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 (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.

The Impact of Spaceflight and Microgravity on the Human Islet-1+ Cardiovascular Progenitor Cell Transcriptome

“…Another significant transcript associated with stemness is TERT which promotes cell proliferation and survival [56]. TERT expression decreases with age under normal circumstances [57,58]; however, in our data, as well as in the NASA Twin Study, TERT expression is significantly elevated by spaceflight.…”

Reviewing the role of cardiac exosomes in myocardial repair at a glance

“…Cardiac pacemaker cells can produce cardiomyocytes from fibroblasts in vitro (Kiuchi et al, 2019). MSCs with increased expression of reverse transcriptase have a greater ability to regenerate myocardial tissue after injury (Le et al, 2019). Myocardial Bmp2 expression has been reported to induce proliferation of immature cardiomyocytes and maintenance of the ventricle (Prados et al, 2018).…”

“…Cardiac pacemaker cells can produce cardiomyocytes from fibroblasts in vitro (Kiuchi et al, 2019). MSCs with increased expression of reverse transcriptase have a greater ability to regenerate myocardial tissue after injury (Le et al, 2019).…”

Human Cardiac Mesenchymal Stromal Cells From Right and Left Ventricles Display Differences in Number, Function, and Transcriptomic Profile

“…In accordance with tissue analysis, a higher amount of C-MSC can be isolated from the human RV than from the left one. Although RV or LV C-MSC have been used and characterized alternatively ( Chong et al, 2013 ; Czapla et al, 2016 ; Sommariva et al, 2016 ; Le et al, 2018 , 2019 ), no previous study performed a direct comparison of cells obtained from the two ventricles of the same individual. This novel approach is useful for a better C-MSC characterization in the human heart.…”