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Circulating exosomes derived from transplanted progenitor cells aid the functional recovery of ischemic myocardium.

ABSTRACT: The stem cell field is hindered by its inability to noninvasively monitor transplanted cells within the target organ in a repeatable, time-sensitive, and condition-specific manner. We hypothesized that quantifying and characterizing transplanted cell-derived exosomes in the recipient plasma would enable reliable, noninvasive surveillance of the conditional activity of the transplanted cells. To test this hypothesis, we used a human-into-rat xenogeneic myocardial infarction model comparing two well-studied progenitor cell types: cardiosphere-derived cells (CDCs) and c-kit+ cardiac progenitor cells (CPCs), both derived from the right atrial appendage of adults undergoing cardiopulmonary bypass. CPCs outperformed the CDCs in cell-based and in vivo regenerative assays. To noninvasively monitor the activity of transplanted CDCs or CPCs in vivo, we purified progenitor cell-specific exosomes from recipient total plasma exosomes. Seven days after transplantation, the concentration of plasma CPC-specific exosomes increased about twofold compared to CDC-specific exosomes. Computational pathway analysis failed to link CPC or CDC cellular messenger RNA (mRNA) with observed myocardial recovery, although recovery was linked to the microRNA (miRNA) cargo of CPC exosomes purified from recipient plasma. We further identified mechanistic pathways governing specific outcomes related to myocardial recovery associated with transplanted CPCs. Collectively, these findings demonstrate the potential of circulating progenitor cell-specific exosomes as a liquid biopsy that provides a noninvasive window into the conditional state of the transplanted cells. These data implicate the surveillance potential of cell-specific exosomes for allogeneic cell therapies.

SUBMITTER: Saha P

PROVIDER: S-EPMC6857931 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Project description:RationaleEndothelial progenitor cell (EPC) survival and function in the injured myocardium is adversely influenced by hostile microenvironment such as ischemia, hypoxia, and inflammatory response, thereby compromising full benefits of EPC-mediated myocardial repair.ObjectiveWe hypothesized that interleukin-10 (IL-10) modulates EPC biology leading to enhanced survival and function after transplantation in the ischemic myocardium.Methods and resultsMyocardial infarction (MI)-induced mobilization of bone marrow EPC (Sca-1+Flk1+cells) into the circulation was significantly impaired in IL-10 knockout (KO) mice. Bone marrow transplantation to replace IL-10 KO marrow with wild-type (WT) marrow attenuated these effects. Impaired mobilization was associated with lower stromal cell-derived factor (SDF)-1 expression levels in the myocardium of KO mice. Interestingly, SDF-1 administration reversed mobilization defect in KO mice. In vitro, hypoxia-mediated increases in CXCR4 expression and cell survival were lower in IL-10-deficient EPCs. Furthermore, SDF-1-induced migration of WT EPCs was inhibited by AMD3100, an inhibitor of CXCR4. To further study the effect of IL-10 on in vivo EPC survival and engraftment into vascular structures, GFP-labeled EPC were injected intramyocardially after induction of MI, and the mice were treated with either saline or recombinant IL-10. The IL-10-treated group showed increased retention of transplanted EPCs in the myocardium and was associated with significantly reduced EPC apoptosis after MI. Interestingly, increased EPC retention and their association with the vascular structures was observed in IL-10-treated mice. Increased EPC survival and angiogenesis in the myocardium of IL-10-treated mice corroborated with improved left ventricular function, reduced infarct size, and fibrosis in the myocardium. In vitro, IL-10-induced increase in VEGF expression in WT EPC was abrogated by STAT3 inhibitor, suggesting IL-10 signals through STAT3 activation.ConclusionsTaken together, our studies demonstrate that MI-induced EPC mobilization was impaired in IL-10 KO mice and that IL-10 increases EPC survival and function possibly through activation of STAT3/VEGF signaling cascades, leading to attenuation of MI-induced left ventricular dysfunction and remodeling.

Project description:BackgroundIschemic stroke in white matter of the brain induces not only demyelination, but also neuroinflammation. Peripheral T lymphocytes, especially regulatory T cells (Tregs), are known to infiltrate into ischemic brain and play a crucial role in modulation of inflammatory response there. We previously reported that transplantation of vascular endothelial cells generated from human induced pluripotent stem cells (iVECs) ameliorated white matter infarct. The aim of this study is to investigate contribution of the immune system, especially Tregs, to the mechanism whereby iVEC transplantation ameliorates white matter infarct.MethodsiVECs and human Tregs were transplanted into the site of white matter lesion seven days after induction of ischemia. The egress of T lymphocytes from lymph nodes was sequestered by treating the animals with fingolimod (FTY720). The infarct size was evaluated by magnetic resonance imaging. Immunohistochemistry was performed to detect the activated microglia and macrophages, T cells, Tregs, and oligodendrocyte lineage cells. Remyelination was examined by Luxol fast blue staining.ResultsiVEC transplantation reduced ED-1+ inflammatory cells and CD4+ T cells, while increased Tregs in the white matter infarct. Treatment of the animals with FTY720 suppressed neuroinflammation and reduced the number of both CD4+ T cells and Tregs in the lesion, suggesting the importance of infiltration of these peripheral immune cells into the lesion in aggravation of neuroinflammation. Suppression of neuroinflammation by FTY720 per se, however, did not promote remyelination in the infarct. FTY720 treatment negated the increase in the number of Tregs by iVEC transplantation in the infarct, and attenuated remyelination promoted by transplanted iVECs, while it did not affect the number of oligodendrocyte lineage cells increased by iVEC transplantation. Transplantation of Tregs together with iVECs into FTY720-treated ischemic white matter did not affect the number of oligodendrocyte lineage cells, while it remarkably promoted myelin regeneration.ConclusionsiVEC transplantation suppresses neuroinflammation, but suppression of neuroinflammation per se does not promote remyelination. Recruitment of Tregs by transplanted iVECs contributes significantly to promotion of remyelination in the injured white matter.

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Circulating exosomes derived from transplanted progenitor cells aid the functional recovery of ischemic myocardium.

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