Molecular and environmental cues in cardiac differentiation of mesenchymal stem cells

Abstract

In this thesis molecular and environmental cues in cardiac differentiation of mesenchymal stem cells were investigated. The main conclusions were that the cardiac differentiation potential of human mesenchymal stem cells negatively correlates with donor age. This in its own shows a negative relationship with connexin 43 levels in these cells. However, a causal relationship between connexin 43 expression levels and cardiomyogenic differentiation potential only exists for human mesenchymal stem cells from prenatal sources, i.e. while knockdown of connexin 43 expression in fetal human mesenchymal stem cells inhibits their ability to differentiate into cardiomyocytes, connexin 43 overexpression in adult human mesenchymal stem cells does not endow them with cardiomyogenic differentiation capacity. In addition, co-culture studies showed that the alignment and distribution of mesenchymal stem cells affect their electrical integration into host myocardium and are major determinants of their pro-arrhythmic risk. The mechanisms underlying the pro-arrhythmic effects of hMSCs are to some extent comparable to those of cardiac myofibroblasts, cells that are found in fibrotic myocardium