Targeting the ALDH-RA Axis with RE-Exo@HA hydrogel to achieve scarless endometrial regeneration and fertility restoration in intrauterine adhesions.

Intrauterine adhesions (IUA), a leading cause of uterine infertility, are characterized by endometrial fibrosis and a loss of functional regeneration. The impairment of endometrial mesenchymal stem/stromal cells (eMSCs) is central to IUA pathogenesis; however, the absence of reliable markers correlating with disease severity and fibrosis has hindered the understanding of their pathological mechanisms and the development of targeted therapies. Here, ALDH1A1 and ALDH1A2 were identified as novel eMSC markers significantly downregulated in IUA patient samples and scar tissue. ALDHHigh eMSCs exhibited superior self-renewal capability, proliferative capacity, decidualization potential, and angiogenic capability, alongside reduced fibrotic characteristics compared to ALDHLow eMSCs. Transplantation of ALDHHigh eMSCs promoted endometrial regeneration in a murine IUA model. Mechanistically, ALDHHigh eMSCs secreted higher levels of ATRA (all-trans retinoic acid), and their pro-regenerative effect was mediated through the ALDH-RA-RAR (RA Receptor) axis. ATRA and E2 (Estradiol) acted synergistically to promote glandular organoid growth and reprogram ALDHLow eMSCs towards a regenerative phenotype. The RE-Exo@HA hydrogel, composed of ATRA and E2 encapsulated in exosomes embedded within a hyaluronic acid hydrogel, effectively facilitated scarless endometrial repair, demonstrated by restored endometrial architecture, increased gland number, reduced fibrosis, and significantly improved pregnancy outcomes in vivo. Our findings establish ALDH1A1/ALDH1A2 as key functional markers of a regenerative eMSC subpopulation depleted in IUA and highlight the ALDH-RA axis as a critical mechanism governing endometrial repair.