineering and Technology, College of Veterinary Medicine, Northwest A&F University, Xianyang, China
| | - Mengfei Zhang
- Shaanxi Centre of Stem Cells Engineering and Technology, College of Veterinary Medicine, Northwest A&F University, Xianyang, China
| | - Ning Tan
- Shaanxi Centre of Stem Cells Engineering and Technology, College of Veterinary Medicine, Northwest A&F University, Xianyang, China
| | - Zheng Kou
- Shaanxi Centre of Stem Cells Engineering and Technology, College of Veterinary Medicine, Northwest A&F University, Xianyang, China
| | - Sha Peng
- Shaanxi Centre of Stem Cells Engineering and Technology, College of Veterinary Medicine, Northwest A&F University, Xianyang, China
| | - Wenwen Jia
- Shanghai East Hospital, East Hospital Affiliated to Tongji University, Shanghai, China
| | - Haiyang Tang
- Shaanxi Centre of Stem Cells Engineering and Technology, College of Veterinary Medicine, Northwest A&F University, Xianyang, China
| | - Jinlian Hua
- Shaanxi Centre of Stem Cells Engineering and Technology, College of Veterinary Medicine, Northwest A&F University, Xianyang, China
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19
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Ahn H, Lee SY, Jung WJ, Lee KH. Treatment of acute ischemic stroke by minimally manipulated umbilical cord-derived mesenchymal stem cells transplantation: A case report. World J Stem Cells 2021; 13:1151-1159. [PMID: 34567432 PMCID: PMC8422927 DOI: 10.4252/wjsc.v13.i8.1151] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 06/23/2021] [Accepted: 08/06/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Stroke is one of the major causes of disability and death worldwide. Some treatments for stroke exist, but existing treatment methods have limitations such as difficulty in the regeneration of damaged neuronal cells of the brain. Recently, mesenchymal stem cells (MSCs) have been studied as a therapeutic alternative for stroke, and various preclinical and case studies have been reported.
CASE SUMMARY A 55-year-old man suffered an acute stroke, causing paralysis in the left upper and lower limbs. He intravenously transplanted the minimally manipulated human umbilical cord-derived MSCs (MM-UC-MSCs) twice with an 8-d interval. At 65 wk after transplantation, the patient returned to his previous occupation as a veterinarian with no adverse reactions.
CONCLUSION MM-UC-MSCs transplantation potentially treats patients who suffer from acute ischemic stroke.
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Affiliation(s)
- Hyunjun Ahn
- bio Beauty&Health Company (bBHC)-Stem Cell Treatment & Research Institute (STRI), Seoul 04420, South Korea
| | - Sang Yeon Lee
- bio Beauty&Health Company (bBHC)-Stem Cell Treatment & Research Institute (STRI), Seoul 04420, South Korea
| | - Won Ju Jung
- 97.7 Beauty&Health (B&H) Clinics, Seoul 04420, South Korea
| | - Kye-Ho Lee
- bio Beauty&Health Company (bBHC)-Stem Cell Treatment & Research Institute (STRI), Seoul 04420, South Korea
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20
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Zhao N, Gao YF, Bao L, Lei J, An HX, Pu FX, Cheng RP, Chen J, Ni H, Sui BD, Ji FP, Hu CH. Glycemic control by umbilical cord-derived mesenchymal stem cells promotes effects of fasting-mimicking diet on type 2 diabetic mice. Stem Cell Res Ther 2021; 12:395. [PMID: 34256832 PMCID: PMC8278637 DOI: 10.1186/s13287-021-02467-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 05/03/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Hepatic steatosis is a big hurdle to treat type 2 diabetes (T2D). Fasting-mimicking diet (FMD) has been shown to be an effective intervention in dyslipidemia of T2D. However, fasting may impair the normal glucose metabolism. Human umbilical cord-derived mesenchymal stem cell (UC-MSC) transplantation has been discovered to regulate immune reactions and reduce hyperglycemia in diabetes. However, the effect of UC-MSCs on improving the lipid metabolism disorder is not quite satisfactory. We have investigated the efficacy comparison and interaction between FMD and UC-MSC infusion, aiming to establish effective T2D therapies and explore its mechanism. METHODS C57/BL6 mice were fed with high-fat diet (HFD) to induce a diet-induced obese (DIO) mouse model. Leptin receptor-deficient (db/db) mice were used for follow-up experiments. DIO or db/db mice were divided into 4 groups: phosphate buffer saline (PBS), UC-MSCs, FMD, and UC-MSCs + FMD. At the end of the study period, mice were fasted and sacrificed, with the measurement of physiological and biochemical indexes. In addition, the fresh liver, skin, and white adipose tissue were analyzed by histology. RESULTS FMD restored the lipid metabolism in DIO mice, whereas its capacity to rescue hyperglycemia was uncertain. Infusion of UC-MSCs was effective in T2D glycemic control but the impact on dyslipidemia was insufficient. Furthermore, both the glucose and the lipid alterations of DIO and db/db mice recovered after UC-MSCs combined with FMD. It was proved that UC-MSCs promoted FMD effects on ameliorating hyperglycemia and restoring the lipid metabolism in T2D mice, while FMD had little promotion effect on UC-MSCs. Mechanistically, we discovered that UC-MSC infusion significantly modulated systematic inflammatory microenvironment, which contributed to concerted actions with FMD. CONCLUSIONS We established a strategy that combined UC-MSC infusion and FMD and was effective in treating T2D, which provided potential approaches for developing novel clinical T2D therapies.
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Affiliation(s)
- Na Zhao
- Institute for Stem Cell & Regenerative Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.,National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.,Xi'an Institute of Tissue Engineering and Regenerative Medicine, Xi'an, Shaanxi, People's Republic of China
| | - Ying-Feng Gao
- Institute for Stem Cell & Regenerative Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.,National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.,Xi'an Institute of Tissue Engineering and Regenerative Medicine, Xi'an, Shaanxi, People's Republic of China
| | - Lei Bao
- Department of Obstetrics and Gynecology, Xi'an No. 4 Hospital, Affiliated Guangren Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
| | - Jing Lei
- Department of Obstetrics and Gynecology, Xi'an No. 4 Hospital, Affiliated Guangren Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
| | - Huan-Xiao An
- Institute for Stem Cell & Regenerative Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
| | - Feng-Xing Pu
- Institute for Stem Cell & Regenerative Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
| | - Rui-Ping Cheng
- Institute for Stem Cell & Regenerative Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
| | - Ji Chen
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China
| | - Hua Ni
- Institute for Stem Cell & Regenerative Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
| | - Bing-Dong Sui
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.
| | - Fan-Pu Ji
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China. .,Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China. .,Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education of China, Xi'an, Shaanxi, People's Republic of China.
| | - Cheng-Hu Hu
- Institute for Stem Cell & Regenerative Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China. .,Xi'an Institute of Tissue Engineering and Regenerative Medicine, Xi'an, Shaanxi, People's Republic of China. .,Department of Obstetrics and Gynecology, Xi'an No. 4 Hospital, Affiliated Guangren Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.
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21
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Ma Y, Wang L, Yang S, Liu D, Zeng Y, Lin L, Qiu L, Lu J, Chang J, Li Z. The tissue origin of human mesenchymal stem cells dictates their therapeutic efficacy on glucose and lipid metabolic disorders in type II diabetic mice. Stem Cell Res Ther 2021; 12:385. [PMID: 34233739 PMCID: PMC8261817 DOI: 10.1186/s13287-021-02463-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 06/15/2021] [Indexed: 12/12/2022] Open
Abstract
Background The therapeutic efficacy of mesenchymal stem cells (MSCs) of different tissue origins on metabolic disorders can be varied in many ways but remains poorly defined. Here we report a comprehensive comparison of human MSCs derived from umbilical cord Wharton’s jelly (UC-MSCs), dental pulp (PU-MSCs), and adipose tissue (AD-MSCs) on the treatment of glucose and lipid metabolic disorders in type II diabetic mice. Methods Fourteen-to-fifteen-week-old male C57BL/6 db/db mice were intravenously administered with human UC-MSCs, PU-MSCs, and AD-MSCs at various doses or vehicle control once every 2 weeks for 6 weeks. Metformin (MET) was given orally to animals in a separate group once a day at weeks 4 to 6 as a positive control. Body weight, blood glucose, and insulin levels were measured every week. Glucose tolerance tests (GTT) and insulin tolerance tests (ITT) were performed every 2 weeks. All the animals were sacrificed at week 6 and the blood and liver tissues were collected for biochemical and histological examinations. Results UC-MSCs showed the strongest efficacy in reducing fasting glucose levels, increasing fasting insulin levels, and improving GTT and ITT in a dose-dependent manner, whereas PU-MSCs showed an intermediate efficacy and AD-MSCs showed the least efficacy on these parameters. Moreover, UC-MSCs also reduced the serum low-density lipoprotein cholesterol (LDL-C) levels with the most prominent potency and AD-MSCs had only very weak effect on LDL-C. In contrast, AD-MSCs substantially reduced the lipid content and histological lesion of liver and accompanying biomarkers of liver injury such as serum aspartate transaminase (AST) and alanine aminotransferase (ALT) levels, whereas UC-MSCs and PU-MSCs displayed no or modest effects on these parameters, respectively. Conclusions Taken together, our results demonstrated that MSCs of different tissue origins can confer substantially different therapeutic efficacy in ameliorating glucose and lipid metabolic disorders in type II diabetes. MSCs with different therapeutic characteristics could be selected according to the purpose of the treatment in the future clinical practice.
