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.

Details

Title
Enhanced cardiac repair by telomerase reverse transcriptase over-expression in human cardiac mesenchymal stromal cells
Author
Thi Yen Loan Le 1   VIAFID ORCID Logo  ; Pickett, Hilda A 2 ; Yang, Andrian 3 ; Ho, Joshua W K 3   VIAFID ORCID Logo  ; Thavapalachandran, Sujitha 4 ; Igoor, Sindhu 1 ; Yang, Sile F 2 ; Farraha, Melad 4   VIAFID ORCID Logo  ; Voges, Holly K 5   VIAFID ORCID Logo  ; Hudson, James E 5 ; dos Remedios, Cristobal G 6 ; Bryan, Tracy M 7   VIAFID ORCID Logo  ; Kizana, Eddy 4 ; Chong, James J H 8   VIAFID ORCID Logo 

1  Centre for Heart Research, Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW, Australia; Department of Cardiology, Westmead Hospital, Westmead, NSW, Australia 
2  Telomere Length Regulation Unit, Children’s Medical Research Institute, The University of Sydney, Westmead, NSW, Australia 
3  Victor Chang Cardiac Research Institute, and St Vincent’s Clinical School, University of New South Wales, Darlinghurst, NSW, Australia 
4  Centre for Heart Research, Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW, Australia; Department of Cardiology, Westmead Hospital, Westmead, NSW, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia 
5  School of Biomedical Sciences, University of Queensland, St Lucia, Queensland, Australia 
6  Department of Anatomy and Histology, School of Medical Sciences, Bosch Institute, The University of Sydney, Sydney, NSW, Australia 
7  Cell Biology Unit, Children’s Medical Research Institute, The University of Sydney, Westmead, NSW, Australia 
8  Centre for Heart Research, Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW, Australia; Department of Cardiology, Westmead Hospital, Westmead, NSW, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia; Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia 
Pages
1-17
Publication year
2019
Publication date
Jul 2019
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41598-019-47022-w
ProQuest document ID
2262077770
Copyright
© 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.