Exploring Vaginal Microbiota–Tissue Resident Stem Cell Crosstalk: VCAM1-Mediated Enhancement of Regenerative Capacity

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 VCAM1 (vascular cell adhesion molecule 1), 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.