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Affiliation(s)
- Yinzhong Ma
- SIAT-GHMSCB Biomedical Laboratory for Major Diseases, Dongguan Enlife Stem Cell Biotechnology Institute, Dongguan Avenue 430, Dongguan, Guangdong, China.,Shenzhen Key Laboratory of Biomimetic Materials and Cellular Immunomodulation, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Xueyuan Blvd 1068, Shenzhen, Guangdong, China
| | - Lisha Wang
- SIAT-GHMSCB Biomedical Laboratory for Major Diseases, Dongguan Enlife Stem Cell Biotechnology Institute, Dongguan Avenue 430, Dongguan, Guangdong, China
| | - Shilun Yang
- Shenzhen Key Laboratory of Biomimetic Materials and Cellular Immunomodulation, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Xueyuan Blvd 1068, Shenzhen, Guangdong, China
| | - Dongyu Liu
- SIAT-GHMSCB Biomedical Laboratory for Major Diseases, Dongguan Enlife Stem Cell Biotechnology Institute, Dongguan Avenue 430, Dongguan, Guangdong, China
| | - Yi Zeng
- Shenzhen Key Laboratory of Biomimetic Materials and Cellular Immunomodulation, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Xueyuan Blvd 1068, Shenzhen, Guangdong, China
| | - Lilong Lin
- SIAT-GHMSCB Biomedical Laboratory for Major Diseases, Dongguan Enlife Stem Cell Biotechnology Institute, Dongguan Avenue 430, Dongguan, Guangdong, China
| | - Linhui Qiu
- Shenzhen Key Laboratory of Biomimetic Materials and Cellular Immunomodulation, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Xueyuan Blvd 1068, Shenzhen, Guangdong, China
| | - Jiahao Lu
- SIAT-GHMSCB Biomedical Laboratory for Major Diseases, Dongguan Enlife Stem Cell Biotechnology Institute, Dongguan Avenue 430, Dongguan, Guangdong, China
| | - Junlei Chang
- Shenzhen Key Laboratory of Biomimetic Materials and Cellular Immunomodulation, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Xueyuan Blvd 1068, Shenzhen, Guangdong, China.
| | - Zhihuan Li
- SIAT-GHMSCB Biomedical Laboratory for Major Diseases, Dongguan Enlife Stem Cell Biotechnology Institute, Dongguan Avenue 430, Dongguan, Guangdong, China.
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22
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Human umbilical cord mesenchymal stem cells in type 2 diabetes mellitus: the emerging therapeutic approach. Cell Tissue Res 2021; 385:497-518. [PMID: 34050823 DOI: 10.1007/s00441-021-03461-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Accepted: 04/11/2021] [Indexed: 12/14/2022]
Abstract
The umbilical cord has been proved to be an easy-access, reliable, and useful source of mesenchymal stem cells (MSC) for clinical applications due to its primitive, immunomodulatory, non-immunogenic, secretory and paracrine, migratory, proliferative, and multipotent properties. This set of characteristics has recently attracted great research interest in the fields of nanotechnology and regenerative medicine and cellular therapy. Accumulating evidence supports a pronounced therapeutic potential of MSC in many different pathologies, from hematology to immunology, wound-healing, tissue regeneration, and oncology. Diabetes mellitus, branded the epidemic of the century, is considered a chronic metabolic disorder, representing a major burden for health system sustainability and an important public health challenge to modern societies. The available treatments for type 2 diabetes mellitus (T2DM) still rely mainly on combinations of oral antidiabetic agents with lifestyle and nutritional adjustments. Despite the continuous development of novel and better hypoglycemic drugs, their efficacy is limited in the installment and progression of silent T2DM complications. T2DM comorbidities and mortality rates still make it a serious, common, costly, and long-term manageable disease. Recently, experimental models, preclinical observations, and clinical studies have provided some insights and preliminary promising results using umbilical cord MSCs to treat and manage diabetes. This review focuses on the latest research and applications of human-derived umbilical cord MSC in the treatment and management of T2DM, exploring and systematizing the key effects of both umbilical cord MSC and its factor-rich secretome accordingly with the major complications associated to T2DM.
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23
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Li Y, Wang F, Liang H, Tang D, Huang M, Zhao J, Yang X, Liu Y, Shu L, Wang J, He Z, Liu Y. Efficacy of mesenchymal stem cell transplantation therapy for type 1 and type 2 diabetes mellitus: a meta-analysis. Stem Cell Res Ther 2021; 12:273. [PMID: 33957998 PMCID: PMC8101194 DOI: 10.1186/s13287-021-02342-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 04/19/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND This meta-analysis was first conducted to evaluate the efficacy and safety of transplantation of mesenchymal stem cells in the treatment of type 1 and type 2 diabetes mellitus (T1DM and T2DM). METHODS We systematically searched PubMed, ScienceDirect, Google Scholar, CNKI, EMBASE, Web of Science, MEDLINE, and the Cochrane Library for studies published from the establishment of the databases to November 2020. Two researchers independently screened the identified studies, based on inclusion and exclusion criteria. The combined standard mean difference (SMD) and 95% confidence interval (CI) of data from the included studies were calculated using fixed- or random-effects models. RESULTS We included 10 studies in our meta-analysis (4 studies on T1DM and 6 on T2DM, with 239 participants) to examine the efficacy of mesenchymal stem cells (MSCs) therapy in the treatment of diabetes mellitus. According to the pooled estimates, the glycated hemoglobin (HbA1c) level of the MSC-treated group was significantly lower than it was at baseline (mean difference (MD) = -1.51, 95% CI -2.42 to -0.60, P = 0.001). The fasting C-peptide level of the MSC-treated group with T1DM was higher than that of the control group (SMD = 0.89, 95% CI 0.36 to 1.42, P = 0.001), and their insulin requirement was significantly lower than it was at baseline (SMD = -1.14, 95% CI -1.52 to -0.77, P < 0.00001). CONCLUSION Transplantation of mesenchymal stem cells has beneficial effects on diabetes mellitus, especially T1DM, and no obvious adverse reactions.
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Affiliation(s)
- Yanju Li
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, Guizhou Province, China.,National & Guizhou Joint Engineering Laboratory for Cell Engineering and Biomedicine Technique, Guizhou Province Key Laboratory of Regenerative Medicine, Key Laboratory of Adult Stem Cell Translational Research, Chinese Academy of Medical Sciences, Guizhou Medical University, Guiyang, 550004, Guizhou Province, China
| | - Feiqing Wang
- Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin, 300072, China.,Department of Scientific Research, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, 550001, Guizhou Province, China
| | - Huiling Liang
- Department of Scientific Research, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, 550001, Guizhou Province, China
| | - Dongxin Tang
- Department of Scientific Research, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, 550001, Guizhou Province, China
| | - Mei Huang
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, Guizhou Province, China
| | - Jianing Zhao
- Department of Scientific Research, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, 550001, Guizhou Province, China
| | - Xu Yang
- Department of Scientific Research, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, 550001, Guizhou Province, China
| | - Yanqing Liu
- Department of Scientific Research, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, 550001, Guizhou Province, China
| | - Liping Shu
- National & Guizhou Joint Engineering Laboratory for Cell Engineering and Biomedicine Technique, Guizhou Province Key Laboratory of Regenerative Medicine, Key Laboratory of Adult Stem Cell Translational Research, Chinese Academy of Medical Sciences, Guizhou Medical University, Guiyang, 550004, Guizhou Province, China
| | - Jishi Wang
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, Guizhou Province, China.
| | - Zhixu He
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, Guizhou Province, China. .,National & Guizhou Joint Engineering Laboratory for Cell Engineering and Biomedicine Technique, Guizhou Province Key Laboratory of Regenerative Medicine, Key Laboratory of Adult Stem Cell Translational Research, Chinese Academy of Medical Sciences, Guizhou Medical University, Guiyang, 550004, Guizhou Province, China.
| | - Yang Liu
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, Guizhou Province, China. .,National & Guizhou Joint Engineering Laboratory for Cell Engineering and Biomedicine Technique, Guizhou Province Key Laboratory of Regenerative Medicine, Key Laboratory of Adult Stem Cell Translational Research, Chinese Academy of Medical Sciences, Guizhou Medical University, Guiyang, 550004, Guizhou Province, China. .,Department of Scientific Research, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, 550001, Guizhou Province, China.
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Ranjbaran H, Mohammadi Jobani B, Amirfakhrian E, Alizadeh‐Navaei R. Efficacy of mesenchymal stem cell therapy on glucose levels in type 2 diabetes mellitus: A systematic review and meta-analysis. J Diabetes Investig 2021; 12:803-810. [PMID: 32926576 PMCID: PMC8089007 DOI: 10.1111/jdi.13404] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2019] [Revised: 08/13/2020] [Accepted: 09/05/2020] [Indexed: 02/06/2023] Open
Abstract
AIMS/INTRODUCTION In recent years, mesenchymal cellular therapies have received much attention in the treatment of diabetes. In this meta-analysis, we aimed to evaluate the efficacy of mesenchymal stem cell therapy in type 2 diabetes mellitus patients. MATERIALS AND METHODS A comprehensive literature search was carried out using PubMed, Scopus, Web of Science and Central databases. A total of 1,721 articles were identified, from which nine full-text clinical trials were qualified to enter the current meta-analysis. The assessment groups included patients with type 2 diabetes, and levels of C-peptide, glycosylated hemoglobin and insulin dose were analyzed before and after mesenchymal stem cell infusion. Data analysis was carried out in Stata version 11, and the Jadad Score Scale was applied for quality assessment. RESULTS Changes in levels of C-peptide after mesenchymal stem cell therapy were: standardized mean difference 0.20, 95% confidence interval -0.61 to 1.00, glycosylated hemoglobin levels were: standardized mean difference -1.45, 95% confidence interval -2.10 to -0.79 and insulin dose were: standardized mean difference -1.40, 95% confidence interval -2.88 to 0.09. CONCLUSIONS This meta-analysis of prospective studies showed associations between mesenchymal stem cell therapy and control of glucose level in patients with type 2 diabetes.
