Engineered CAR-monocytes coordinate fibrosis clearance and cardiac regeneration following myocardial infarction.

Abstract

Overwhelming cardiomyocyte death and excessive cardiac fibrosis post myocardial infarction (MI) collectively lead to heart failure and mortality. For treating this devastating disease, it is essential to eliminate fibrosis and reconstitute the damaged myocardium, yet effective strategies remain elusive. Here, we created pleiotropic chimeric antigen receptor-monocytes (pCAR-Mos), revitalizing the injured heart via synergistic fibrosis clearance and myocardial reconstitution. Specifically, we engineered monocytes to express fibroblast activation protein (FAP)-chimeric antigen receptor (CAR) and secrete the cardioregenerative protein Agrin. CAR-mediated phagocytosis of myofibroblasts, which was further enhanced by Agrin, significantly attenuated fibrotic scar formation. Moreover, Agrin secretion promoted cardiomyocyte regeneration, thereby facilitating replenishment of functional myocardium. Treatment with pCAR-Mos remodeled the cardiac fibrotic microenvironment and substantially restored cardiac function in MI mice. In sum, our findings confirmed that pCAR-Mos exerted potent phagocytic activity against profibrotic myofibroblasts while simultaneously enabling myocardial reconstitution, thereby providing a reversible treatment strategy for MI with broad application in other fibrotic diseases.