Molecular discoveries and treatment strategies by direct reprogramming in cardiac regeneration

Abstract

Cardiac tissue has minimal endogenous regenerative capacity in response to injury. Treatment options are limited following tissue damage after events such as myocardial infarction. Current strategies are aimed primarily at injury prevention, but attention has been increasingly targeted toward the development of regenerative therapies. This review focuses on recent developments in the field of cardiac fibroblast reprogramming into induced cardiomyocytes. Early efforts to produce cardiac regeneration centered around induced pluripotent stem cells, but clinical translation has proved elusive. Currently, techniques are being developed to directly transdifferentiate cardiac fibroblasts into induced cardiomyocytes. Viral vector-driven expression of a combination of transcription factors including Gata4, Mef2c, and Tbx5 induced cardiomyocyte development in mice. Subsequent combinational modifications have extended these results to human cell lines and increased efficacy. The miRNAs including combinations of miR-1, miR-133, miR-208, and miR-499 can improve or independently drive regeneration of cardiomyocytes. Similar results could be obtained by combinations of small molecules with or without transcription factor or miRNA expression. The local tissue environment greatly impacts favorability for reprogramming. Modulation of signaling pathways, especially those mediated by VEGF and TGF-β, enhance differentiation to cardiomyocytes. Current reprogramming strategies are not ready for clinical application, but recent breakthroughs promise regenerative cardiac therapies in the near future.

Multicellular In vitro Models of Cardiac Arrhythmias: Focus on Atrial Fibrillation

“…More information on the currently available protocols to generate PSC-derived CMs and criteria to distinguish the different subtypes of PSC-derived CMs can be found in some recent reviews (116,127,(132)(133)(134). An alternative strategy to generate CMs from non-CMs is through the direct cardiomyogenic reprogramming of fibroblasts by (cardiomyogenic) transcription factors, miRNAs or small molecules (135,136). However, thus far, the reprogramming efficiencies are low and the resulting so-called induced CM-like cells (iCMs) are rather immature and comprise a mixture of different CM subtypes, limiting their suitability for cardiac disease modeling.…”

Potential roles of microRNA-1 and microRNA-133 in cardiovascular disease

“…GATA4 is currently the most studied cardiac transcription factor (Rasekhi et al, 2017). Like miR-133, GATA4 also inhibits the Snai1 pathway (Werner et al, 2019), therefore, it is speculated that miR-133 and GATA4 play a synergistic role in cardiac reprogramming. It has been shown that combined injection of miR-133, miR-1, miR-499, and miR-208 into ischemic myocardial tissue induces fibroblasts to reprogram and transform into cardiomyocyte-like cells that then improve cardiac function (Cheng et al, 2019).…”

Strategies and Challenges to Improve Cellular Programming-Based Approaches for Heart Regeneration Therapy

“…The combination of miR-1and miR-133 with GMTH cocktail generated significantly more matured iCMs [ 93 , 100 ]. Supplementing the viral GMT, GMTH, or GMTHMyMe cocktail with a TGF-β inhibitor or synthetic mimics of miR-1, miR-133, or miR-590 increased the CM reprogramming efficiency and speed of mouse, pig, or human cells, which provided new insight into the molecular mechanism of cardiac reprogramming [ 80 , 101 , 102 ].…”