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Laundos TL, Vasques-Nóvoa F, Gomes RN, Sampaio-Pinto V, Cruz P, Cruz H, Santos JM, Barcia RN, Pinto-do-Ó P, Nascimento DS. Consistent Long-Term Therapeutic Efficacy of Human Umbilical Cord Matrix-Derived Mesenchymal Stromal Cells After Myocardial Infarction Despite Individual Differences and Transient Engraftment. Front Cell Dev Biol 2021; 9:624601. [PMID: 33614654 PMCID: PMC7890004 DOI: 10.3389/fcell.2021.624601] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Accepted: 01/11/2021] [Indexed: 11/24/2022] Open
Abstract
Human mesenchymal stem cells gather special interest as a universal and feasible add-on therapy for myocardial infarction (MI). In particular, human umbilical cord matrix-derived mesenchymal stromal cells (UCM-MSC) are advantageous since can be easily obtained and display high expansion potential. Using isolation protocols compliant with cell therapy, we previously showed UCM-MSC preserved cardiac function and attenuated remodeling 2 weeks after MI. In this study, UCM-MSC from two umbilical cords, UC-A and UC-B, were transplanted in a murine MI model to investigate consistency and durability of the therapeutic benefits. Both cellular products improved cardiac function and limited adverse cardiac remodeling 12 weeks post-ischemic injury, supporting sustained and long-term beneficial therapeutic effect. Donor associated variability was found in the modulation of cardiac remodeling and activation of the Akt-mTOR-GSK3β survival pathway. In vitro, the two cell products displayed similar ability to induce the formation of vessel-like structures and comparable transcriptome in normoxia and hypoxia, apart from UCM-MSCs proliferation and expression differences in a small subset of genes associated with MHC Class I. These findings support that UCM-MSC are strong candidates to assist the treatment of MI whilst calling for the discussion on methodologies to characterize and select best performing UCM-MSC before clinical application.
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Affiliation(s)
- Tiago L. Laundos
- Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal
- Instituto Nacional de Engenharia Biomédica (INEB), University of Porto, Porto, Portugal
- Instituto de Ciências Biomédicas Abel Salazar (ICBAS), University of Porto, Porto, Portugal
| | - Francisco Vasques-Nóvoa
- Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal
- Instituto Nacional de Engenharia Biomédica (INEB), University of Porto, Porto, Portugal
- Cardiovascular RandD Center, Faculty of Medicine of the University of Porto, Porto, Portugal
- Department of Internal Medicine, Centro Hospitalar Universitário São João, Porto, Portugal
| | - Rita N. Gomes
- Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal
- Instituto Nacional de Engenharia Biomédica (INEB), University of Porto, Porto, Portugal
- Instituto de Ciências Biomédicas Abel Salazar (ICBAS), University of Porto, Porto, Portugal
| | - Vasco Sampaio-Pinto
- Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal
- Instituto Nacional de Engenharia Biomédica (INEB), University of Porto, Porto, Portugal
- Instituto de Ciências Biomédicas Abel Salazar (ICBAS), University of Porto, Porto, Portugal
| | | | | | | | | | - Perpétua Pinto-do-Ó
- Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal
- Instituto Nacional de Engenharia Biomédica (INEB), University of Porto, Porto, Portugal
- Instituto de Ciências Biomédicas Abel Salazar (ICBAS), University of Porto, Porto, Portugal
| | - Diana S. Nascimento
- Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal
- Instituto Nacional de Engenharia Biomédica (INEB), University of Porto, Porto, Portugal
- Instituto de Ciências Biomédicas Abel Salazar (ICBAS), University of Porto, Porto, Portugal
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Hsiao CY, Chen TH, Huang BS, Chen PH, Su CH, Shyu JF, Tsai PJ. Comparison between the therapeutic effects of differentiated and undifferentiated Wharton's jelly mesenchymal stem cells in rats with streptozotocin-induced diabetes. World J Stem Cells 2020; 12:139-151. [PMID: 32184938 PMCID: PMC7062039 DOI: 10.4252/wjsc.v12.i2.139] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 12/27/2019] [Accepted: 01/06/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Despite the availability of current therapies, including oral antidiabetic drugs and insulin, for controlling the symptoms caused by high blood glucose, it is difficult to cure diabetes mellitus, especially type 1 diabetes mellitus.
AIM Cell therapies using mesenchymal stem cells (MSCs) may be a promising option. However, the therapeutic mechanisms by which MSCs exert their effects, such as whether they can differentiate into insulin-producing cells (IPCs) before transplantation, are uncertain.
METHODS In this study, we used three types of differentiation media over 10 d to generate IPCs from human Wharton’s jelly MSCs (hWJ-MSCs). We further transplanted the undifferentiated hWJ-MSCs and differentiated IPCs derived from them into the portal vein of rats with streptozotocin-induced diabetes, and recorded the physiological and pathological changes.
RESULTS Using fluorescent staining and C-peptide enzyme-linked immunoassay, we were able to successfully induce the differentiation of hWJ-MSCs into IPCs. Transplantation of both IPCs derived from hWJ-MSCs and undifferentiated hWJ-MSCs had the therapeutic effect of ameliorating blood glucose levels and improving intraperitoneal glucose tolerance tests. The transplanted IPCs homed to the pancreas and functionally survived for at least 8 wk after transplantation, whereas the undifferentiated hWJ-MSCs were able to improve the insulitis and ameliorate the serum inflammatory cytokine in streptozotocin-induced diabetic rats.
CONCLUSION Differentiated IPCs can significantly improve blood glucose levels in diabetic rats due to the continuous secretion of insulin by transplanted cells that survive in the islets of diabetic rats. Transplantation of undifferentiated hWJ-MSCs can significantly improve insulitis and re-balance the inflammatory condition in diabetic rats with only a slight improvement in blood glucose levels.
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Affiliation(s)
- Chen-Yuan Hsiao
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114, Taiwan
- Department of Surgery, Landseed International Hospital, Taoyuan 324, Taiwan
| | - Tien-Hua Chen
- Institute of Anatomy and Cell Biology, School of Medicine, National Yang Ming University, Taipei 112, Taiwan
- Trauma Center, Department of Surgery, Veterans General Hospital, Taipei 112, Taiwan
- Division of General Surgery, Department of Surgery, Veterans General Hospital, Taipei 112, Taiwan
| | - Ben-Shian Huang
- Department of Obstetrics and Gynecology, Veterans General Hospital, Taipei 112, Taiwan
| | - Po-Han Chen
- Institute of Anatomy and Cell Biology, School of Medicine, National Yang Ming University, Taipei 112, Taiwan
| | - Cheng-Hsi Su
- Department of Surgery, Cheng Hsin General Hospital, Taipei 112, Taiwan
| | - Jia-Fwu Shyu
- Department of Biology and Anatomy, National Defense Medical Center, Taipei 114, Taiwan
| | - Pei-Jiun Tsai
- Institute of Anatomy and Cell Biology, School of Medicine, National Yang Ming University, Taipei 112, Taiwan
- Trauma Center, Department of Surgery, Veterans General Hospital, Taipei 112, Taiwan
- Department of Critical Care Medicine, Veterans General Hospital, Taipei 112, Taiwan
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