MEGF10 Accelerates a Developing Niche to Improve Engrafted Progenitor Cell Retention in Dystrophic and Regenerating Skeletal Muscle

Skeletal muscle cell therapies are limited by poor long-term engraftment, particularly in diseased muscle, where retention of a PAX7+ stem cell pool depends on formation of a supportive niche. Here, we used spatial transcriptomics to map niche development across engraftment time, healthy versus dystrophic microenvironments, and secondary injury. Engrafted myogenic cells underwent rapid early transcriptional remodeling and marked donor-cell loss, whereas regenerating myofibers acquired niche-associated programs that stabilized surviving PAX7+ cells. Dystrophic microenvironments impaired niche maturation, altered donor-cell state, and blunted regenerative adaptation after reinjury. MEGF10 emerged as an early niche-associated regulator that was transiently expressed during healthy regeneration but persisted in dystrophic muscle. Using CRISPR-engineered hPSC models, we found that MEGF10 induction during the first 10 days after transplantation more than doubled PAX7+ cell retention and donor-derived myofiber output, whereas MEGF10 loss of function, which models a severe early onset myopathy, failed to maintain engrafted PAX7+ cells. Spatial profiling of Tet-On engraftments identified a MEGF10-responsive regenerative myofiber program linked to early niche support. These findings define an early therapeutic window for improving muscle cell transplantation.