Lnc‐HZ05 Suppresses Trophoblast Cell Migrasome Formation by Disrupting TGFβ2 Pathway in Unexplained Recurrent Miscarriage

Unexplained recurrent miscarriage (RM) is a clinical challenge due to its unclear pathogenesis. TGFβ2 plays essential roles in reproductive events. Migrasomes are newly identified organelles. Herein, whether TGFβ2 might regulate trophoblast cell migrasome formation (MF) and miscarriage, and the epigenetic regulation mechanisms, is completely unknown. In this study, we find that TGFβ2-mediated MF is suppressed and is negatively associated with RM based on a case-control study, further confirmed by a mouse model with miscarriage. In cellular mechanism, TGFβ2 promotes trophoblast cell MF, specifically suppressed by lnc-HZ05. In details, lnc-HZ05 (1) suppresses FOXP3-mediated TGFβ2 transcription, (2) promotes autophagy degradation of TGFβ2, and (3) impairs TGFβ2/TGFβR2 interactions by binding to both proteins with 1-83 nt of lnc-HZ05, three of which suppress TGFβ2 pathway. Meanwhile, DNMT1 suppresses FOXP3-mediated lnc-HZ05 transcription, forming a FOXP3/lnc-HZ05 negative regulatory loop. The cellular mechanisms are consistent with those in RM villous tissues. Moreover, higher levels of TGFβ2 protein and lnc-HZ05 in serum well predict miscarriage risk. Supplement with murine Tgfβ2 protein recovers MF and alleviates mouse miscarriage. Collectively, this study discovers novel biological mechanisms of lnc-HZ05 and TGFβ2 pathway in the pathogenesis of RM and provides potential targets for prediction and therapy of RM.