TFEB safeguards trophoblast syncytialization in humans and mice

• 成果类型: Article
• 署名作者: Zheng, Wanshan; Zhang, Yue; Xu, Peiqun; Wang, Zexin; Shao, Xuan; Chen, Chunyan; Cai, Han; Wang, Yinan; Sun, Ming-an; Deng, Wenbo; Liu, Fan; Lu, Jinhua; Zhang, Xueqin; Cheng, Dunjin; Mysorekar, Indira U.; Wang, Haibin; Wang, Yan- Ling; Hu, Xiaoqian; Cao, Bin
• 署名单位: Xiamen University; Xiamen University; Chinese Academy of Sciences; Institute of Zoology, CAS; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Beijing Institute for Stem Cell & Regenerative Medicine; Yangzhou University; Guangzhou Medical University; Guangzhou Medical University; Baylor College of Medicine; Baylor College of Medicine
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-15150
• DOI: 10.1073/pnas.2404062121
• 发表日期: 2024-07-09
• 关键词: syncytin-a; expression; autophagy; placenta; cells; receptor; network; protein

摘要

Nutrient sensing and adaptation in the placenta are essential for pregnancy viability and proper fetal growth. Our recent study demonstrated that the placenta adapts to nutrient insufficiency through mechanistic target of rapamycin (mTOR) inhibition- mediated trophoblast differentiation toward syncytiotrophoblasts (STBs), a highly specialized multinucleated trophoblast subtype mediating extensive maternal-fetal interactions. However, the underlying mechanism remains elusive. Here, we unravel the indispensable role of the mTORC1 downstream transcriptional factor TFEB in STB formation both in vitro and in vivo. TFEB deficiency significantly impaired STB differentiation in human trophoblasts and placenta organoids. Consistently, systemic or trophoblast- specific deletion of Tfeb compromised STB formation and placental vascular construction, leading to severe embryonic lethality. Mechanistically, TFEB conferred direct transcriptional activation of the fusogen ERVFRD- 1 in human trophoblasts and thereby promoted STB formation, independent of its canonical function as a master regulator of the autophagy- lysosomal pathway. Moreover, we demonstrated that TFEB directed the trophoblast syncytialization response driven by mTOR complex 1 (mTORC1) signaling. TFEB expression positively correlated with the reinforced trophoblast syncytialization in human fetal growth-restricted placentas exhibiting suppressed mTORC1 activity. Our findings substantiate that the TFEB- fusogen axis ensures proper STB formation during placenta development and under nutrient stress, shedding light on TFEB as a mechanistic link between nutrient- sensing machinery and trophoblast differentiation.