Cardiomyogenic Differentiation Potential of Human Dilated Myocardium-Derived Mesenchymal Stem/Stromal Cells: The Impact of HDAC Inhibitor SAHA and Biomimetic Matrices

Abstract

Dilated cardiomyopathy (DCM) is the most common type of nonischemic cardiomyopathy characterized by left ventricular or biventricular dilation and impaired contraction leading to heart failure and even patients’ death. Therefore, it is important to search for new cardiac tissue regenerating tools. Human mesenchymal stem/stromal cells (hmMSCs) were isolated from post-surgery healthy and DCM myocardial biopsies and their differentiation to the cardiomyogenic direction has been investigated in vitro. Dilated hmMSCs were slightly bigger in size, grew slower, but had almost the same levels of MSC-typical surface markers as healthy hmMSCs. Histone deacetylase (HDAC) activity in dilated hmMSCs was 1.5-fold higher than in healthy ones, which was suppressed by class I and II HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) showing activation of cardiomyogenic differentiation-related genes alpha-cardiac actin (ACTC1) and cardiac troponin T (TNNT2). Both types of hmMSCs cultivated on collagen I hydrogels with hyaluronic acid (HA) or 2-methacryloyloxyethyl phosphorylcholine (MPC) and exposed to SAHA significantly downregulated focal adhesion kinase (PTK2) and activated ACTC1 and TNNT2. Longitudinal cultivation of dilated hmMSC also upregulated alpha-cardiac actin. Thus, HDAC inhibitor SAHA, in combination with collagen I-based hydrogels, can tilt the dilated myocardium hmMSC toward cardiomyogenic direction in vitro with further possible therapeutic application in vivo.

The origin, progress, and application of cell‐based cardiac regeneration therapy

“…Muscle structure and increased expression of cardiogenic differentiation markers were observed in transduced cells (Neshati et al, 2018). The combination of HDAC inhibitor SAHA and biomimetic matrix collagen I‐based hydrogels or incorporation of vascular endothelial growth factor (VEGF) into nanofibers increases the potential of hMSCs to differentiate into cardiomyocytes (Kai et al, 2017; Miksiunas et al, 2021) and accelerates differentiation by altering cell adhesion or matrix hydrogel carrier (Li, Guo, et al, 2012; Roberts et al, 2016) (Figure 2). Some studies have also shown that MSCs predifferentiated into cardiomyocytes have better cardiac regeneration ability than undifferentiated MSCs injected into the heart (Guan et al, 2011).…”

Biochip Surfaces Containing Recombinant Cell-Binding Domains of Fibronectin

“…We demonstrated that such substrates can be efficiently used for the covalent immobilization and patterning of different proteins. Covalent immobilization of Fn in micropatterns with a high density of molecules in a hydrogel-like state has proved useful, for example, in studies of human primary cardiac stem cell differentiation [18]. Therefore, in the present study, we report on the possibility of fabricating biochip surfaces consisting of FnIII9-10 or FnIII10 covalently immobilized on a chemically activated PEG MA surface by microcontact printing [19].…”

Effects of HDAC inhibitors on neuroblastoma SH-SY5Y cell differentiation into mature neurons via the Wnt signaling pathway

“…Histone deacetylase (HDAC) inhibitors affect various cellular signals, such as cell proliferation, terminal differentiation, apoptosis, cell homeostasis, cell cycle arrest, and gene expression [ 1 , 2 ]. When histone acetyltransferase (HAT) transfers the acetyl groups of acetyl-CoA to the lysine residues in the NH 2 terminal tails of core histones, the chromosome is uncoiled into chromatin, making transcription easier [ 3 ]. When HDACs remove the acetyl group, the chromatin condenses back into a chromosome [ 1 , 4 ].…”