Fibroblast Reprogramming in Cardiac Repair

Cardiovascular disease is one of the major causes of death worldwide. Limited proliferative capacity of adult mammalian cardiomyocytes has prompted researchers to exploit regenerative therapy after myocardial injury, such as myocardial infarction, to attenuate heart dysfunction caused by such injury. Direct cardiac reprogramming is a recently emerged promising approach to repair damaged myocardium by directly converting resident cardiac fibroblasts into cardiomyocyte-like cells. The achievement of in vivo direct reprogramming of fibroblasts has been shown, by multiple laboratories independently, to improve cardiac function and mitigate fibrosis post-myocardial infarction, which holds great potential for clinical application. There have been numerous pieces of valuable work in both basic and translational research to enhance our understanding and continued refinement of direct cardiac reprogramming in recent years. However, there remain many challenges to overcome before we can truly take advantage of this technique to treat patients with ischemic cardiac diseases. Here, we review recent progress of fibroblast reprogramming in cardiac repair, including the optimization of several reprogramming strategies, mechanistic exploration, and translational efforts, and we make recommendations for future research to further understand and translate direct cardiac reprogramming from bench to bedside. Challenges relating to these efforts will also be discussed. (J Am Coll Cardiol Basic Trans Science 2024;9:145-160) (c) 2024 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY -NC -ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).