Donor-intrinsic regenerative potential outweighs histocompatibility in iPSC-derived skeletal muscle engraftment in nonhuman primates.

Cell-based regenerative therapies represent a promising platform for muscular dystrophies, but the role of histocompatibility for muscle engraftment remains poorly defined. Given their close genetic relationship to humans, nonhuman primate (NHP) models provide an ideal system to investigate this question. Here, we generated myogenic progenitors from induced pluripotent stem cell (iPSC) lines derived from five major histocompatibility complex (MHC)-typed Mauritian-origin cynomolgus macaques (MCMs). Following extensive characterization, one iPSC clone from each donor was selected for transplantation across distinct MHC matching conditions, including fully matched, partially matched, and mismatched recipient-donor pairs. We found that variation in regenerative potential was primarily donor-intrinsic. Strikingly, fully mismatched donor-derived myogenic progenitors exhibiting high regenerative potential consistently outperformed partially and fully matched grafts across recipients. Our results suggest that, under clinically relevant immunosuppression, donor-intrinsic regenerative potential may outweigh histocompatibility as a determinant of early skeletal muscle engraftment, supporting the development of broadly applicable off-the-shelf allogeneic iPSC-based therapies for muscular dystrophies.