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Syngeneic Mesenchymal Stem Cells Reduce Immune Rejection After Induced Pluripotent Stem Cell-Derived Allogeneic Cardiomyocyte Transplantation.

ABSTRACT: Avoiding immune rejection after allogeneic induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) transplantation is a concern. However, mesenchymal stem cells (MSCs) can suppress immune rejection. To determine whether MSC co-transplantation can reduce immune rejection after allogeneic iPSC-CM transplantation, the latter cell type, harbouring a luciferase transgene, was subcutaneously transplanted alone or together with syngeneic MSCs into BALB/c mice. Bioluminescence imaging revealed that MSC co-transplantation significantly improved graft survival (day 7: iPSC-CMs alone 34?±?5%; iPSC-CMs with MSCs, 61?±?7%; P?=?0.008). MSC co-transplantation increased CD4?+?CD25?+?FOXP3?+?regulatory T cell numbers, apoptotic CD8-positive T cells, and IL-10 and TGF-beta expression at the implantation site. Analysis using a regulatory T cell depletion model indicated that enhanced regulatory T cell populations in the iPSC-CM with MSC group partially contributed to the extended iPSC-CM survival. Further, MSCs affected activated lymphocytes directly through cell-cell contact, which reduced the CD8/CD4 ratio, the proportion of Th1-positive cells among CD4-positive cells, and the secretion of several inflammation-related cytokines. Syngeneic MSC co-transplantation might thus control allogeneic iPSC-CM rejection by mediating immune tolerance via regulatory T cells and cell-cell contact with activated lymphocytes; this approach has promise for cardiomyogenesis-based therapy using allogeneic iPSC-CMs for severe heart failure.

SUBMITTER: Yoshida S

PROVIDER: S-EPMC7067786 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Syngeneic Mesenchymal Stem Cells Reduce Immune Rejection After Induced Pluripotent Stem Cell-Derived Allogeneic Cardiomyocyte Transplantation.

Yoshida Shohei S Miyagawa Shigeru S Toyofuku Toshihiko T Fukushima Satsuki S Kawamura Takuji T Kawamura Ai A Kashiyama Noriyuki N Nakamura Yuki Y Toda Koichi K Sawa Yoshiki Y

Scientific reports 20200312 1

Avoiding immune rejection after allogeneic induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) transplantation is a concern. However, mesenchymal stem cells (MSCs) can suppress immune rejection. To determine whether MSC co-transplantation can reduce immune rejection after allogeneic iPSC-CM transplantation, the latter cell type, harbouring a luciferase transgene, was subcutaneously transplanted alone or together with syngeneic MSCs into BALB/c mice. Bioluminescence imaging revealed tha ...[more]

PMID: 32165680

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Project description:Cell loss after transplantation is a major limitation for cell replacement approaches in regenerative medicine. To assess the survival kinetics of induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CM) we generated transgenic murine iPSC lines which, in addition to CM-specific expression of puromycin N-acetyl-transferase and enhanced green fluorescent protein (EGFP), also constitutively express firefly luciferase (FLuc) for bioluminescence (BL) in vivo imaging. While undifferentiated iPSC lines generated by random integration of the transgene into the genome retained stable FLuc activity over many passages, the BL signal intensity was strongly decreased in purified iPS-CM compared to undifferentiated iPSC. Targeted integration of FLuc-expression cassette into the ROSA26 genomic locus using zinc finger nuclease (ZFN) technology strongly reduced transgene silencing in iPS-CM, leading to a several-fold higher BL compared to iPS-CM expressing FLuc from random genomic loci. To investigate the survival kinetics of iPS-CM in vivo, purified CM obtained from iPSC lines expressing FLuc from a random or the ROSA26 locus were transplanted into cryoinfarcted hearts of syngeneic mice. Engraftment of viable cells was monitored by BL imaging over 4 weeks. Transplanted iPS-CM were poorly retained in the myocardium independently of the cell line used. However, up to 8% of cells survived for 28 days at the site of injection, which was confirmed by immunohistological detection of EGFP-positive iPS-CM in the host tissue. Transplantation of iPS-CM did not affect the scar formation or capillary density in the periinfarct region of host myocardium. This report is the first to determine the survival kinetics of drug-selected iPS-CM in the infarcted heart using BL imaging and demonstrates that transgene silencing in the course of iPSC differentiation can be greatly reduced by employing genome editing technology. FLuc-expressing iPS-CM generated in this study will enable further studies to reduce their loss, increase long-term survival and functional integration upon transplantation.

Project description:Erectile dysfunction (ED) is an important kind of postoperative complication of pelvic surgery that affects patients' quality of life. Transplantation of mesenchymal stem cells (MSC) has been found to alleviate ED caused by cavernous nerve injury (CNI) in rats. However, little is known about whether induced pluripotent stem cell-derived mesenchymal stem cells (iMSC) have a therapeutic effect on CNI ED. We established an ED model on rats and evaluated the effect of iMSC on it. Methods: Eight-week-old male Sprague-Dawley rats were assigned to four groups and received following operation: sham operation (sham group); bilateral CNI and phosphate-buffered saline (PBS) injections (PBS group); bilateral CNI and adipose-derived mesenchymal stem cells transplantation (adMSC group); or bilateral CNI and iMSC injection (iMSC group). After therapy, the cavernous nerve was stimulated by electricity and the intracavernous pressure (IAP)/mean arterial blood pressure (MAP) was measured. The endothelial and smooth muscle tissue in the penis was assessed histologically with Masson's trichrome stain. Immunofluorescence/immunohistochemical stains were applied for the detection of nNOS, vWF, eNOS, SMA, Desmin, S100?, and caspase-3. Nude rats CNI ED model was established for the evaluation of iMSC longevity and differentiation capacity. The paracrine factors were assessed by real-time PCR. Results: Transplantation of iMSC significantly restored the IAP/MAP in this CNI ED model and showed long-term effects. It could rescue the expression of vWF, eNOS, SMA, and Desmin, which indicated the alleviation of endothelial and smooth muscle tissues of the penis. iMSC therapy also could increase the expression of nNOS in the cavernosum and S100? in the major pelvic ganglia (MPG) which contributed to the erectile function. Moreover, the level of BAX and caspase-3 were reduced and Bcl-2 was increased, which indicated the anti-apoptosis effects of iMSC. The iMSC showed little transdifferentiation and exerted their function by activating the secretome of the host. Conclusion: Transplantation of iMSC significantly improved ED induced by CNI. The iMSC may exert their effects via paracrine factors and may be a promising therapeutic candidate for treating CNI ED in the future.

Dataset Information

Syngeneic Mesenchymal Stem Cells Reduce Immune Rejection After Induced Pluripotent Stem Cell-Derived Allogeneic Cardiomyocyte Transplantation.

Publications

Syngeneic Mesenchymal Stem Cells Reduce Immune Rejection After Induced Pluripotent Stem Cell-Derived Allogeneic Cardiomyocyte Transplantation.

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