Abstract
We have previously reported a subpopulation of mesenchymal stromal cells (MSCs) within the platelet-derived growth factor receptor-alpha (PDGFRα)/CD90 co-expressing cardiac interstitial and adventitial cell fraction. Here we further characterise PDGFRα/CD90-expressing cardiac MSCs (PDGFRα + 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 PDGFRα + cardiac MSCs (hTERT + PDGFRα + cMSCs) modulates cell differentiation, proliferation, survival and angiogenesis related genes. In vivo, transplantation of hTERT + PDGFRα + 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 + PDGFRα + cMSCs (which generate catalytically-inactive telomerase) failed to replicate this cardiac functional improvement, indicating a telomerase-dependent mechanism. There was no hTERT + PDGFRα + cMSCs engraftment 14 days after transplantation indicating functional improvement occurred by paracrine mechanisms. Mass spectrometry on hTERT + PDGFRα + 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 PDGFRα + 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.
Highlights
Progenitor and stem cell senescence is regulated by telomerase activity and telomere length[5,6]
PDGFRα + cardiac mesenchymal stromal cells (cMSCs) expressed MYC, KLF4 and SOX4, which are implicated in self-renewal and pluripotency of stem cells (Fig. 1A)
We have previously focused on cardiac progenitor cells in rodents and humans within the cardiac PDGFRα+/CD31− mesenchymal stromal cell population[15,16,17]
Summary
Progenitor and stem cell senescence is regulated by telomerase activity and telomere length[5,6]. Dysfunction of telomerase and telomere shortening are Length Regulation Unit, Children’s Medical Research Institute, The University of Sydney, Westmead, NSW, 2145, Australia. Transplantation of hTERT + PDGFRα + cMSCs improved cardiac function by decreasing scar size and pro-fibrotic factors, increasing angiogenesis, and enhancing both cardiomyocyte (CM) and non-myocyte cell proliferation. These findings shed light on hTERT’s role in mesenchymal progenitors and are proof-of-principle that cell therapy augmented with hTERT over-expression can be an effective means to promote cardiac repair
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