Differentiation and reprogrammig of human mesenchymal stromal cells: insights from epigenetic assessments and pre-clinical studies

Mesenchymal stromal cells (StC) are cells with plastic properties virtually present in every adult tissue. Recently, StC have also been isolated from adult human cardiac tissue (CStC) and the hypothesis has been raised that StC deriving from the heart may be genetically committed to cardiovascular differentiation. In this light, the enhancement of CStC cardiovascular precursor properties may represent a potentially successful strategy for cardiac regeneration purposes. Although of adult origin, CStC exhibit Islet1 expression and respond to chemically-determined cardiogenic epigenetic stimuli. Specifically we created an epigenetic chemical cocktail (EpiC)that is able to up-regulate the expression of cardiac resident stem cell markers c-Kit and MDR-1, together with the expression of a large number of cardiovascular-associated genes and regulatory RNAs including c-Kit, MDR-1, KDR, GATA6, Nkx2.5, GATA4, HCN4, NaV1.5, ALPHA-MHC, Alpha-sarcomeric actin, miR-1 and miR-499. Remarkably, EpiC-treated CStC also exhibited immature electrophysiological properties. Mechanistically, the EpiC treatment determined genome-wide histone modifications associated with a transcriptionally competent chromatin. Chromatin immunoprecipitation experiments (Chip) revealed that permissive histone modification H3K4Me3 was present in c-Kit, MDR-1 and Nkx2.5 promoter regions, possibly contributing to their expression. Altogether these data indicate that Isl1+ CStC may be epigenetically reprogrammed to acquire functionally competent cardiovascular precursor properties. CStC therefore appear as a potentially useful cell type for potential cardiac and vascular reconstructive therapies