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Affiliation(s)
- Hossein Ranjbaran
- Immunogenetics Research Center, Non‐communicable Diseases InstituteMazandaran University of Medical SciencesSariIran
| | - Bahareh Mohammadi Jobani
- Pediatric Urology Research CenterDepartment of Pediatric Urology, Children’s Hospital Medical CenterTehran University of Medical SciencesTehranIran
| | - Elham Amirfakhrian
- Hemoglobinopathy InstituteMazandaran University of Medical SciencesSariMazandaranIran
| | - Reza Alizadeh‐Navaei
- Gastrointestinal Cancer Research Center, Non‐communicable Diseases InstituteMazandaran University of Medical SciencesSariIran
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25
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Li W, Jiao X, Song J, Sui B, Guo Z, Zhao Y, Li J, Shi S, Huang Q. Therapeutic potential of stem cells from human exfoliated deciduous teeth infusion into patients with type 2 diabetes depends on basal lipid levels and islet function. Stem Cells Transl Med 2021; 10:956-967. [PMID: 33660433 PMCID: PMC8235136 DOI: 10.1002/sctm.20-0303] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 01/02/2021] [Accepted: 02/06/2021] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cells (MSCs) hold great potential in treating patients with diabetes, but the therapeutic effects are not always achieved. Particularly, the clinical factors regulating MSC therapy in this setting are largely unknown. In this study, 24 patients with type 2 diabetes mellitus (T2DM) treated with insulin were selected to receive three intravenous infusions of stem cells from human exfoliated deciduous teeth (SHED) over the course of 6 weeks and were followed up for 12 months. We observed a significant reduction of glycosylated serum albumin level (P < .05) and glycosylated hemoglobin level (P < .05) after SHED transplantation. The total effective rate was 86.36% and 68.18%, respectively, at the end of treatment and follow‐up periods. Three patients ceased insulin injections after SHED transplantation. A steamed bread meal test showed that the serum levels of postprandial C‐peptide at 2 hours were significantly higher than those at the baseline (P < .05). Further analysis showed that patients with a high level of blood cholesterol and a low baseline level of C‐peptide had poor response to SHED transplantation. Some patients experienced a transient fever (11.11%), fatigue (4.17%), or rash (1.39%) after SHED transplantation, which were easily resolved. In summary, SHED infusion is a safe and effective therapy to improve glucose metabolism and islet function in patients with T2DM. Blood lipid levels and baseline islet function may serve as key factors contributing to the therapeutic outcome of MSC transplantation in patients with T2DM.
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Affiliation(s)
- Wenwen Li
- Department of Endocrinology, Changhai Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Xuan Jiao
- Department of Endocrinology, Changhai Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Jingyun Song
- Department of Endocrinology, Changhai Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Bingdong Sui
- South China Center of Craniofacial Stem Cell Research, Guanghua School and Hospital of Stomatology, Sun Yat-sen University, Guangzhou, People's Republic of China.,Research and Development Center for Tissue Engineering, School of Stomatology, Air Force Medical University, People's Republic of China
| | - Zhili Guo
- Department of Dermatology, Changhai Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Yingji Zhao
- South China Center of Craniofacial Stem Cell Research, Guanghua School and Hospital of Stomatology, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Jun Li
- Easter Greenland Hospital, People's Republic of China
| | - Songtao Shi
- South China Center of Craniofacial Stem Cell Research, Guanghua School and Hospital of Stomatology, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Qin Huang
- Department of Endocrinology, Changhai Hospital, Second Military Medical University, Shanghai, People's Republic of China
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Chen J, Zheng CX, Jin Y, Hu CH. Mesenchymal stromal cell-mediated immune regulation: A promising remedy in the therapy of type 2 diabetes mellitus. STEM CELLS (DAYTON, OHIO) 2021; 39:838-852. [PMID: 33621403 DOI: 10.1002/stem.3357] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 02/03/2021] [Indexed: 11/09/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is a major threat to global public health, with increasing prevalence as well as high morbidity and mortality, to which immune dysfunction has been recognized as a crucial contributor. Mesenchymal stromal cells (MSCs), obtained from various sources and possessing potent immunomodulatory abilities, have displayed great therapeutic potential for T2DM. Interestingly, the immunomodulatory capabilities of MSCs are endowed and plastic. Among the multiple mechanisms involved in MSC-mediated immune regulation, the paracrine effects of MSCs have attracted much attention. Of note, extracellular vesicles (EVs), an important component of MSC secretome, have emerged as pivotal mediators of their immunoregulatory effects. Particularly, the necrobiology of MSCs, especially apoptosis, has recently been revealed to affect their immunomodulatory functions in vivo. In specific, a variety of preclinical studies have demonstrated the beneficial effects of MSCs on improving islet function and ameliorating insulin resistance. More importantly, clinical trials have further uncovered the therapeutic potential of MSCs for T2DM. In this review, we outline current knowledge regarding the plasticity and underlying mechanisms of MSC-mediated immune modulation, focusing on the paracrine effects. We also summarize the applications of MSC-based therapies for T2DM in both preclinical studies and clinical trials, with particular emphasis on the modulation of immune system.
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Affiliation(s)
- Ji Chen
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases，Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, People's Republic of China.,Department of Oral Implantology, School of Stomatology, Fourth Military Medical University, Xi'an, People's Republic of China
| | - Chen-Xi Zheng
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases，Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, People's Republic of China
| | - Yan Jin
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases，Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, People's Republic of China
| | - Cheng-Hu Hu
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases，Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, People's Republic of China.,Xi'an Institute of Tissue Engineering and Regenerative Medicine, Xi'an, People's Republic of China
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Wang Y, Shan SK, Guo B, Li F, Zheng MH, Lei LM, Xu QS, Ullah MHE, Xu F, Lin X, Yuan LQ. The Multi-Therapeutic Role of MSCs in Diabetic Nephropathy. Front Endocrinol (Lausanne) 2021; 12:671566. [PMID: 34163437 PMCID: PMC8216044 DOI: 10.3389/fendo.2021.671566] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Accepted: 05/20/2021] [Indexed: 12/16/2022] Open
Abstract
Diabetic nephropathy (DN) is one of the most common diabetes mellitus (DM) microvascular complications, which always ends with end-stage renal disease (ESRD). Up to now, as the treatment of DN in clinic is still complicated, ESRD has become the main cause of death in diabetic patients. Mesenchymal stem cells (MSCs), with multi-differentiation potential and paracrine function, have attracted considerable attention in cell therapy recently. Increasing studies concerning the mechanisms and therapeutic effect of MSCs in DN emerged. This review summarizes several mechanisms of MSCs, especially MSCs derived exosomes in DN therapy, including hyperglycemia regulation, anti-inflammatory, anti-fibrosis, pro-angiogenesis, and renal function protection. We also emphasize the limitation of MSCs application in the clinic and the enhanced therapeutic role of pre-treated MSCs in the DN therapy. This review provides balanced and impartial views for MSC therapy as a promising strategy in diabetic kidney disease amelioration.
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Affiliation(s)
- Yi Wang
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Su-Kang Shan
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Bei Guo
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Fuxingzi Li
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Ming-Hui Zheng
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Li-Min Lei
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Qiu-Shuang Xu
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Muhammad Hasnain Ehsan Ullah
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Feng Xu
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Xiao Lin
- Department of Radiology, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Ling-Qing Yuan
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Ling-Qing Yuan,
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Sun Y, Tao Q, Wu X, Zhang L, Liu Q, Wang L. The Utility of Exosomes in Diagnosis and Therapy of Diabetes Mellitus and Associated Complications. Front Endocrinol (Lausanne) 2021; 12:756581. [PMID: 34764939 PMCID: PMC8576340 DOI: 10.3389/fendo.2021.756581] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 10/01/2021] [Indexed: 12/12/2022] Open
Abstract
Diabetes mellitus and the associated complications are metabolic diseases with high morbidity that result in poor quality of health and life. The lack of diagnostic methods for early detection results in patients losing the best treatment opportunity. Oral hypoglycemics and exogenous insulin replenishment are currently the most common therapeutic strategies, which only yield temporary glycemic control rather than curing the disease and its complications. Exosomes are nanoparticles containing bioactive molecules reflecting individual physiological status, regulating metabolism, and repairing damaged tissues. They function as biomarkers of diabetes mellitus and diabetic complications. Considering that exosomes are bioactive molecules, can be obtained from body fluid, and have cell-type specificity, in this review, we highlight the multifold effects of exosomes in the pathology and therapy of diabetes mellitus and diabetic complications.
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Affiliation(s)
- Yaoxiang Sun
- Department of Clinical Laboratory, Yixing People's Hospital, Yixing, China
| | - Qing Tao
- Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China
| | - Xueqin Wu
- Department of Clinical Laboratory, Yixing People's Hospital, Yixing, China
| | - Ling Zhang
- Department of Clinical Laboratory, Yixing People's Hospital, Yixing, China
| | - Qi Liu
- Department of Clinical Laboratory, Yixing People's Hospital, Yixing, China
| | - Lei Wang
- Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China
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Kassem DH, Kamal MM. Therapeutic efficacy of umbilical cord-derived stem cells for diabetes mellitus: a meta-analysis study. Stem Cell Res Ther 2020; 11:484. [PMID: 33198815 PMCID: PMC7667841 DOI: 10.1186/s13287-020-01996-x] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 10/24/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Stem cell therapy provides great hope for patients with diabetes mellitus (DM). DM is a seriously alarming metabolic disease characterized by hyperglycemia and β cell dysfunction. Efficient novel therapeutic modalities to treat DM are indeed warranted. Stem cells (SC) derived from the umbilical cord specifically provide several advantages and unique characteristics being a readily available non-invasive source, with an additional credit for their banking potential. This meta-analysis study aims to provide a focused assessment for therapeutic efficacy of umbilical cord (UC)-derived SC-transplantation, namely Wharton's jelly mesenchymal stem cells (WJ-MSCs) and umbilical cord blood (UCB) for DM. METHODS The clinical efficacy was evaluated based on glycemic control status (reflected on HbA1c%) and β cell function (reflected on C-peptide levels), as well as the daily insulin requirement in diabetic patients after receiving UC-derived SC-transplantation compared to baseline values. Moreover, we assessed these outcome measures in patients who received such intervention compared to those who did not receive it in randomized/non-randomized controlled clinical trials. We employed a random-effects model and standardized mean difference for this meta-analysis. RESULTS Eleven eligible clinical studies were included; WJ-MSCs (6 studies; 172 patients including 71 controls) and UCB (5 studies; 74 patients including 15 controls). WJ-MSCs significantly improved HbA1c% (pooled-estimate - 1.085; 95%CI (- 1.513, - 0.657); p < 0.001) and C-peptide levels (pooled-estimate 1.008; 95%CI (0.475, 1.541); p < 0.001), as well as the daily insulin-requirement (pooled-estimate - 2.027; 95%CI (- 3.32, - 0.733); p = 0.002). On the contrary, UCB was found to be uniformly ineffective; HbA1c% (pooled-estimate - 0.091, 95%CI (- 0.454, 0.271); p = 0.622), significantly deteriorated C-peptide levels (pooled-estimate - 0.789; 95%CI (- 1.252, - 0.325); p < 0.001) and daily insulin-requirement (pooled-estimate 0.916; 95%CI (0.247, 1.585); p = 0.007). All these observations remained consistent when we carried out sub-group meta-analysis for T1DM and T2DM and also when we compared patients who received WJ-MSCs or UCB to controls. CONCLUSIONS The results of our meta-analysis provide a clear evidence for the superior efficacy of WJ-MSCs over UCB in DM. This sheds lights on the importance to consider banking of WJ-MSCs together with the well-established routine UCB-banking, especially for those with family history of DM. Additionally, further clinical studies are required to investigate therapeutic efficacy of selected/enriched UCB-derived cell populations with immunomodulatory/regenerative potential in DM.
