Conserved stromal EMT program controls regenerative capacity of mesenchymal stromal cells across multiple tissues.

The regenerative function of stem cells is orchestrated by specialized niches, yet the mechanisms underlying mesenchymal stromal cell (MSC)-mediated support remain unclear. Here, we demonstrate that the epithelial-to-mesenchymal transition (EMT) gradient, together with stemness and pericyte-like properties, is a critical regulator of MSC niche function. High EMT gradients characterize functional MSC subsets that functions as niche supporting hematopoietic stem cells (HSCs), while attenuation of the EMT program impairs HSC support and reproduced in degenerative hematological disorders. Notably, enhancing the EMT program in MSCs (aEMT-MSCs) markedly augments their capacity to promote HSC regeneration and restores defective niches in patients with aplastic anemia. Furthermore, the regenerative effects of aEMT-MSCs extend beyond hematopoiesis to neuronal and cardiovascular tissues, suggesting a conserved niche-supporting program across multiple tissue systems. These findings establish the EMT program as a central regulator of the mesenchymal niche and propose a strategy to address unmet needs in regenerative medicine.