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Transplantation of Isl1+ cardiac progenitor cells in small intestinal submucosa improves infarcted heart function.

ABSTRACT: BACKGROUND:Application of cardiac stem cells combined with biomaterial scaffold is a promising therapeutic strategy for heart repair after myocardial infarction. However, the optimal cell types and biomaterials remain elusive. METHODS:In this study, we seeded Isl1+ embryonic cardiac progenitor cells (CPCs) into decellularized porcine small intestinal submucosa extracellular matrix (SIS-ECM) to assess the therapeutic potential of Isl1+ CPCs and the biocompatibility of SIS-ECM with these cells. RESULTS:We observed that SIS-ECM supported the viability and attachment of Isl1+ CPCs. Importantly, Isl1+ CPCs differentiated into cardiomyocytes and endothelial cells 7 days after seeding into SIS-ECM. In addition, SIS-ECM with CPC-derived cardiomyocytes showed spontaneous contraction and responded to ?-adrenergic stimulation. Next, patches of SIS-ECM seeded with CPCs for 7 days were transplanted onto the outer surface of infarcted myocardium in mice. Four weeks after transplantation, the patches were tightly attached to the surface of the host myocardium and remained viable. Transplantation of patches improved cardiac function, decreased the left ventricular myocardial scarring area, and reduced fibrosis and heart failure. CONCLUSIONS:Transplantation of Isl1+ CPCs seeded in SIS-ECM represents an effective approach for cell-based heart therapy.

SUBMITTER: Wang L

PROVIDER: S-EPMC5644064 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Transplantation of Isl1<sup>+</sup> cardiac progenitor cells in small intestinal submucosa improves infarcted heart function.

Wang Lingjun L Meier Elizabeth M EM Tian Shuo S Lei Ienglam I Liu Liu L Xian Shaoxiang S Lam Mai T MT Wang Zhong Z

Stem cell research & therapy 20171016 1

<h4>Background</h4>Application of cardiac stem cells combined with biomaterial scaffold is a promising therapeutic strategy for heart repair after myocardial infarction. However, the optimal cell types and biomaterials remain elusive.<h4>Methods</h4>In this study, we seeded Isl1<sup>+</sup> embryonic cardiac progenitor cells (CPCs) into decellularized porcine small intestinal submucosa extracellular matrix (SIS-ECM) to assess the therapeutic potential of Isl1<sup>+</sup> CPCs and the biocompatib ...[more]

PMID: 29037258

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Project description:Pericytes are key regulators of vascular maturation, but their value for cardiac repair remains unknown.We investigated the therapeutic activity and mechanistic targets of saphenous vein-derived pericyte progenitor cells (SVPs) in a mouse myocardial infarction (MI) model.SVPs have a low immunogenic profile and are resistant to hypoxia/starvation (H/S). Transplantation of SVPs into the peri-infarct zone of immunodeficient CD1/Foxn-1(nu/nu) or immunocompetent CD1 mice attenuated left ventricular dilatation and improved ejection fraction compared to vehicle. Moreover, SVPs reduced myocardial scar, cardiomyocyte apoptosis and interstitial fibrosis, improved myocardial blood flow and neovascularization, and attenuated vascular permeability. SVPs secrete vascular endothelial growth factor A, angiopoietin-1, and chemokines and induce an endogenous angiocrine response by the host, through recruitment of vascular endothelial growth factor B expressing monocytes. The association of donor- and recipient-derived stimuli activates the proangiogenic and prosurvival Akt/eNOS/Bcl-2 signaling pathway. Moreover, microRNA-132 (miR-132) was constitutively expressed and secreted by SVPs and remarkably upregulated, together with its transcriptional activator cyclic AMP response element-binding protein, on stimulation by H/S or vascular endothelial growth factor B. We next investigated if SVP-secreted miR-132 acts as a paracrine activator of cardiac healing. In vitro studies showed that SVP conditioned medium stimulates endothelial tube formation and reduces myofibroblast differentiation, through inhibition of Ras-GTPase activating protein and methyl-CpG-binding protein 2, which are validated miR-132 targets. Furthermore, miR-132 inhibition by antimiR-132 decreased SVP capacity to improve contractility, reparative angiogenesis, and interstitial fibrosis in infarcted hearts.SVP transplantation produces long-term improvement of cardiac function through a novel paracrine mechanism involving the secretion of miR-132 and inhibition of its target genes.

Dataset Information

Transplantation of Isl1+ cardiac progenitor cells in small intestinal submucosa improves infarcted heart function.

Publications

Transplantation of Isl1<sup>+</sup> cardiac progenitor cells in small intestinal submucosa improves infarcted heart function.

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