Inhibition of G9a Histone Methyltransferase Converts Bone Marrow Mesenchymal Stem Cells to Cardiac Competent Progenitors

Abstract

The G9a histone methyltransferase inhibitor BIX01294 was examined for its ability to expand the cardiac capacity of bone marrow cells. Inhibition of G9a histone methyltransferase by gene specific knockdown or BIX01294 treatment was sufficient to induce expression of precardiac markers Mesp1 and brachyury in bone marrow cells. BIX01294 treatment also allowed bone marrow mesenchymal stem cells (MSCs) to express the cardiac transcription factors Nkx2.5, GATA4, and myocardin when subsequently exposed to the cardiogenic stimulating factor Wnt11. Incubation of BIX01294-treated MSCs with cardiac conditioned media provoked formation of phase bright cells that exhibited a morphology and molecular profile resembling similar cells that normally form from cultured atrial tissue. Subsequent aggregation and differentiation of BIX01294-induced, MSC-derived phase bright cells provoked their cardiomyogenesis. This latter outcome was indicated by their widespread expression of the primary sarcomeric proteins muscle α-actinin and titin. MSC-derived cultures that were not initially treated with BIX01294 exhibited neither a commensurate burst of phase bright cells nor stimulation of sarcomeric protein expression. Collectively, these data indicate that BIX01294 has utility as a pharmacological agent that could enhance the ability of an abundant and accessible stem cell population to regenerate new myocytes for cardiac repair.

BIX01294, an inhibitor of histone methyltransferase, induces autophagy-dependent differentiation of glioma stem-like cells

“…Inhibition of G9a activity with BIX01294 or siRNA significantly increased myogenic differentiation37. Bone marrow mesenchymal stem cells differentiated to cardiac-competent progenitors after BIX01294 treatment3839. Combination of small molecule inhibitors, BIX01294 and BayK8644 interfered with reprogramming of Oct4/Klf4-transduced mouse embryonic fibroblast into pluripotent stem cells40.…”

G9a histone methyltransferase inhibitor BIX01294 promotes expansion of adult cardiac progenitor cells without changing their phenotype or differentiation potential

“…In previous studies, we reported that BIX01294 can enhance the cardiac competency of bone marrow cells . As a follow‐up to that earlier finding, we wanted to investigate whether BIX01294 may also have a positive effect on progenitor cells within the heart.…”

“…In the present study, BIX01294 was used to treat non‐dissociated tissue chunks, from which emerged the phase bright cells. While our previous studies with bone marrow used dissociated cells, those cultures were fully confluent when treated with BIX01294 . Under those conditions, the drug promoted a proliferative phenotype.…”

Long noncoding RNA Braveheart promotes cardiogenic differentiation of mesenchymal stem cells in vitro

“…Evidence shows that Mesp1 regulates EMT and cardiovascular differentiation in ESCs and CPCs [20, 39]. Several pharmacological agents have been introduced to enhance the cardiomyogenic ability of MSCs for cardiac repair [40]. MSCs treated with these agents show an appreciably elevated expression of Mesp1, with a later widespread upregulation of the structural genes of cardiomyocytes.…”