Resident cardiac macrophage-like cells induced by an ILC2 cytokine cocktail confer cardioprotection through enhanced efferocytosis in a mouse model of myocardial infarction

Resident cardiac macrophages (RCM) are essential for myocardial repair following acute myocardial infarction (AMI); however, their therapeutic application is hindered by limited availability. Here, we show that RCM transplantation from healthy mice markedly attenuates cardiac injury in mice. Importantly, we identify a pro-reparative CD301b⁺ RCM population profoundly depleted after AMI and show that adoptive transfer of this subset alone mitigates cardiac injury following myocardial infarction. To overcome the scarcity of native RCMs and favour their replenishment, we expand ex vivo a CD301b+ macrophage-like population (RCML) by polarizing bone marrow-derived macrophages with an ILC2-derived cytokine cocktail, and show that RCML transplantation confers robust post-AMI cardioprotection. Mechanistically, CD301b promotes efferocytosis by enhancing TFEB-mediated lysosomal function via a GATM-AMPK-mTOR axis, a pathway conserved in human macrophages. Thus, our findings identify a key pro-reparative macrophage subset and establish a feasible cell-based strategy for cardiac repair. Resident cardiac macrophages (RCM) contribute to cardiac repair after myocardial infarction (MI); however, their number is reduced upon injury. Here, the authors identify a population of efferocytosing CD301b+ macrophages that promote post-ischemic cardiac repair and develop an ex vivo protocol to generate RCM-like cells induced with enhanced efferocytic potential for post-MI cardioprotection.