WNT and NOTCH signaling in human trophoblast development and differentiation

Dietrich, Bianca; Haider, Sandra; Meinhardt, Gerold; Pollheimer, Jürgen; Knöfler, Martin

doi:10.1007/s00018-022-04285-3

Cited by 45 publications

(37 citation statements)

References 147 publications

(225 reference statements)

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“…The WNT signaling pathway has also been implicated in the CTB self-renewal process ( 26 ), as well as the differentiation to EVTs ( 42 ). Gene expression analyses reported by earlier studies ( 25 , 34 ) showed that along with various WNT molecules, several other components of the WNT signaling pathway are highly expressed in trophoblast cells of a developing placenta. The WNT receptors FZD5 and FZD6 are highly expressed in CTBs and EVTs, and β-catenin is abundantly expressed in all three trophoblast cell types of a developing human placenta ( 25 , 34 ).…”

Section: Discussionmentioning

confidence: 90%

“…Gene expression analyses reported by earlier studies ( 25 , 34 ) showed that along with various WNT molecules, several other components of the WNT signaling pathway are highly expressed in trophoblast cells of a developing placenta. The WNT receptors FZD5 and FZD6 are highly expressed in CTBs and EVTs, and β-catenin is abundantly expressed in all three trophoblast cell types of a developing human placenta ( 25 , 34 ). The WNT processing enzyme PORCN is also expressed, albeit at a low level, in CTBs and EVTs, and its expression is induced in STBs.…”

Section: Discussionmentioning

confidence: 90%

Section: Resultsmentioning

confidence: 99%

“…The WNT signaling pathway is pivotal for maintenance of self-renewal in CTB progenitors [reviewed in ( 34 )]. Along with WNT molecules, other components of the WNT-signaling pathway, including Frizzled 5,6, beta catenin, and several T cell factor (TCF) family members, are highly expressed in CTBs and CTB-derived human TSCs ( 25 , 34 ). Thus, our experiments showing direct regulation of WNT7A, WNT3, and WNT4 in human TSCs indicate a WWTR1–WNT regulatory axis that could orchestrate gene expression programs in human CTB progenitors.…”

Section: Resultsmentioning

confidence: 99%

“…The WNT processing enzyme PORCN is also expressed, albeit at a low level, in CTBs and EVTs, and its expression is induced in STBs. Furthermore, repressors of the WNT signaling pathway, including GSK3β, TCF7, and TCF7L2, are highly expressed in CTBs and EVTs of a developing human placenta ( 25 , 34 ). These findings indicate a major role of the WNT signaling pathway in the dynamics of human trophoblast development.…”

Section: Discussionmentioning

confidence: 99%

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Hippo signaling cofactor, WWTR1, at the crossroads of human trophoblast progenitor self-renewal and differentiation

Ray

Saha

Ghosh

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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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.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

Hippo signaling cofactor, WWTR1, at the crossroads of human trophoblast progenitor self-renewal and differentiation

Ray

Saha

Ghosh

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Similarities and differences in placental development between humans and cynomolgus monkeys

Matsumoto

Okamura

Muto

et al. 2023

Reprod Medicine & Biology

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BackgroundThe placenta is an extraembryonic organ, which is essential to maintain a normal pregnancy. However, placental development in humans is poorly understood because of technical and ethical reasons.MethodsWe analyzed the anatomical localization of each trophoblastic subtype in the cynomolgus monkey placenta by immunohistochemistry in the early second trimester. Histological differences among the mouse, cynomolgus monkey, and human placenta were compared. The PubMed database was used to search for studies on placentation in rodents and primates.Main findingsThe anatomical structures and subtypes of the placenta in cynomolgus monkeys are highly similar to those in humans, with the exception of fewer interstitial extravillous trophoblasts in cynomolgus monkeys.ConclusionThe cynomolgus monkey appears to be a good animal model to investigate human placentation.

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Exosomal encapsulation of miR-3198 promotes proliferation and migration of trophoblasts in preeclampsia

Li,

Yu,

et al. 2024

J Assist Reprod Genet

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Purpose Preeclampsia (PE) is a vascular remodeling disorder cloesly linked to trophoblast dysfunction, involving defects in their proliferation, migration, and apoptosis. Maternal exosomal microRNAs (miRNAs) have been reported to play pivotal roles in the development of PE. However, the mechanism underlying the role of maternal exosomes in trophoblast dysfunction regarding the development of PE is poorly understood. Methods Plasma exosomes from maternal peripheral blood were collected from pregnant women with PE and from those with normal pregnancy. Bioinformatics analysis was used to identify significantly differentially expressed miRNAs under these two conditions. The expression of the miR-3198 gene in plasma exosomes was detected using quantitative real-time polymerase chain reaction. Dual luciferase reporter assay was used to confirm binding of miR-3198 and 3′UTR region of WNT3. Cell proliferation was examined using the Cell Count Kit-8 and EdU assays, and flow cytometry was performed to detect apoptosis and cell cycle. Changes in cell migration were examined using transwell and scratch assays. Results Patients with PE showed decreased expression of plasma-derived exosomal miR-3198. The proliferation and migration abilities of HTR-8/SVneo and primary human trophoblast cells were both improved when cocultured with miR-3198-rich exosomes. Exposure to miR-3198-enriched exosomes facilitated cell cycle progression but reduced apoptosis in HTR-8/SVneo cells. Notably, overexpression of miR-3198 partially prevented the inhibitory effects of WNT3 on proliferation and migration in HTR-8/SVneo cells. Conclusion Exosomal miR-3198 in the maternal peripheral blood may regulate the biological functions of trophoblasts by targeting WNT3 and influence the development of diseases of placental origin. Graphical Abstract

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WNT and NOTCH signaling in human trophoblast development and differentiation

Cited by 45 publications

References 147 publications

Hippo signaling cofactor, WWTR1, at the crossroads of human trophoblast progenitor self-renewal and differentiation

Hippo signaling cofactor, WWTR1, at the crossroads of human trophoblast progenitor self-renewal and differentiation

Similarities and differences in placental development between humans and cynomolgus monkeys

Exosomal encapsulation of miR-3198 promotes proliferation and migration of trophoblasts in preeclampsia

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