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Affiliation(s)
- Dina H Kassem
- Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Cairo, 11566, Egypt.
| | - Mohamed M Kamal
- Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Cairo, 11566, Egypt.
- Pharmacology and Biochemistry Department, Faculty of Pharmacy, The British University in Egypt (BUE), Cairo, Egypt.
- The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt (BUE), Cairo, 11837, Egypt.
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30
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Raghavan S, Malayaperumal S, Mohan V, Balasubramanyam M. A comparative study on the cellular stressors in mesenchymal stem cells (MSCs) and pancreatic β-cells under hyperglycemic milieu. Mol Cell Biochem 2020; 476:457-469. [PMID: 32997307 DOI: 10.1007/s11010-020-03922-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 09/19/2020] [Indexed: 12/30/2022]
Abstract
β-cell dysfunction is a critical determinant for both type 1 diabetes and type 2 diabetes and β-cells are shown to be highly susceptible to cellular stressors. Mesenchymal stem cells (MSCs) on the other hand are known to have immunomodulatory potential and preferred in clinical applications. However, there is paucity of a comparative study on these cells in relation to several cellular stressors in response to hyperglycemia and this forms the rationale for the present study. INS1 β-cells and MSCs were subjected to high-glucose treatment without and with Metformin, Lactoferrin, or TUDCA and assessed for stress signaling alterations using gene expression, protein expression, as well as functional read-outs. Compared to the untreated control cells, INS1 β-cells or MSCs treated with high glucose showed significant increase in mRNA expressions of ER stress, senescence, and proinflammation. This was accompanied by increased miR146a target genes and decreased levels of SIRT1, NRF2, and miR146a in both the cell types. Consistent with the mRNA results, protein expression levels do reflect the same alterations. Notably, the alterations are relatively less extent in MSCs compared to INS1 β-cells. Interestingly, three different agents, viz., Metformin, Lactoferrin, or TUDCA, were found to overcome the high glucose-induced cellular stresses in a concerted and inter-linked way and restored the proliferation and migration capacity in MSCs as well as normalized the glucose-stimulated insulin secretion in INS1 β-cells. While our study gives a directionality for potential supplementation of metformin/lactoferrin/TUDCA in optimization protocols of MSCs, we suggest that in vitro preconditioning of MSCs with such factors should be further explored with in-depth investigations to harness and enhance the therapeutic capacity/potential of MSCs.
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Affiliation(s)
- Srividhya Raghavan
- Department of Cell and Molecular Biology, Dr. Mohan's Diabetes Specialties Centre, ICMR- Centre for Advanced Research On Diabetes, Madras Diabetes Research Foundation, Gopalapuram, Chennai, 600 086, India
| | - Sarubala Malayaperumal
- Department of Cell and Molecular Biology, Dr. Mohan's Diabetes Specialties Centre, ICMR- Centre for Advanced Research On Diabetes, Madras Diabetes Research Foundation, Gopalapuram, Chennai, 600 086, India
| | - Viswanathan Mohan
- Department of Cell and Molecular Biology, Dr. Mohan's Diabetes Specialties Centre, ICMR- Centre for Advanced Research On Diabetes, Madras Diabetes Research Foundation, Gopalapuram, Chennai, 600 086, India
| | - Muthuswamy Balasubramanyam
- Department of Cell and Molecular Biology, Dr. Mohan's Diabetes Specialties Centre, ICMR- Centre for Advanced Research On Diabetes, Madras Diabetes Research Foundation, Gopalapuram, Chennai, 600 086, India. .,Medical and Health Sciences (MHS), SRM Institute of Science and Technology (SRMIST), SRM Nagar, Kattankulathur, Kanchipuram, Chennai, 603 203, India.
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31
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Large-Scale Expansion of Human Mesenchymal Stem Cells. Stem Cells Int 2020; 2020:9529465. [PMID: 32733574 PMCID: PMC7378617 DOI: 10.1155/2020/9529465] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Revised: 06/07/2020] [Accepted: 07/01/2020] [Indexed: 12/15/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent stem cells with strong immunosuppressive property that renders them an attractive source of cells for cell therapy. MSCs have been studied in multiple clinical trials to treat liver diseases, peripheral nerve damage, graft-versus-host disease, autoimmune diseases, diabetes mellitus, and cardiovascular damage. Millions to hundred millions of MSCs are required per patient depending on the disease, route of administration, frequency of administration, and patient body weight. Multiple large-scale cell expansion strategies have been described in the literature to fetch the cell quantity required for the therapy. In this review, bioprocessing strategies for large-scale expansion of MSCs were systematically reviewed and discussed. The literature search in Medline and Scopus databases identified 26 articles that met the inclusion criteria and were included in this review. These articles described the large-scale expansion of 7 different sources of MSCs using 4 different bioprocessing strategies, i.e., bioreactor, spinner flask, roller bottle, and multilayered flask. The bioreactor, spinner flask, and multilayered flask were more commonly used to upscale the MSCs compared to the roller bottle. Generally, a higher expansion ratio was achieved with the bioreactor and multilayered flask. Importantly, regardless of the bioprocessing strategies, the expanded MSCs were able to maintain its phenotype and potency. In summary, the bioreactor, spinner flask, roller bottle, and multilayered flask can be used for large-scale expansion of MSCs without compromising the cell quality.
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32
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Wang Z, Zhu H, Dai S, Liu K, Ge C. Alleviation of medial meniscal transection-induced osteoarthritis pain in rats by human adipose derived mesenchymal stem cells. Stem Cell Investig 2020; 7:10. [PMID: 32695803 DOI: 10.21037/sci-2020-003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2020] [Accepted: 06/09/2020] [Indexed: 12/13/2022]
Abstract
Knee osteoarthritis (KOA) is a degenerative joint disorder manifested with deformity, pain, and functional disability due to damage of the articular cartilage. Cell therapy with mesenchymal stem cells (MSCs) holds great promise to alleviate or even cure the degenerative diseases including KOA. However, the evidence of efficacy of human adipose tissue-derived MSCs (hAdMSCs) on KOA therapy remains limited. Here, we evaluate the therapeutic efficacy of hAdMSCs for KOA, using a medial meniscal transection (MMT) rat model. Our study demonstrated that intra-articular injection of 1.25×106 hAdMSCs significantly attenuated MMT-induced joint pain in a KOA rats model. The results of this study provide strong evidence that hAdMSCs-based therapy can be regarded as a prominent treatment option for patients with KOA.
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Affiliation(s)
- Zhifeng Wang
- Sinoneural Cell Engineering Group Co., Ltd., Shanghai, China.,Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Tongji University, Shanghai, China
| | - Hao Zhu
- Sinoneural Cell Engineering Group Co., Ltd., Shanghai, China
| | - Shuhang Dai
- Sinoneural Cell Engineering Group Co., Ltd., Shanghai, China
| | - Ke Liu
- Sinoneural Cell Engineering Group Co., Ltd., Shanghai, China
| | - Chenxi Ge
- Sinoneural Cell Engineering Group Co., Ltd., Shanghai, China
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Li L, Sima Y, Wang Y, Zhou J, Wang L, Chen Y. The cytotoxicity of advanced glycation end products was attenuated by UCMSCs in human vaginal wall fibroblasts by inhibition of an inflammatory response and activation of PI3K/AKT/PTEN. Biosci Trends 2020; 14:263-270. [PMID: 32493859 DOI: 10.5582/bst.2020.03125] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Pelvic organ prolapse (POP) occurs when the pelvic organs (bladder, bowel or uterus) herniate into the vagina, causing incontinence, voiding, and bowel and sexual dysfunction, negatively impacting upon a woman's quality of life. Intermediate intermolecular cross-links and advanced glycation cross-links increase in prolapsed tissue. Stem cells are able to participate in tissue repair due to their ability to differentiate into multiple lineages, and thus into various types of connective tissue cells, so they therefore hold great promise for treating pelvic floor dysfunction. The current study found that advanced glycation end products (AGEs) inhibited the viability and proliferation of human vaginal wall fibroblasts (VWFs), were cytotoxic to VWFs, and also induced the apoptosis of VWFs. In contrast, umbilical cord-derived mesenchymal stem cells (UCMSCs) secreted anti-inflammation cytokines to protect against the cytotoxic effects of fibroblasts induced by AGEs and attenuated the cytotoxic effect of AGE on fibroblasts by activation of the PI3K/Akt-PTEN pathway. This study demonstrated that UCMSCs inhibited the cytotoxic effect of AGE in cells from patients with POP by inducing an anti-inflammatory reaction and activating the PI3K/AKT/PTEN signaling pathway. The current results provide important insights into use of stem cells to treat POP.
