2. Academic Validation
  3. Lnc-HZ05 Suppresses Trophoblast Cell Migrasome Formation by Disrupting TGFβ2 Pathway in Unexplained Recurrent Miscarriage

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

  • Adv Sci (Weinh). 2025 Oct 30:e17558. doi: 10.1002/advs.202417558.
Weina Chen 1 2,  Ying Zhang 1 3,  Zimeng Zhao 1 4,  Yang Yang 1,  Geng Guo 5,  Yi Sun 1,  Tao Zhang 6,  Zhihong Zhang 7,  Liqin Zeng 8,  Wenxin Huang 1,  Qingjun Shen 8,  Ruining Han 8,  Zhaohui He 9,  Depeng Zhao 10,  Huidong Zhang 1
Affiliations

Affiliations

  • 1 Research Center for Environment and Female Reproductive Health, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, China.
  • 2 Department of Endocrinology, Metabolic and Chronic Disease Science Innovation Center, The Second Affiliated Hospital of Army Medical University, Chongqing, 400037, China.
  • 3 Department of Obstetrics/Gynecology, Joint Laboratory of Reproductive Medicine, West China Second University Hospital, Sichuan University, Chengdu, 610041, China.
  • 4 Reproductive Medical Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
  • 5 Department of Emergency, Cerebrovascular disease center, First Hospital of Shanxi Medical University, Taiyuan, 030001, China.
  • 6 Department of Obstetrics and Gynaecology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, 999077, China.
  • 7 MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan, 030001, China.
  • 8 Department of Obstetrics, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, Guangdong Province, 518033, China.
  • 9 Department of Urology, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518033, China.
  • 10 Shenzhen Maternity and Child Healthcare Hospital, Southern Medical University, Shenzhen, Guangdong, 518028, China.
PMID: 41168951 DOI: 10.1002/advs.202417558
Abstract

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.

Keywords

LncRNA or lnc‐HZ05; TGFβ2/TGFβR2/Smad3/FOXP3; female trophoblast cells; migration/invasion and migrasome formation; miscarriage.

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