Restoring mammary gland structures and functions with autogenous cell therapy

In somatic cell reprogramming, cells must escape the somatic cell-specific gene expression program to adopt other cell fates. Here, in vitro chemical induction with RepSox generated chemically induced mammary epithelial cells (CiMECs) with milk secreting functions from goat ear fibroblasts (GEFs). Transplanted CiMECs regenerated the normal mammary gland structure with milk-secreting functions in nude mice. Single-cell RNA sequencing revealed that during the reprogramming process, GEFs may sequentially undergo embryonic ectoderm (EE)-like and different MEC developmental states and finally achieve milk secreting functions, bypassing the pluripotent state. Mechanistically, Smad3 upregulation induced by transforming growth factor β (TGFβ) receptor 1 (TGFβR1) downregulation led to GEF reprogramming into CiMECs without other reprogramming factors. The TGFβR1-Smad3 regulatory effects will provide new insight into the TGFβ signaling pathway regulation of somatic cell reprogramming. These findings suggest an innovative strategy for autogenous cell therapy for mammary gland defects and the production of transgenic mammary gland bioreactors.