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Affiliation(s)
- Lisha Li
- Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.,The Academy of Integrative Medicine of Fudan University, Shanghai, China.,Shanghai Key Laboratory of Female Reproductive Endocrine-related Diseases, Shanghai, China
| | - Yizhen Sima
- Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Yan Wang
- Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Jing Zhou
- Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.,The Academy of Integrative Medicine of Fudan University, Shanghai, China.,Shanghai Key Laboratory of Female Reproductive Endocrine-related Diseases, Shanghai, China
| | - Ling Wang
- Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.,The Academy of Integrative Medicine of Fudan University, Shanghai, China.,Shanghai Key Laboratory of Female Reproductive Endocrine-related Diseases, Shanghai, China
| | - Yisong Chen
- Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
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Gu X, Li Y, Chen K, Wang X, Wang Z, Lian H, Lin Y, Rong X, Chu M, Lin J, Guo X. Exosomes derived from umbilical cord mesenchymal stem cells alleviate viral myocarditis through activating AMPK/mTOR-mediated autophagy flux pathway. J Cell Mol Med 2020; 24:7515-7530. [PMID: 32424968 PMCID: PMC7339183 DOI: 10.1111/jcmm.15378] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 04/01/2020] [Accepted: 04/22/2020] [Indexed: 12/24/2022] Open
Abstract
Human umbilical cord mesenchymal stem cell‐derived exosomes (hucMSC‐exosomes) have been implicated as a novel therapeutic approach for tissue injury repair and regeneration, but the effects of hucMSC‐exosomes on coxsackievirus B3 (CVB3)‐induced myocarditis remain unknown. The object of the present study is to investigate whether hucMSC‐exosomes have therapeutic effects on CVB3‐induced myocarditis (VMC). HucMSC‐exosomes were identified using nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM) and Western blot. The purified hucMSC‐exosomes tagged with PKH26 were tail intravenously injected into VMC model mice in vivo and used to administrate CVB3‐infected human cardiomyocytes (HCMs) in vitro, respectively. The effects of hucMSC‐exosomes on myocardial pathology injury, proinflammatory cytokines and cardiac function were evaluated through haematoxylin and eosin (H&E) staining, quantitative polymerase chain reaction (qPCR) and Doppler echocardiography. The anti‐apoptosis role and potential mechanism of hucMSC‐exosomes were explored using TUNEL staining, flow cytometry, immunohistochemistry, Ad‐mRFP‐GFP‐LC3 transduction and Western blot. In vivo results showed that hucMSC‐exosomes (50 μg iv) significantly alleviated myocardium injury, shrank the production of proinflammatory cytokines and improved cardiac function. Moreover, in vitro data showed that hucMSC‐exosomes (50 μg/mL) inhibited the apoptosis of CVB3‐infected HCM through increasing pAMPK/AMPK ratio and up‐regulating autophagy proteins LC3II/I, BECLIN‐1 and anti‐apoptosis protein BCL‐2 as well as decreasing pmTOR/mTOR ratio, promoting the degradation of autophagy flux protein P62 and down‐regulating apoptosis protein BAX. In conclusion, hucMSC‐exosomes could alleviate CVB3‐induced myocarditis via activating AMPK/mTOR‐mediated autophagy flux pathway to attenuate cardiomyocyte apoptosis, which will be benefit for MSC‐exosome therapy of myocarditis in the future.
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Affiliation(s)
- Xiaohong Gu
- Institute of Cardiovascular Development and Translational Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yuechun Li
- Institute of Cardiovascular Development and Translational Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Kaixin Chen
- Institute of Cardiovascular Development and Translational Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xingang Wang
- Institute of Cardiovascular Development and Translational Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zhongyu Wang
- Institute of Cardiovascular Development and Translational Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Hao Lian
- Institute of Cardiovascular Development and Translational Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yuanzheng Lin
- Institute of Cardiovascular Development and Translational Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xing Rong
- Institute of Cardiovascular Development and Translational Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Maoping Chu
- Institute of Cardiovascular Development and Translational Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Center of Scientific Research, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jiafeng Lin
- Institute of Cardiovascular Development and Translational Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiaoling Guo
- Institute of Cardiovascular Development and Translational Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Center of Scientific Research, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
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35
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Identifying the Therapeutic Significance of Mesenchymal Stem Cells. Cells 2020; 9:cells9051145. [PMID: 32384763 PMCID: PMC7291143 DOI: 10.3390/cells9051145] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 05/04/2020] [Accepted: 05/05/2020] [Indexed: 12/12/2022] Open
Abstract
The pleiotropic behavior of mesenchymal stem cells (MSCs) has gained global attention due to their immense potential for immunosuppression and their therapeutic role in immune disorders. MSCs migrate towards inflamed microenvironments, produce anti-inflammatory cytokines and conceal themselves from the innate immune system. These signatures are the reason for the uprising in the sciences of cellular therapy in the last decades. Irrespective of their therapeutic role in immune disorders, some factors limit beneficial effects such as inconsistency of cell characteristics, erratic protocols, deviating dosages, and diverse transfusion patterns. Conclusive protocols for cell culture, differentiation, expansion, and cryopreservation of MSCs are of the utmost importance for a better understanding of MSCs in therapeutic applications. In this review, we address the immunomodulatory properties and immunosuppressive actions of MSCs. Also, we sum up the results of the enhancement, utilization, and therapeutic responses of MSCs in treating inflammatory diseases, metabolic disorders and diabetes.
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36
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Alatyyat SM, Alasmari HM, Aleid OA, Abdel-Maksoud MS, Elsherbiny N. Umbilical cord stem cells: Background, processing and applications. Tissue Cell 2020; 65:101351. [PMID: 32746993 DOI: 10.1016/j.tice.2020.101351] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 03/15/2020] [Accepted: 03/15/2020] [Indexed: 12/26/2022]
Abstract
Stem cells have currently gained attention in the field of medicine not only due to their ability to repair dysfunctional or damaged cells, but also they could be used as drug delivery system after being engineered to do so. Human umbilical cord is attractive source for autologous and allogenic stem cells that are currently amenable to treatment of various diseases. Human umbilical cord stem cells are -in contrast to embryonic and fetal stem cells- ethically noncontroversial, inexpensive and readily available source of cells. Umbilical cord, umbilical cord vein, amnion/placenta and Wharton's jelly are all rich of many types of multipotent stem cell populations capable of forming many different cell types. This review will focus on umbilical cord stem cells processing and current application in medicine.
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Affiliation(s)
- Shumukh M Alatyyat
- Pharm D Program, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia
| | - Houton M Alasmari
- Pharm D Program, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia
| | - Omamah A Aleid
- Pharm D Program, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia
| | - Mohamed S Abdel-Maksoud
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia
| | - Nehal Elsherbiny
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia; Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
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Zhang Y, Chen W, Feng B, Cao H. The Clinical Efficacy and Safety of Stem Cell Therapy for Diabetes Mellitus: A Systematic Review and Meta-Analysis. Aging Dis 2020; 11:141-153. [PMID: 32010488 PMCID: PMC6961772 DOI: 10.14336/ad.2019.0421] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 04/21/2019] [Indexed: 12/11/2022] Open
Abstract
Diabetes mellitus (DM) is a chronic metabolic disease with high morbidity and mortality. Recently, stem cell-based therapy for DM has shown considerable promise. Here, we undertook a systematic review and meta-analysis of published clinical studies to evaluate the efficacy and safety of stem cell therapy for both type 1 DM (T1DM) and type 2 DM (T2DM). The PubMed, Cochrane Central Register of Controlled Trials, EMBASE, and ClinicalTrials.gov databases were searched up to November 2018. We employed a fixed-effect model using 95% confidence intervals (CIs) when no statistically significant heterogeneity existed. Otherwise, a random-effects statistical model was used. Twenty-one studies met our inclusion criteria: ten T1DM studies including 226 patients and eleven T2DM studies including 386 patients. Stem cell therapy improved C-peptide levels (mean difference (MD), 0.41; 95% CI, 0.06 to 0.76) and glycosylated hemoglobin (HbA1c; MD, -3.46; 95% CI, -6.01 to -0.91) for T1DM patients. For T2DM patients, stem cell therapy improved C-peptide levels (MD, 0.33; 95% CI, 0.07 to 0.59), HbA1c (MD, -0.87; 95% CI, -1.37 to -0.37) and insulin requirements (MD, -35.76; 95% CI, -40.47 to -31.04). However, there was no significant change in fasting plasma glucose levels (MD, -0.52; 95% CI, -1.38 to 0.34). Subgroup analyses showed significant HbA1c and C-peptide improvements in patients with T1DM treated with bone marrow hematopoietic stem cells (BM-HSCs), while there was no significant change in the mesenchymal stem cell (MSC) group. In T2DM, HbA1c and insulin requirements decreased significantly after MSC transplantation, and insulin requirements and C-peptide levels were significantly improved after bone marrow mononuclear cell (BM-MNC) treatment. Stem cell therapy is a relatively safe and effective method for selected individuals with DM. The data showed that BM-HSCs are superior to MSCs in the treatment of T1DM. In T2DM, MSC and BM-MNC transplantation showed favorable therapeutic effects.
