Epigenetically modified cardiac mesenchymal stromal cells limit myocardial fibrosis and promote functional recovery in a model of chronic ischemic cardiomyopathy

Abstract

Preclinical investigations support the concept that donor cells more oriented towards a cardiovascular phenotype favor repair. In light of this philosophy, we previously identified HDAC1 as a mediator of cardiac mesenchymal cell (CMC) cardiomyogenic lineage commitment and paracrine signaling potency in vitro—suggesting HDAC1 as a potential therapeutically exploitable target to enhance CMC cardiac reparative capacity. In the current study we examined the effects of pharmacologic HDAC1 inhibition, using the benzamide class 1 isoform selective HDAC inhibitor entinostat (MS-275), on CMC cardiomyogenic lineage commitment and CMC-mediated myocardial repair in vivo. Human CMCs pretreated with entinostat or DMSO diluent control were delivered intramyocardially in an athymic nude rat model of chronic ischemic cardiomyopathy 30 days after a reperfused myocardial infarction. Indices of cardiac function were assessed by echocardiography and left ventricular (LV) Millar conductance catheterization 35 days after treatment. Compared with naïve CMCs, entinostat-treated CMCs exhibited heightened capacity for myocyte-like differentiation in vitro and superior ability to attenuate LV remodeling and systolic dysfunction in vivo. The improvement in CMC therapeutic efficacy observed with entinostat pretreatment was not associated with enhanced donor cell engraftment, cardiomyogenesis, or vasculogenesis, but instead with more efficient inhibition of myocardial fibrosis and greater increase in myocyte size. These results suggest that HDAC inhibition enhances the reparative capacity of CMCs, likely via a paracrine mechanism that improves ventricular compliance and contraction and augments myocyte growth and function.

RETRACTED ARTICLE: Large tumor suppressor kinase 2 overexpression attenuates 5-FU-resistance in colorectal cancer via activating the JNK-MIEF1-mitochondrial division pathway

“…Recently, mitochondrial elongation factor 1 (MIEF1) was identified as a potential novel mitochondrial division mediator [9]. Higher expression of MIEF1 has been observed in models of brain ischemia reperfusion injury [10] and ultraviolet irradiation-induced epidermal injury [9]. However, the biological role of MIEF1-related mitochondrial division in 5-FU resistance is not fully understood.…”

Administration of cardiac mesenchymal cells modulates innate immunity in the acute phase of myocardial infarction in mice

“…Although cell therapy is a promising and safe approach for the treatment of heart failure (HF) 1 , 2 , the mechanism whereby injected cells improve heart function remains poorly understood. Preclinical studies have shown that improvement of left ventricular (LV) function after cell therapy is associated with increased angiogenesis and reduction of fibrosis and inflammation 1 , 3 – 7 . It is now well accepted that injected cells do not improve heart function by differentiating into cardiomyocytes and endothelium 1 , 8 – 12 .…”

Human CardioChimeras: Creation of a Novel ‘Next Generation’ Cardiac Cell

“…3) SMA expression was lower in hCC than either parental cell, but higher in mouse CCs than the been suggested as the mechanistic basis for cardioprotection using cell therapy 44,45,46 , so the 19 relevance of the secretome from hCCs deserves further detailed analyses to establish a putative 20 role in enhancing survival signaling. The potential contribution of cell fusion to heart regeneration 21 is essentially unexplored despite the established role of cell fusion as a reprogramming mechanism 22 leading to enhanced proliferation and growth rate in differentiated cells 47 .…”