Date on Master's Thesis/Doctoral Dissertation

5-2017

Document Type

Master's Thesis

Degree Name

M.S.

Department

Biochemistry and Molecular Biology

Degree Program

Biochemistry and Molecular Biology, MS

Committee Chair

Moore IV, Joseph

Committee Co-Chair (if applicable)

Samuelson, David

Committee Member

Tooley, E. Schaner

Author's Keywords

cell therapy; histone deacetylases; cardiac mesenchymal stoma cell; HDAC1

Abstract

Cardiac mesenchymal stromal cell (CMC) administration has improved cardiac function in pre-clinical animal models of heart failure. Specifically, both transdifferentiation and secretion of paracrine signaling molecules are potential mechanisms by which transplanted cells exert their cardiac reparative effects. The inhibition of histone deacetylases (HDACs) has been shown to enhance the cardiogenic differentiation capacity of various progenitor cell types. In the current study the consequences of HDAC1 inhibition on CMC in vitro differentiation, in vivo cardiac reparative capabilities, and in vitro cytokine secretion were investigated using either genetic depletion of HDAC1 or pharmacological inhibition with entinostat. CMCs depleted of HDAC1 exhibit induction of a core cardiogenic program and greater aptitude to acquire a cardiomyogenic/vasulogenic cell-like fate in vitro through a mechanism involving hyperacetylation and stabilization of p53. In preliminary in vivo studies, entinostat-treated CMCs exhibited superior ability to attenuate adverse left ventricle remodeling and increased ventricular function relative to untreated CMCs. Compared with untreated cells and vehicle, entinostat-treated CMC hearts exhibit smaller end-systolic volume, greater cardiac output and left ventricle ejection fractions, decreased scar size, increased capillary density and increased vessel density. Furthermore, HDAC1 inhibited CMCs secrete cytokines which more efficiently promoted endothelial cell proliferation and tube formation through the enhanced secretion of basic fibroblast growth factor (bFGF). These results suggest that HDAC1 inhibition enhances the therapeutic efficacy of CMCs, possibly by augmenting CMC cardiogenic lineage-commitment and by enhancing secretion of paracrine signaling molecules to stimulate endogenous repair mechanisms.

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