The multifaceted role of GCM1 during trophoblast differentiation in the human placenta.
The multifaceted role of GCM1 during trophoblast differentiation in the human placenta.
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DOI：
10.1073/pnas.2203071119
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发表时间：
2022-12-06
影响因子：
11.1
通讯作者：
Renaud, Stephen J.
中科院分区：
文献类型：
--
作者：
Jeyarajah, Mariyan J.;Bhattad, Gargi Jaju;Kelly, Rachel D.;Baines, Kelly J.;Jaremek, Adam;Yang, Fei-Hung P.;Okae, Hiroaki;Arima, Takahiro;Dumeaux, Vanessa;Renaud, Stephen J.
胎盘的正常发育对怀孕成功至关重要。胎盘发育不良与严重的妊娠并发症有关，危及母亲和婴儿的健康。胎盘的实质细胞是滋养层细胞，其由滋养层干细胞通过两种不同谱系途径之一分化而产生：合胞体滋养层细胞，其调节母胎营养转移，和绒毛外滋养层细胞（EVT），其重塑子宫脉管系统。胶质细胞缺失-1（GCM 1）是一种典型的与合体滋养层形成相关的转录因子，但GCM 1也在EVT中表达。在这项研究中，人类滋养层干细胞被用来证实GCM 1在合体滋养层形成中的作用，并揭示其在EVT发展中的关键作用。我们的结论是，GCM 1有助于人类胎盘的多个方面。侵袭性绒毛外滋养层细胞（EVT）对子宫血管的重塑是人类胎盘形成的一个重要方面。EVT侵入不足可导致严重的产科并发症，如先兆子痫、宫内生长受限和早产。神经胶质细胞缺失-1（GCM 1）是一种转录因子，对小鼠胎盘形成至关重要，在人类合体滋养层（ST）和EVT中高度表达。GCM 1被经典地认为是ST形成的主调节器，但关于其对EVT的发展和功能的贡献知之甚少。因此，在本研究中，我们检验了GCM 1是EVT和ST发展和功能的关键调节因子的假设。我们发现，GCM 1是高度表达的人滋养层干细胞（TS）分化成ST或EVT。TS细胞中GCM 1的敲低阻碍了向ST和EVT途径的分化。当置于ST培养基中时，GCM 1敲除细胞形成小的不稳定簇;当置于EVT培养基中时，细胞具有改变的形态和转录谱，类似于被困在CT和EVT之间的中间状态的细胞，并且通过基质的侵袭能力降低。GCM 1缺陷TS细胞的RNA测序分析显示EVT相关基因的下调和与WNT信号传导相关的转录物的富集，这与EVT主调节因子ASCL 2和WNT拮抗剂NOTUM的表达降低有关。我们的研究结果揭示了GCM 1在ST和EVT发展过程中的重要作用，并表明GCM 1通过诱导ASCL 2和NOTUM的表达来调节人TS细胞向EVT的分化。
Proper placental development is critical for pregnancy success. Placental maldevelopment is linked with serious pregnancy complications that jeopardize the health of both mother and child. The parenchymal cells of the placenta are trophoblasts, which arise from trophoblast stem cells differentiating through one of two distinct lineage pathways: syncytiotrophoblast, which regulates maternal-fetal nutrient transfer, and extravillous trophoblasts (EVTs), which remodel the uterine vasculature. Glial cells missing-1 (GCM1) is a transcription factor classically associated with syncytiotrophoblast formation, but GCM1 is also expressed in EVTs. In this study, human trophoblast stem cells were used to corroborate the role of GCM1 in syncytiotrophoblast formation and uncover its critical role in EVT development. We conclude that GCM1 contributes to multiple aspects of human placentation. Remodeling of the uterine vasculature by invasive extravillous trophoblasts (EVTs) is a critical aspect of human placentation. Insufficient EVT invasion can lead to severe obstetrical complications like preeclampsia, intrauterine growth restriction, and preterm birth. Glial cells missing-1 (GCM1) is a transcription factor that is crucial for proper placentation in mice, and is highly expressed in human syncytiotrophoblast (ST) and EVTs. GCM1 is classically considered a master regulator of ST formation, but little is known about its contribution to the development and function of EVTs. Therefore, in this study we test the hypothesis that GCM1 is a critical regulator of both EVT and ST development and function. We show that GCM1 is highly expressed in human trophoblast stem (TS) cells differentiated into either ST or EVTs. Knockdown of GCM1 in TS cells hindered differentiation into both ST and EVT pathways. When placed in ST media, GCM1-knockdown cells formed small, unstable clusters; when placed in EVT media, cells had altered morphology and transcript profiles resembling cells trapped in an intermediate state between CT and EVT, and invasive capacity through matrix was reduced. RNA sequencing analysis of GCM1-deficient TS cells revealed downregulation of EVT-associated genes and enrichment in transcripts related to WNT signaling, which was linked to decreased expression of the EVT master regulator ASCL2 and the WNT antagonist NOTUM. Our findings reveal an essential role of GCM1 during ST and EVT development, and suggest that GCM1 regulates differentiation of human TS cells into EVTs by inducing expression of ASCL2 and NOTUM.
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