Abstract
Japan faces an increasing incidence of heart disease, owing to a shift towards a westernized lifestyle and an aging demographic. In cases where conventional interventions are not appropriate, regenerative medicine offers a promising therapeutic option. However, the use of stem cells has limitations, and therefore, “direct cardiac reprogramming” is emerging as an alternative treatment. Myocardial regeneration transdifferentiates cardiac fibroblasts into cardiomyocytes in situ.Three cardiogenic transcription factors: Gata4, Mef2c, and Tbx5 (GMT) can induce direct reprogramming of fibroblasts into induced cardiomyocytes (iCMs), in mice. However, in humans, additional factors, such as Mesp1 and Myocd, are required. Inflammation and immune responses hinder the reprogramming process in mice, and epigenetic modifiers such as TET1 are involved in direct cardiac reprogramming in humans. The three main approaches to improving reprogramming efficiency are (1) improving direct cardiac reprogramming factors, (2) improving cell culture conditions, and (3) regulating epigenetic factors. miR-133 is a potential candidate for the first approach. For the second approach, inhibitors of TGF-β and Wnt signals, Akt1 overexpression, Notch signaling pathway inhibitors, such as DAPT ((S)-tert-butyl 2-((S)-2-(2-(3,5-difluorophenyl) acetamido) propanamido)-2-phenylacetate), fibroblast growth factor (FGF)-2, FGF-10, and vascular endothelial growth factor (VEGF: FFV) can influence reprogramming. Reducing the expression of Bmi1, which regulates the mono-ubiquitination of histone H2A, alters histone modification, and subsequently the reprogramming efficiency, in the third approach. In addition, diclofenac, a non-steroidal anti-inflammatory drug, and high level of Mef2c overexpression could improve direct cardiac reprogramming.Direct cardiac reprogramming needs improvement if it is to be used in humans, and the molecular mechanisms involved remain largely elusive. Further advances in cardiac reprogramming research are needed to bring us closer to cardiac regenerative therapy.
Highlights
In Japan, the incidence of ischemic heart diseases is increasing, due to the adoption of a westernized lifestyle, and an increase in hypertension and valvular diseases due to an aging population
In 2010, we reported a novel strategy for the direct reprogramming of fibroblasts into cardiomyocytes
Introducing these three factors into cardiac fibroblasts resulted in approximately 17% of Green fluorescent protein (GFP)-positive cells, subsequently named induced cardiomyocytes
Summary
In Japan, the incidence of ischemic heart diseases is increasing, due to the adoption of a westernized lifestyle, and an increase in hypertension and valvular diseases due to an aging population. The number of candidate factors was reduced from the initial 14 to three cardiogenic transcription factors, Gata, Mef2c, and Tbx: GMT, which were essential for direct cardiac reprogramming Introducing these three factors into cardiac fibroblasts resulted in approximately 17% of GFP-positive cells, subsequently named induced cardiomyocytes (iCMs). A combination of fibroblast growth factor (FGF)-2, FGF-10 and vascular endothelial growth factor (VEGF: FFV) enhanced the induction efficiency of beating iCMs approximately 40-fold compared to conventional culture methods The mechanism behind this effect was the activation of the PI3K/Akt and p38MAPK pathways by cell growth factors, which upregulated the gene clusters involved in cardiac function [24].
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