Researchers have developed a Perturb-seq platform to systematically identify and rank genetic barriers that prevent the conversion of fibroblasts into functional heart muscle cells following a heart attack. By screening 140 potential inhibitors in a living mouse model, the study pinpointed calreticulin (Calr) as the primary obstacle to successful cardiac regeneration. High levels of this protein in damaged heart tissue suppress calcium signaling, which in turn keeps a vital regenerative gene called MEF2C inactive. The team demonstrated that silencing Calr restores calcium levels and significantly boosts the efficiency and maturity of newly formed cardiomyocytes in both mouse and human cell models. These findings suggest that targeting the Calr-calcium-MEF2C pathway can improve heart repair, reduce scarring, and restore essential pumping functions. This work provides a strategic framework for using single-cell genetic screening to overcome the complex pathological environment of the injured heart.

References:

• Cai Y, Yang Y, Yang J, et al. Perturb-seq uncovers pathological obstacles to direct cardiac reprogramming in vivo[J]. Cell Stem Cell, 2026.