Calr-mediated calcium buffering: a molecular barrier to in vivo cardiac reprogramming

Abstract

In a recent publication in Cell Stem Cell , Cai et al. 1 employed an in vivo Perturb-seq strategy to systematically identify molecular barriers that limit direct cardiac reprogramming following myocardial infarction (MI). This study provides a conceptual and technological framework for improving fi broblast-to-cardiomyocyte conversion in vivo and identi fi es a key regulatory pathway that can be targeted to enhance cardiac regeneration. The limited regenerative capacity of the adult mammalian heart and the resulting loss of functional myocardium after MI under-score the urgent need for strategies that can restore cardiac muscle and improve heart function. Direct cardiac reprogramming has emerged as a promising approach for myocardial repair whereby fi broblasts can be directly converted into induced cardiomyocytes (iCMs). Pioneering studies have demonstrated that de fi ned transcription factors including Mef2c, Gata4, and Tbx5 (collectively referred to as MGT), and later extended combinations such as Myocd and Sall4 (collectively termed MGTMyoS) can induce transdifferentiation of fi broblasts to a cardiomyocyte-like state both in vitro and in vivo. 2 – 4 However, the ef fi ciency and fi delity of in vivo direct reprogramming remain low, representing a major obstacle for clinical translation. This limitation is thought to arise, at least in part, from the complex post-injury microenvironment, where in fl ammatory signaling, extracellular matrix remodeling, and cellular stress responses collectively constrain cell fate conversion. Despite growing recognition of these in fl uences, the molecular mechanisms that restrict cardiac reprogramming ef fi ciency in the injured heart have not been de fi ned. A comprehensive and quantitative understanding of the molecular barriers operating in this context is therefore