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Affiliation(s)
- Yazhen Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Wenyi Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Bing Feng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Hongcui Cao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
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Ma Z, Wang Y, Li H. Applications of extracellular vesicles in tissue regeneration. BIOMICROFLUIDICS 2020; 14:011501. [PMID: 32002105 PMCID: PMC6984977 DOI: 10.1063/1.5127077] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Accepted: 01/15/2020] [Indexed: 05/05/2023]
Abstract
Extracellular vesicles (EVs) can be classified into several types based on their different biosyntheses or release pathways, including exosomes, microvesicles, apoptotic bodies, and large oncosomes. As they contain DNAs, RNAs, proteins, and other bioactive signals, EVs have been utilized in the diagnosis field for a long time. Considering the fact that stem cells have been widely used for tissue regeneration and EVs possess similar biological properties to their source cells, tissue regeneration abilities of EVs have recently attracted much attention in the regenerative medicine field. In this paper, recent advances and challenges of EVs applied in the repair and regeneration of damaged tissues, such as skin, heart, liver, kidney, bone, and central nervous system, have been summarized. Specifically, critical bioactive molecules, which are encapsulated within EVs and play significant roles in the tissue regeneration, have been highlighted. Finally, the prospects and future development directions of the application of EVs in the field of tissue regeneration have been discussed.
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Affiliation(s)
| | | | - Haiyan Li
- Author to whom correspondence should be addressed:. Tel.: +86 18717902901
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Wang L, Huang S, Li S, Li M, Shi J, Bai W, Wang Q, Zheng L, Liu Y. Efficacy and Safety of Umbilical Cord Mesenchymal Stem Cell Therapy for Rheumatoid Arthritis Patients: A Prospective Phase I/II Study. Drug Des Devel Ther 2019; 13:4331-4340. [PMID: 31908418 PMCID: PMC6930836 DOI: 10.2147/dddt.s225613] [Citation(s) in RCA: 93] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Accepted: 12/02/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The traditional anti-inflammation disease-modifying anti-rheumatic drugs (DMARDs) have limited therapeutic effects in rheumatoid arthritis (RA) patients. We previously reported the safety and efficacy of umbilical cord mesenchymal stem cell (UC-MSC) treatment in RA patients that were observed for up to 8 months after UC-MSC infusion. The aim of this study is to assess the long-term efficacy and safety of UC-MSC along with DMARDs for the treatment of RA. METHODS 64 RA patients aged 18-64 years were recruited in the study. During the treatment, patients were treated with 40 mL UC-MSC suspension product (2 × 107 cells/20 mL) via intravenous injection immediately after the infusion of 100 mL saline. The serological markers tests were used to assess safety and the 28-joint disease activity score (DAS28) and the Health Assessment Questionnaire (HAQ) to assess efficacy. RESULTS 1 year and 3 years after UC-MSC cells treatment, the blood routine, liver and kidney function and immunoglobulin examination showed no abnormalities, which were all in the normal range. The ESR, CRP, RF of 1 year and 3 years after treatment and anti-CCP of 3 years after treatment were detected to be lower than that of pretreatment, which showed significant change (P < 0.05). Health index (HAQ) and joint function index (DAS28) decreased 1 year and 3 years after treatment than before treatment (P < 0.05). CONCLUSION UC-MSC cells plus DMARDs therapy can be a safe, effective and feasible therapeutic option for RA patients.
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Affiliation(s)
- Liming Wang
- Cell Therapy Center, 986 Hospital of People’s Liberation Army Air Force, Xi’an, Shaanxi, People’s Republic of China
| | - Shigao Huang
- Cancer Center, Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macao SAR, People’s Republic of China
| | - Shimei Li
- Cell Therapy Center, 986 Hospital of People’s Liberation Army Air Force, Xi’an, Shaanxi, People’s Republic of China
| | - Ming Li
- Cell Therapy Center, 986 Hospital of People’s Liberation Army Air Force, Xi’an, Shaanxi, People’s Republic of China
| | - Jun Shi
- Cell Therapy Center, 986 Hospital of People’s Liberation Army Air Force, Xi’an, Shaanxi, People’s Republic of China
| | - Wen Bai
- Cell Therapy Center, 986 Hospital of People’s Liberation Army Air Force, Xi’an, Shaanxi, People’s Republic of China
| | - Qianyun Wang
- Cell Therapy Center, 986 Hospital of People’s Liberation Army Air Force, Xi’an, Shaanxi, People’s Republic of China
| | - Libo Zheng
- Stem Cell Biology and Regenerative Medicine Institution, Yi-Chuang Institute of Bio-Industry, Beijing, People’s Republic of China
| | - Yongjun Liu
- Stem Cell Biology and Regenerative Medicine Institution, Yi-Chuang Institute of Bio-Industry, Beijing, People’s Republic of China
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Khiatah B, Qi M, Du W, T-Chen K, van Megen KM, Perez RG, Isenberg JS, Kandeel F, Roep BO, Ku HT, Al-Abdullah IH. Intra-pancreatic tissue-derived mesenchymal stromal cells: a promising therapeutic potential with anti-inflammatory and pro-angiogenic profiles. Stem Cell Res Ther 2019; 10:322. [PMID: 31730488 PMCID: PMC6858763 DOI: 10.1186/s13287-019-1435-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 09/26/2019] [Accepted: 09/30/2019] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Human pancreata contain many types of cells, such as endocrine islets, acinar, ductal, fat, and mesenchymal stromal cells (MSCs). MSCs are important and shown to have a promising therapeutic potential to treat various disease conditions. METHODS We investigated intra-pancreatic tissue-derived (IPTD) MSCs isolated from tissue fractions that are routinely discarded during pancreatic islet isolation of human cadaveric donors. Furthermore, whether pro-angiogenic and anti-inflammatory properties of these cells could be enhanced was investigated. RESULTS IPTD-MSCs were expanded in GMP-compatible CMRL-1066 medium supplemented with 5% human platelet lysate (hPL). IPTD-MSCs were found to be highly pure, with > 95% positive for CD90, CD105, and CD73, and negative for CD45, CD34, CD14, and HLA-DR. Immunofluorescence staining of pancreas tissue demonstrated the presence of CD105+ cells in the vicinity of islets. IPTD-MSCs were capable of differentiation into adipocytes, chondrocytes, and osteoblasts in vitro, underscoring their multipotent features. When these cells were cultured in the presence of a low dose of TNF-α, gene expression of tumor necrosis factor alpha-stimulated gene-6 (TSG-6) was significantly increased, compared to control. In contrast, treating cells with dimethyloxallyl glycine (DMOG) (a prolyl 4-hydroxylase inhibitor) enhanced mRNA levels of nuclear factor erythroid 2-related factor 2 (NRF2) and vascular endothelial growth factor (VEGF). Interestingly, a combination of TNF-α and DMOG stimulated the optimal expression of all three genes in IPTD-MSCs. Conditioned medium of IPTD-MSCs treated with a combination of DMOG and TNF-α contained higher levels of pro-angiogenic (VEGF, IL-6, and IL-8) compared to controls, promoting angiogenesis of human endothelial cells in vitro. In contrast, levels of MCP-1, a pro-inflammatory cytokine, were reduced in the conditioned medium of IPTD-MSCs treated with a combination of DMOG and TNF-α. CONCLUSIONS The results demonstrate that IPTD-MSCs reside within the pancreas and can be separated as part of a standard islet-isolation protocol. These IPTD-MSCs can be expanded and potentiated ex vivo to enhance their anti-inflammatory and pro-angiogenic profiles. The fact that IPTD-MSCs are generated in a GMP-compatible procedure implicates a direct clinical application.
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Affiliation(s)
- Bashar Khiatah
- Department of Translational Research and Cellular Therapeutics, Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010 USA
| | - Meirigeng Qi
- Department of Translational Research and Cellular Therapeutics, Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010 USA
| | - Weiting Du
- Department of Translational Research and Cellular Therapeutics, Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010 USA
| | - Kuan T-Chen
- Department of Translational Research and Cellular Therapeutics, Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010 USA
| | - Kayleigh M. van Megen
- Department of Diabetes Immunology, Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA USA
| | - Rachel G. Perez
- Department of Translational Research and Cellular Therapeutics, Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010 USA
| | - Jeffrey S. Isenberg
- Department of Translational Research and Cellular Therapeutics, Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010 USA
| | - Fouad Kandeel
- Department of Translational Research and Cellular Therapeutics, Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010 USA
| | - Bart O. Roep
- Department of Diabetes Immunology, Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA USA
| | - Hsun Teresa Ku
- Department of Translational Research and Cellular Therapeutics, Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010 USA
| | - Ismail H. Al-Abdullah
- Department of Translational Research and Cellular Therapeutics, Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010 USA
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Selich A, Zimmermann K, Tenspolde M, Dittrich-Breiholz O, von Kaisenberg C, Schambach A, Rothe M. Umbilical cord as a long-term source of activatable mesenchymal stromal cells for immunomodulation. Stem Cell Res Ther 2019; 10:285. [PMID: 31547865 PMCID: PMC6755709 DOI: 10.1186/s13287-019-1376-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 08/02/2019] [Accepted: 08/07/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Mesenchymal stromal cells (MSCs) are used in over 800 clinical trials mainly due to their immune inhibitory activity. Umbilical cord (UC), the second leading source of clinically used MSCs, is usually cut in small tissue pieces. Subsequent cultivation leads to a continuous outgrowth of MSC explant monolayers (MSC-EMs) for months. Currently, the first MSC-EM culture takes approximately 2 weeks to grow out, which is then expanded and applied to patients. The initiating tissue pieces are then discarded. However, when UC pieces are transferred to new culture dishes, MSC-EMs continue to grow out. In case the functional integrity of these cells is maintained, later induced cultures could also be expanded and used for cell therapy. This would drastically increase the number of available cells for each patient. To test the functionality of MSC-EMs from early and late induction time points, we compared the first cultures to those initiated after 2 months by investigating their clonality and immunomodulatory capacity. METHODS We analyzed the clonal composition of MSC-EM cultures by umbilical cord piece transduction using integrating lentiviral vectors harboring genetic barcodes assessed by high-throughput sequencing. We investigated the transcriptome of these cultures by microarrays. Finally, the secretome was analyzed by multiplexed ELISAs, in vitro assays, and in vivo in mice. RESULTS DNA barcode analysis showed polyclonal MSC-EMs even after months of induction cycles. A transcriptome and secretome analyses of early and late MSC cultures showed only minor changes over time. However, upon activation with TNF-α and IFN-γ, cells from both induction time points produced a multitude of immunomodulatory cytokines. Interestingly, the later induced MSC-EMs produced higher amounts of cytokines. To test whether the different cytokine levels were in a therapeutically relevant range, we used conditioned medium (CM) in an in vitro MLR and an in vivo killing assay. CM from late induced MSC-EMs was at least as immune inhibitory as CM from early induced MSC-EMs. CONCLUSION Human umbilical cord maintains a microenvironment for the long-term induction of polyclonal and immune inhibitory active MSCs for months. Thus, our results would offer the possibility to drastically increase the number of therapeutically applicable MSCs for a substantial amount of patients.
