Exploring vaginal microbiota–tissue resident stem cell crosstalk: VCAM1/Akt signaling ‐mediated enhancement of regenerative capacity

Abstract The vaginal microbiota plays a critical role in regulating endometrial development, which is key for successful embryo implantation and pregnancy. However, the extent to which the vaginal microbiota contributes to various tissue regeneration‐associated functions of human endometrial stem cells, which play pivotal roles in endometrial development and subsequent endometrial receptivity, remains largely unexplored. Here, we demonstrate that exposure to microbiota‐derived secretory factors enhances key regenerative functions of endometrial stem cells, including self‐renewal, migratory capacity, multilineage differentiation potential, and metabolic activity via upregulation of vascular cell adhesion molecule 1 (VCAM1), which serves as a central regulatory hub, and the subsequent activation of the PI3K/Akt signaling pathway, highlighting a critical microbiota‐driven mechanism governing endometrial stem cell function and tissue regeneration. Functional knockdown of VCAM1 and pharmacological inhibition of the Akt signaling pathway attenuated the microbiota‐driven beneficial effects, confirming their functional roles. Notably, depletion of the vaginal microbiota impaired endometrial development and significantly reduced the clonogenicity of endometrial stem cells in vivo, reinforcing the essential role of microbiota‐derived factors in endometrial homeostasis. These findings provide critical insights into the microbiota‐endometrial stem cell crosstalk and highlight the therapeutic potential of microbiota‐derived secretory factors in stem cell‐based regenerative medicine and reproductive health.