Tipping the balance toward trophoblast development

Soares, Michael J.; Vivian, Jay L.

doi:10.1073/pnas.1604914113

Cited by 8 publications

(4 citation statements)

References 18 publications

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“…However, experimental studies are hampered by ethical constraints to obtain tissues from early human gestation as well as difficulties in establishing self-renewing human trophoblast stem and progenitor cells from trophoblast isolates (34)(35)(36). As a consequence, alternative models, such as bone morphogenetic protein (BMP)-treated human ESCs (hESCs), have been developed, allowing in vitro formation of the trophoblast lineage (37,38).…”

Section: Discussionmentioning

confidence: 99%

Notch1 controls development of the extravillous trophoblast lineage in the human placenta

Haider

Meinhardt

Saleh

et al. 2016

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

124

144

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Development of the human placenta and its different epithelial trophoblasts is crucial for a successful pregnancy. Besides fusing into a multinuclear syncytium, the exchange surface between mother and fetus, progenitors develop into extravillous trophoblasts invading the maternal uterus and its spiral arteries. Migration into these vessels promotes remodelling and, as a consequence, adaption of blood flow to the fetal–placental unit. Defects in remodelling and trophoblast differentiation are associated with severe gestational diseases, such as preeclampsia. However, mechanisms controlling human trophoblast development are largely unknown. Herein, we show that Notch1 is one such critical regulator, programming primary trophoblasts into progenitors of the invasive differentiation pathway. At the 12th wk of gestation, Notch1 is exclusively detected in precursors of the extravillous trophoblast lineage, forming cell columns anchored to the uterine stroma. At the 6th wk, Notch1 is additionally expressed in clusters of villous trophoblasts underlying the syncytium, suggesting that the receptor initiates the invasive differentiation program in distal regions of the developing placental epithelium. Manipulation of Notch1 in primary trophoblast models demonstrated that the receptor promotes proliferation and survival of extravillous trophoblast progenitors. Notch1 intracellular domain induced genes associated with stemness of cell columns, myc and VE-cadherin, in Notch1−fusogenic precursors, and bound to themycpromoter and enhancer region at RBPJκ cognate sequences. In contrast, Notch1 repressed syncytialization and expression of TEAD4 and p63, two regulators controlling self-renewal of villous cytotrophoblasts. Our results revealed Notch1 as a key factor promoting development of progenitors of the extravillous trophoblast lineage in the human placenta.

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Section: Discussionmentioning

confidence: 99%

Notch1 controls development of the extravillous trophoblast lineage in the human placenta

Haider

Meinhardt

Saleh

et al. 2016

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

124

144

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“…Our observations may raise the idea that free heme can induce special cell and organ damage based on its subcellular localization. This hypothesis is supported by the fact labile heme can be detected in the ER, the plasma membrane, mitochondria, nucleus, and the cytosol as elegantly demonstrated by Hamza’s group 70 . Further research is needed to reveal free heme-induced cell damages in a subcellular compartment-specific manner.…”

Section: Discussionmentioning

confidence: 78%

Heme cytotoxicity is the consequence of endoplasmic reticulum stress in atherosclerotic plaque progression

Pethő

Hendrik

Nagy

et al. 2021

Sci Rep

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Hemorrhage and hemolysis with subsequent heme release are implicated in many pathologies. Endothelial cells (ECs) encounter large amount of free heme after hemolysis and are at risk of damage from exogenous heme. Here we show that hemorrhage aggravates endoplasmic reticulum (ER) stress in human carotid artery plaques compared to healthy controls or atheromas without hemorrhage as demonstrated by RNA sequencing and immunohistochemistry. In EC cultures, heme also induces ER stress. In contrast, if cultured ECs are pulsed with heme arginate, cells become resistant to heme-induced ER (HIER) stress that is associated with heme oxygenase-1 (HO-1) and ferritin induction. Knocking down HO-1, HO-2, biliverdin reductase, and ferritin show that HO-1 is the ultimate cytoprotectant in acute HIER stress. Carbon monoxide-releasing molecules (CORMs) but not bilirubin protects cultured ECs from HIER stress via HO-1 induction, at least in part. Knocking down HO-1 aggravates heme-induced cell death that cannot be counterbalanced with any known cell death inhibitors. We conclude that endothelium and perhaps other cell types can be protected from HIER stress by induction of HO-1, and heme-induced cell death occurs via HIER stress that is potentially involved in the pathogenesis of diverse pathologies with hemolysis and hemorrhage including atherosclerosis.

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“…Despite a drop in DNA methylation (from >80% to 30%), ELF5 expression remains very low in these cells, transcript levels of the miRNA cluster are much lower than expected from bona fide trophoblast, and their HLA I expression pattern does not reflect that of primary trophoblast (Lee et al, 2016). Furthermore, a comparison of ST obtained from hESCs and from term placenta revealed that, despite overall gene expression similarities, they are sufficiently different to be considered two different cell types (Soares and Vivian, 2016;Yabe et al, 2016). Thus, although these trophoblast-resembling cells may serve as a useful tool for some functional analyses, some caution is necessary in their use and in data interpretation, and hESC-derived trophoblast-like cells should not per se be regarded as identical to primary placental trophoblast.…”

Section: Reprogramming Into Itscsmentioning

confidence: 88%

From the stem of the placental tree: trophoblast stem cells and their progeny

2016

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Trophoblast stem cells (TSCs) retain the capacity to self-renew indefinitely and harbour the potential to differentiate into all trophoblast subtypes of the placenta. Recent studies have shown how signalling cascades integrate with transcription factor circuits to govern the fine balance between TSC self-renewal and differentiation. In addition, breakthroughs in reprogramming strategies have enabled the generation of TSCs from fibroblasts, opening up exciting new avenues that may allow the isolation of this stem cell type from other species, notably humans. Here, we review these recent advances in light of their importance for understanding placental pathologies and developing personalised medicine approaches for pregnancy complications.

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Tipping the balance toward trophoblast development

Cited by 8 publications

References 18 publications

Notch1 controls development of the extravillous trophoblast lineage in the human placenta

Notch1 controls development of the extravillous trophoblast lineage in the human placenta

Heme cytotoxicity is the consequence of endoplasmic reticulum stress in atherosclerotic plaque progression

From the stem of the placental tree: trophoblast stem cells and their progeny

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