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Affiliation(s)
- Anton Selich
- Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany
| | - Katharina Zimmermann
- Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany
| | - Michel Tenspolde
- Department of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Hannover, Germany
| | | | | | - Axel Schambach
- Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.,REBIRTH Cluster of Excellence, Hannover Medical School, Hannover, Germany.,Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Michael Rothe
- Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany. .,REBIRTH Cluster of Excellence, Hannover Medical School, Hannover, Germany.
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Liau LL, Ruszymah BHI, Ng MH, Law JX. Characteristics and clinical applications of Wharton's jelly-derived mesenchymal stromal cells. Curr Res Transl Med 2019; 68:5-16. [PMID: 31543433 DOI: 10.1016/j.retram.2019.09.001] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Revised: 08/23/2019] [Accepted: 09/10/2019] [Indexed: 12/14/2022]
Abstract
Mesenchymal stromal cells (MSCs) are widely used in the clinic because they involve fewer ethical issues and safety concerns compared to other stem cells such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). MSCs derived from umbilical cord Wharton's jelly (WJ-MSCs) have excellent proliferative potential and a faster growth rate and can retain their multipotency for more passages in vitro compared to adult MSCs from bone marrow or adipose tissue. WJ-MSCs are used clinically for repairing tissue injuries of the spinal cord, liver and heart with the aim of regenerating tissue. On the other hand, WJ-MSCs are also used clinically to ameliorate immune-mediated diseases based on their ability to modulate immune responses. In the field of tissue engineering, WJ-MSCs capable of differentiating into multiple cell lineages have been used to produce a variety of engineered tissues in vitro that can then be transplanted in vivo. This review discusses the characteristics of WJ-MSCs, the differences between WJ-MSCs and adult MSCs, clinical studies involving WJ-MSCs and future perspectives of WJ-MSC research and clinical applications. To summarize, WJ-MSCs have shown promise in treating a variety of diseases clinically. However, most clinical trials/studies reported thus far are relatively smaller in scale. The collected evidence is insufficient to support the routine use of WJ-MSC therapy in the clinic. Thus, rigorous clinical trials are needed in the future to obtain more information on WJ-MSC therapy safety and efficacy.
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Affiliation(s)
- L L Liau
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, 56000 Kuala Lumpur, Malaysia
| | - B H I Ruszymah
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, 56000 Kuala Lumpur, Malaysia
| | - M H Ng
- Tissue Engineering Centre, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, 56000 Kuala Lumpur, Malaysia
| | - J X Law
- Tissue Engineering Centre, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, 56000 Kuala Lumpur, Malaysia.
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Qi Y, Ma J, Li S, Liu W. Applicability of adipose-derived mesenchymal stem cells in treatment of patients with type 2 diabetes. Stem Cell Res Ther 2019; 10:274. [PMID: 31455405 PMCID: PMC6712852 DOI: 10.1186/s13287-019-1362-2] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) is mainly characterized by insulin resistance (IR) and impaired insulin secretion. The chronic inflammatory process contributed to IR and could also hamper pancreatic β cell function. However, currently applied treatment cannot reverse β cell damage or alleviate inflammation. Mesenchymal stem cells (MSCs), the cell-based therapy for their self-renewable, differentiation potential, and immunosuppressive properties, have been demonstrated in displaying therapeutic effects in T2DM. Adipose-derived MSCs (AD-MSCs) attracted more attention due to less harvested inconvenience and ethical issues commonly accompany with bone marrow-derived MSCs (BM-MSCs) and fetal annex-derived MSCs. Both AD-MSC therapy studies and mechanism explorations in T2DM animals presented that AD-MSCs could translate to clinical application. However, hyperglycemia, hyperinsulinemia, and metabolic disturbance in T2DM are crucial for impairment of AD-MSC function, which may limit the therapeutical effects of MSCs. This review focuses on the outcomes and the molecular mechanisms of MSC therapies in T2DM which light up the hope of AD-MSCs as an innovative strategy to cure T2DM.
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Affiliation(s)
- Yicheng Qi
- Division of Endocrinology and Metabolism, Department of Internal Medicine, RenJi Hospital, School of Medicine, Shanghai Jiaotong University, 160# Pujian Road, Pudong, Shanghai, 200127, China
| | - Jing Ma
- Division of Endocrinology and Metabolism, Department of Internal Medicine, RenJi Hospital, School of Medicine, Shanghai Jiaotong University, 160# Pujian Road, Pudong, Shanghai, 200127, China
| | - Shengxian Li
- Division of Endocrinology and Metabolism, Department of Internal Medicine, RenJi Hospital, School of Medicine, Shanghai Jiaotong University, 160# Pujian Road, Pudong, Shanghai, 200127, China
| | - Wei Liu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, RenJi Hospital, School of Medicine, Shanghai Jiaotong University, 160# Pujian Road, Pudong, Shanghai, 200127, China.
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Karaöz E, Tepeköy F. Differentiation Potential and Tumorigenic Risk of Rat Bone Marrow Stem Cells Are Affected By Long-Term In Vitro Expansion. Turk J Haematol 2019; 36:255-265. [PMID: 31284704 PMCID: PMC6863016 DOI: 10.4274/tjh.galenos.2019.2019.0100] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Objective: Mesenchymal stem cells (MSCs) have the capacity for extensive expansion and adipogenic, osteogenic, chondrogenic, myogenic, and neural differentiation in vitro. The aim of our study was to determine stemness, differentiation potential, telomerase activity, and ultrastructural characteristics of long-term cultured rat bone marrow (rBM)-MSCs. Materials and Methods: rBM-MSCs from passages 3, 50, and 100 (P3, P50, and P100) were evaluated through immunocytochemistry, reverse transcription-polymerase chain reaction, telomerase activity assays, and electron microscopy. Results: A dramatic reduction in the levels of myogenic markers actin and myogenin was detected in P100. Osteogenic markers Coll1, osteonectin (Sparc), and osteocalcin as well as neural marker c-Fos and chondrogenic marker Coll2 were significantly reduced in P100 compared to P3 and P50. Osteogenic marker bone morphogenic protein-2 (BMP2) and adipogenic marker peroxisome proliferator-activated receptor gamma (Pparγ) expression was reduced in late passages. The expression of stemness factor Rex-1 was lower in P100, whereas Oct4 expression was decreased in P50 compared to P3 and P100. Increased telomerase activity was observed in long-term cultured cells, signifying tumorigenic risk. Electron microscopic evaluations revealed ultrastructural changes such as smaller number of organelles and increased amount of autophagic vacuoles in the cytoplasm in long-term cultured rBM-MSCs. Conclusion: This study suggests that long-term culture of rBM-MSCs leads to changes in differentiation potential and increased tumorigenic risk.
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Affiliation(s)
- Erdal Karaöz
- İstinye University Faculty of Medicine, Department of Histology and Embryology, İstanbul, Turkey,İstinye University Center for Stem Cell and Tissue Engineering Research and Practice, İstanbul, Turkey,Center for Regenerative Medicine and Stem Cell Research and Manufacturing (LivMedCell), İstanbul, Turkey
| | - Filiz Tepeköy
- İstinye University Faculty of Medicine, Department of Histology and Embryology, İstanbul, Turkey,Altınbaş University Faculty of Medicine, Department of Histology and Embryology, İstanbul, Turkey
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Sheykhhasan M. Towards Standardized Stem Cell Therapy in Type 2 Diabetes Mellitus: A Systematic Review. Curr Stem Cell Res Ther 2019; 14:75-76. [PMID: 30684321 DOI: 10.2174/1574888x1401181217125608] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Mohsen Sheykhhasan
- Department of Mesenchymal Stem Cell, the Academic Center for Education, Culture and Research, Qom, Iran
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Päth G, Perakakis N, Mantzoros CS, Seufert J. Stem cells in the treatment of diabetes mellitus - Focus on mesenchymal stem cells. Metabolism 2019; 90:1-15. [PMID: 30342065 DOI: 10.1016/j.metabol.2018.10.005] [Citation(s) in RCA: 89] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Revised: 09/25/2018] [Accepted: 10/14/2018] [Indexed: 12/14/2022]
Abstract
Diabetes mellitus type 1 and type 2 have become a global epidemic with dramatically increasing incidences. Poorly controlled diabetes is associated with severe life-threatening complications. Beside traditional treatment with insulin and oral anti-diabetic drugs, clinicians try to improve patient's care by cell therapies using embryonic stem cells (ESC), induced pluripotent stem cells (iPSC) and adult mesenchymal stem cells (MSC). ESC display a virtually unlimited plasticity, including the differentiation into insulin producing β-cells, but they raise ethical concerns and bear, like iPSC, the risk of tumours. IPSC may further inherit somatic mutations and remaining somatic transcriptional memory upon incomplete re-programming, but allow the generation of patient/disease-specific cell lines. MSC avoid such issues but have not been successfully differentiated into β-cells. Instead, MSC and their pericyte phenotypes outside the bone marrow have been recognized to secrete numerous immunomodulatory and tissue regenerative factors. On this account, the term 'medicinal signaling cells' has been proposed to define the new conception of a 'drug store' for injured tissues and to stay with the MSC nomenclature. This review presents the biological background and the resulting clinical potential and limitations of ESC, iPSC and MSC, and summarizes the current status quo of cell therapeutic concepts and trials.
