Enhanced cardiac repair by telomerase reverse transcriptase over-expression in human cardiac mesenchymal stromal cells.

ABSTRACT: We have previously reported a subpopulation of mesenchymal stromal cells (MSCs) within the platelet-derived growth factor receptor-alpha (PDGFR?)/CD90 co-expressing cardiac interstitial and adventitial cell fraction. Here we further characterise PDGFR?/CD90-expressing cardiac MSCs (PDGFR??+?cMSCs) and use human telomerase reverse transcriptase (hTERT) over-expression to increase cMSCs ability to repair the heart after induced myocardial infarction. hTERT over-expression in PDGFR??+?cardiac MSCs (hTERT?+?PDGFR??+?cMSCs) modulates cell differentiation, proliferation, survival and angiogenesis related genes. In vivo, transplantation of hTERT?+?PDGFR??+?cMSCs in athymic rats significantly increased left ventricular function, reduced scar size, increased angiogenesis and proliferation of both cardiomyocyte and non-myocyte cell fractions four weeks after myocardial infarction. In contrast, transplantation of mutant hTERT?+?PDGFR??+?cMSCs (which generate catalytically-inactive telomerase) failed to replicate this cardiac functional improvement, indicating a telomerase-dependent mechanism. There was no hTERT?+?PDGFR??+?cMSCs engraftment 14 days after transplantation indicating functional improvement occurred by paracrine mechanisms. Mass spectrometry on hTERT?+?PDGFR??+?cMSCs conditioned media showed increased proteins associated with matrix modulation, angiogenesis, cell proliferation/survival/adhesion and innate immunity function. Our study shows that hTERT can activate pro-regenerative signalling within PDGFR??+?cMSCs and enhance cardiac repair after myocardial infarction. An increased understanding of hTERT's role in mesenchymal stromal cells from various organs will favourably impact clinical regenerative and anti-cancer therapies.

SUBMITTER: Le TYL 

PROVIDER: S-EPMC6646304 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature