文章基本信息

标题：Hippo signaling cofactor, WWTR1, at the crossroads of human trophoblast progenitor self-renewal and differentiation
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作者：Soma Ray ; Abhik Saha ; Ananya Ghosh 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：36
DOI：10.1073/pnas.2204069119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance Human pregnancy relies on the formation of the transient organ placenta, and trophoblast cells are the major building blocks of the placenta. A defect in trophoblast progenitor self-renewal or its differentiation is associated with either pregnancy loss or pathological pregnancies, yet the underlying molecular mechanisms that regulate trophoblast differentiation are poorly understood. In this study, we discovered that WW domain containing transcription regulator 1 (WWTR1), a transcription cofactor and a component of the conserved Hippo signaling pathway, optimizes trophoblast progenitor self-renewal and is essential for its differentiation into the invasive extravillous trophoblast cell lineage. Our findings establish WWTR1 as a critical regulator for success in human placentation and progression of a healthy pregnancy. Healthy progression of human pregnancy relies on cytotrophoblast (CTB) progenitor self-renewal and its differentiation toward multinucleated syncytiotrophoblasts (STBs) and invasive extravillous trophoblasts (EVTs). However, the underlying molecular mechanisms that fine-tune CTB self-renewal or direct its differentiation toward STBs or EVTs during human placentation are poorly defined. Here, we show that Hippo signaling cofactor WW domain containing transcription regulator 1 (WWTR1) is a master regulator of trophoblast fate choice during human placentation. Using human trophoblast stem cells (human TSCs), primary CTBs, and human placental explants, we demonstrate that WWTR1 promotes self-renewal in human CTBs and is essential for their differentiation to EVTs. In contrast, WWTR1 prevents induction of the STB fate in undifferentiated CTBs. Our single-cell RNA sequencing analyses in first-trimester human placenta, along with mechanistic analyses in human TSCs revealed that WWTR1 fine-tunes trophoblast fate by directly regulating WNT signaling components. Importantly, our analyses of placentae from pathological pregnancies show that extreme preterm births (gestational time ≤28 wk) are often associated with loss of WWTR1 expression in CTBs. In summary, our findings establish the critical importance of WWTR1 at the crossroads of human trophoblast progenitor self-renewal versus differentiation. It plays positive instructive roles in promoting CTB self-renewal and EVT differentiation and safeguards undifferentiated CTBs from attaining the STB fate.
关键词：enplacentacytotrophoblasthuman TSCHippo signalingWWTR1