近日，北京大学赵扬小组发现了Perturb-seq揭示了体内直接心脏重编程的病理障碍。相关论文发表在2026年3月30日出版的《细胞—干细胞》杂志上。

利用为复杂病理环境量身定制的Perturb-seq平台，研究人员系统地比较并排名了体内心脏重编程的140个潜在障碍。基于它们在单细胞RNA-seq轨迹上的shRNA分布和富集，钙网蛋白（calreticulin, Calr）成为了顶级抑制剂。Calr敲低大大提高了体外诱导iCM的效率，使iCM中的钙振荡同步，加速心肌梗死后的原位重编程，改善心功能，减少纤维化。从机制上讲，Calr敲低激活钙信号，促进MEF2C活性驱动重编程，甚至替代外源MEF2C。总的来说，他们的研究揭示了病理微环境中阻碍原位心肌细胞诱导的关键调节因子，为心肌梗死后的心脏修复和再生提供了有效的重编程因子和战略框架。

据悉，从成纤维细胞直接诱导心肌细胞是一种很有前途的心脏再生策略。然而，体内转分化效率仍然很低。

附：英文原文

Title: Perturb-seq uncovers pathological obstacles to direct cardiac reprogramming in vivo

Author: Yihong Cai, Yang Yang, Junbo Yang, Ruohan Ding, Qihan Zhang, Xin Dang, Chenxuan Li, Yang Zhao

Issue&Volume: 2026-03-30

Abstract: Direct induction of cardiomyocytes from fibroblasts represents a promising strategy for cardiac regeneration. However, the transdifferentiation efficiency in vivo remains low. Leveraging a Perturb-seq platform tailored to complex pathological environments, we systematically compared and ranked 140 potential barriers of in vivo cardiac reprogramming. Based on their shRNA distribution and enrichment along the single-cell RNA-seq trajectory, calreticulin (Calr) emerged as a top inhibitor. Calr knockdown greatly enhanced iCM induction efficiency in vitro, enabling synchronized calcium oscillations in iCMs, and accelerated in situ reprogramming after myocardial infarction, improving cardiac function and reducing fibrosis. Mechanistically, Calr knockdown activates calcium signaling, boosting MEF2C activity to drive reprogramming and even substitute for exogenous MEF2C. Collectively, our study reveals critical regulators hindering in situ cardiomyocyte induction in a pathological microenvironment, providing effective reprogramming factors and a strategic framework for cardiac repair and regeneration after myocardial infarction.

DOI: 10.1016/j.stem.2026.03.006

Source: https://www.cell.com/cell-stem-cell/abstract/S1934-5909(26)00116-5