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Affiliation(s)
- Günter Päth
- Division of Endocrinology and Diabetology, Department of Medicine II, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.
| | - Nikolaos Perakakis
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Christos S Mantzoros
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Jochen Seufert
- Division of Endocrinology and Diabetology, Department of Medicine II, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany
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Gharravi AM, Jafar A, Ebrahimi M, Mahmodi A, Pourhashemi E, Haseli N, Talaie N, Hajiasgarli P. Current status of stem cell therapy, scaffolds for the treatment of diabetes mellitus. Diabetes Metab Syndr 2018; 12:1133-1139. [PMID: 30168429 DOI: 10.1016/j.dsx.2018.06.021] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 06/25/2018] [Indexed: 12/24/2022]
Abstract
Diabetes mellitus (DM) remains the 7th leading cause of death in the world. Daily insulin injection is one component of a treatment plan for people with Diabetes mellitus type 1 (T1DM) that restores normal or near-normal blood sugar levels. However, Insulin treatment depends upon a variety of individual factors and leads to poor and drastic glycemic control. The need for an effective cell replacement strategy will be the aim of future clinical trials. Therefore, the aim of this systematic review is to outline the latest advances in scaffolding and stem cell therapy as a non-pharmacologic treatment for T1DM. It also emphasizes on some pancreas differentiation protocols and the clinical trials associated with stem cell therapy regarding T1DM in vitro and in vivo.
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Affiliation(s)
- Anneh Mohammad Gharravi
- Stem Cells and Tissue Engineering Research Center, Shahroud University of Medical Sciences, Shahroud, Iran.
| | - Alireza Jafar
- Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Mehrdad Ebrahimi
- Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Ahmad Mahmodi
- Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Erfan Pourhashemi
- Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Nasrin Haseli
- Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Niloofar Talaie
- Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Parinaz Hajiasgarli
- Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
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Sun Y, Shi H, Yin S, Ji C, Zhang X, Zhang B, Wu P, Shi Y, Mao F, Yan Y, Xu W, Qian H. Human Mesenchymal Stem Cell Derived Exosomes Alleviate Type 2 Diabetes Mellitus by Reversing Peripheral Insulin Resistance and Relieving β-Cell Destruction. ACS NANO 2018; 12:7613-7628. [PMID: 30052036 DOI: 10.1021/acsnano.7b07643] [Citation(s) in RCA: 312] [Impact Index Per Article: 44.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/15/2023]
Abstract
Exosomes are nanosized extracellular vesicles (EVs) that show great promise in tissue regeneration and injury repair as mesenchymal stem cell (MSC). MSC has been shown to alleviate diabetes mellitus (DM) in both animal models and clinical trials. In this study, we aimed to investigate whether exosomes from human umbilical cord MSC (hucMSC-ex) have a therapeutic effect on type 2 DM (T2DM). We established a rat model of T2DM using a high-fat diet and streptozotocin (STZ). We found that the intravenous injection of hucMSC-ex reduced blood glucose levels as a main paracrine approach of MSC. HucMSC-ex partially reversed insulin resistance in T2DM indirectly to accelerate glucose metabolism. HucMSC-ex restored the phosphorylation (tyrosine site) of the insulin receptor substrate 1 and protein kinase B in T2DM, promoted expression and membrane translocation of glucose transporter 4 in muscle, and increased storage of glycogen in the liver to maintain glucose homeostasis. HucMSC-ex inhibited STZ-induced β-cell apoptosis to restore the insulin-secreting function of T2DM. Taken together, exosomes from hucMSC can alleviate T2DM by reversing peripheral insulin resistance and relieving β-cell destruction, providing an alternative approach for T2DM treatment.
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Affiliation(s)
- Yaoxiang Sun
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine , Jiangsu University , Zhenjiang , Jiangsu 212013 , China
- Department of Clinical Laboratory , The Affiliated Yixing Hospital of Jiangsu University , Yixing , Jiangsu 214200 , China
| | - Hui Shi
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine , Jiangsu University , Zhenjiang , Jiangsu 212013 , China
| | - Siqi Yin
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine , Jiangsu University , Zhenjiang , Jiangsu 212013 , China
| | - Cheng Ji
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine , Jiangsu University , Zhenjiang , Jiangsu 212013 , China
| | - Xu Zhang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine , Jiangsu University , Zhenjiang , Jiangsu 212013 , China
| | - Bin Zhang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine , Jiangsu University , Zhenjiang , Jiangsu 212013 , China
| | - Peipei Wu
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine , Jiangsu University , Zhenjiang , Jiangsu 212013 , China
| | - Yinghong Shi
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine , Jiangsu University , Zhenjiang , Jiangsu 212013 , China
| | - Fei Mao
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine , Jiangsu University , Zhenjiang , Jiangsu 212013 , China
| | - Yongmin Yan
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine , Jiangsu University , Zhenjiang , Jiangsu 212013 , China
| | - Wenrong Xu
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine , Jiangsu University , Zhenjiang , Jiangsu 212013 , China
| | - Hui Qian
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine , Jiangsu University , Zhenjiang , Jiangsu 212013 , China
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Wang M, Song L, Strange C, Dong X, Wang H. Therapeutic Effects of Adipose Stem Cells from Diabetic Mice for the Treatment of Type 2 Diabetes. Mol Ther 2018; 26:1921-1930. [PMID: 30005867 DOI: 10.1016/j.ymthe.2018.06.013] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Revised: 05/30/2018] [Accepted: 06/12/2018] [Indexed: 02/07/2023] Open
Abstract
To assess the potential therapeutic effects of adipose tissue-derived mesenchymal stem cells (ASCs) for the treatment of type 2 diabetes (T2D), we compared the phenotype and functionality of ASCs isolated from high-fat diet and streptozotocin (STZ)-induced T2D and the leptin receptor-deficient (db/db) mice with cells from healthy C57BL/6 mice. ASCs from T2D or db/db mice showed similar expression patterns of cellular markers and abilities to differentiate into adipocytes, osteoblasts, and chondrocytes. However, the rate of proliferation was reduced. ASCs from db/db mice secreted less hepatocyte growth factor (HGF). T2D mice receiving a single intravenous injection of T2D or db/db ASCs showed increased insulin sensitivity, reduced inflammation and fat content in adipose tissue and the liver and increased pancreatic β cell mass through 5 weeks post-infusion. Our data show that, although ASCs from T2D or db/db mice had inferior proliferative capacity compared to cells from healthy controls, improved insulin sensitivity and less β cell death was seen in T2D mice receiving mesenchymal stem cell (MSC) therapy. This study offers evidence that ASCs from diabetic donors have the potential to be used for cell therapy in the treatment of insulin resistance and T2D.
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Affiliation(s)
- Mengmeng Wang
- College of Life Science, Qingdao Agricultural University, Qingdao, Shandong 266109, China
| | - Lili Song
- China Agricultural University, Beijng 100094, China
| | - Charlie Strange
- Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Xiao Dong
- College of Life Science, Qingdao Agricultural University, Qingdao, Shandong 266109, China.
| | - Hongjun Wang
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA.
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Zhu H, Zhang X, He Y, Yu L, Lü Y, Pan K, Wang B, Chen G. [Research progress on the donor cell sources of pancreatic islet transplantation for treatment of diabetes mellitus]. ZHONGGUO XIU FU CHONG JIAN WAI KE ZA ZHI = ZHONGGUO XIUFU CHONGJIAN WAIKE ZAZHI = CHINESE JOURNAL OF REPARATIVE AND RECONSTRUCTIVE SURGERY 2018; 32:104-111. [PMID: 29806374 PMCID: PMC8414200 DOI: 10.7507/1002-1892.201707049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Revised: 12/13/2017] [Indexed: 11/03/2022]
Abstract
Objective To summarize the research progress on the source and selection of donor cells in the field of islet replacement therapy for diabetes mellitus. Methods Domestic and abroad literature concerning islet replacement therapy for diabetes mellitus, as well as donor source and donor selection was reviewed and analyzed thoroughly. Results The shortage of donor supply is still a major obstacle for the widely clinical application of pancreatic islet transplantation (PIT). Currently, in addition to the progress on the allogeneic/autologous donor islet supply, some remarkable achievements have been also attained in the application of xenogeneic islet (from pig donor), as well as islet like cells derived from stem cells and islet cell line, potentially enlarging the source of implantable cells. Conclusion Adequate and suitable donor cell supply is an essential prerequisite for widely clinical application of PIT therapy for type 1 diabetes mellitus (T1DM). Further perfection of organ donation system, together with development of immune-tolerance induction, gene and bioengineering technology etc. will possibly solve the problem of donor cell shortage and provide a basis for clinical application of cellular replacement therapy for T1DM.
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Affiliation(s)
- Haitao Zhu
- Department of Pediatrics (No. 3 Ward), Northwest Women's and Children's Hospital, Xi'an Shaanxi, 710061, P.R.China;Department of Hepatobiliary Surgery, the First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an Shaanxi, 710061, P.R.China
| | - Xiaoge Zhang
- Department of Pediatrics (No. 3 Ward), Northwest Women's and Children's Hospital, Xi'an Shaanxi, 710061, P.R.China
| | - Yayi He
- Department of Endocrinology, the First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an Shaanxi, 710061, P.R.China
| | - Liang Yu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an Shaanxi, 710061, P.R.China
| | - Yi Lü
- Department of Hepatobiliary Surgery, the First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an Shaanxi, 710061, P.R.China;Research Institute of Advanced Surgical Technology and Engineering, Xi'an Jiaotong University, Xi'an Shaanxi, 710061, P.R.China
| | - Kaili Pan
- Department of Pediatrics (No. 2 Ward), Northwest Women's and Children's Hospital, Xi'an Shaanxi, 710061, P.R.China
| | - Bo Wang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an Shaanxi, 710061, P.R.China;Department of Endocrinology, the First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an Shaanxi, 710061,
| | - Guoqiang Chen
- Department of Pediatrics (No. 3 Ward), Northwest Women's and Children's Hospital, Xi'an Shaanxi, 710061,
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