Abstract 16933: Targeted Inhibition of Histone Deacetylase 1 Promotes the Activation of a Cardiomyogenic/Vasculogenic Genetic Program in Human Cardiac-derived Mesenchymal Stromal Cells
Alterations in chromatin structure, as mediated by the inhibition of specific HDAC family members, enhance the cardiogenic differentiation capacity of various progenitor cell types; a key property of donor cell populations shown to contribute to the benefits they provide in cardiac cell therapy applications. The influence of HDAC inhibition on cardiac-derived mesenchymal stromal cell (CStC) transdifferentiation or the role of specific HDAC family members in dictating cardiovascular cell lineage specification has not been investigated. In the current study, the consequences of HDAC inhibition on patient-derived CStC proliferation, early induction of cardiac cell lineage commitment markers, and cardiovascular differentiation/cell lineage specification were investigated using the pan-HDAC inhibitor sodium butyrate (NaBu) or shRNA constructs targeting various HDAC family members. CStCs treated with NaBu for 72 hours resulted in a dose-dependent reduction in cell proliferation and a simultaneous induction of cardiogenic transcripts relative to untreated. Further, NaBu treatment stimulated enhanced expression of myocyte- and endothelial-specific markers following dexamethasone-induced differentiation in vitro. shRNA knockdown screens were employed in effort to identify specific HDAC family members responsible for these effects. Accordingly, we revealed the inhibition of HDAC1, but not HDAC4 or HDAC7 (both previously implicated in cardiac differentiation) to promote the activation of a cardiomyogenic/vasculogenic transcriptional program, as well as enhance the expression of early cardiac lineage commitment proteins. Such results identify HDAC1 as a modulator of CStC cardiovascular transdifferentiation and an exploitable target to facilitate CStC-mediated myocardial repair.
Author Disclosures: J.B. Moore: None. J. Zhao: None. M. Wysoczynski: None. R. Bolli: None.
- © 2015 by American Heart Association, Inc.