Cell therapy: enhancing the therapeutic potential of a cardiac stromal cell population for delivery after myocardial infarction using miR-210

Cardiovascular diseases are the number one cause of death globally and are a major contributor to reduced quality of life. Despite the development of improved pharmacological therapy and surgical interventions, myocardial infarction (MI) still has a poor prognosis. Therefore, the search for new treatment strategies is becoming increasingly urgent. Many avenues have been under investigation, but this thesis addressed the use of cardiac cell therapy to repair the heart after MI. Cell therapy using cardiac stromal or progenitor populations emerged about two decades ago. However, the identity of these populations has been under debate and the field has been hindered by limitations that include low cell retention following transplantation. Firstly, this thesis aimed to characterise a slowly adhering population of unsorted stromal cells isolated from adult mouse atrial appendages using a collagenase and trypsin protocol (CTs). CTs were compared to other atrial stromal populations including the cardiosphere-derived cells (CDCs), which have been shown to have a therapeutic effect in pre-clinical models of MI. Single-cell qRT-PCR revealed that CTs resembled CDCs in the expression of cardiogenic transcription factors but were also enriched for Tcf21 and the macrophage-associated genes Mrc1 and Csf1r. Secondly, I investigated the overexpression of miR-210, as a pro-survival miRNA, in our population of interest, the CTs. In vitro studies showed that miR-210 has an anti-apoptotic effect and a role in downregulating mitochondrial autophagy and fission. Moreover, miR-210 partially rescued the gene expression profile of CTs that shifted following starvation and enhanced their paracrine potential. Finally, we tested the ability of miR-210 to enhance the retention of CTs in vivo in a mouse MI model but did not find a significant improvement. In summary, this thesis provides valuable insights into the heterogeneity of cardiac stromal populations, the mechanisms of action of miR-210, and the use of this miRNA to enhance the therapeutic potential of cells for cardiac cell therapy.