Niche environment remodeling promotes long-term endometrium stromal stem cell engraftment and tissue regeneration in thin endometrium.

Reconstituting the endometrium with tissue-resident stem cells is a promising therapy for thin endometrium (TE), often caused by uterine cavity injury. However, low engraftment rates have hindered clinical success, and mechanisms of action remain unclear. In a rat model of TE, we observed that autologous endometrial stromal stem cells (eSSCs) had poor survival post transplantation due to a disrupted stem cell niche characterized by immune activation and reduced angiogenesis. To restore a supportive niche, we suppressed immune activation using either immunosuppressants or Cd47 mRNA expression and promoted vascular reconstruction via vascular endothelial growth factor (VEGF) mRNA engineering. Together, this strategy significantly improved engraftment rates, endometrial pathology, and pregnancy outcome. Single-cell RNA sequencing (scRNA-seq) revealed that transplanted eSSCs contributed to tissue repair through self-renewal and differentiation. Validation using a xenotransplantation model with human eSSCs yielded similar results. This niche-remodeling strategy highlights the therapeutic potential of engineered autologous eSSCs for treating endometrial disorders such as TE.