Mechanisms of early placental development in mouse and humans

Hemberger, Myriam; Hanna, Courtney W.; Dean, Wendy

doi:10.1038/s41576-019-0169-4

Cited by 346 publications

(358 citation statements)

References 190 publications

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“…The placenta with the three cellular layers, the Dz, Jz, and Lz, is formed at E9.5 and fully mature by E14.5. 3 Both qPCR and Western blot analyses revealed that Acer2 is expressed in the placenta between E9.5 and E12.5 (Figure 1), suggesting that Acer2 is expressed in the placenta at its early developmental stage. Histology revealed that Acer2 deficiency does not affect the formation of the three distinct cellular layers in the placenta at E12.5 ( Figure 5).…”

Section: Discussionmentioning

confidence: 96%

Maternal and fetal alkaline ceramidase 2 is required for placental vascular integrity in mice

Lin

et al. 2020

The FASEB Journal

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Sphingolipids have been implicated in mammalian placental development and function, but their regulation in the placenta remains unclear. Herein we report that alkaline ceramidase 2 (ACER2) plays a key role in sustaining the integrity of the placental vasculature by regulating the homeostasis of sphingolipids in mice. The mouse alkaline ceramidase 2 gene (Acer2) is highly expressed in the placenta between embryonic day (E) 9.5 and E12.5. Acer2 deficiency in both the mother and fetus decreases the placental levels of sphingolipids, including sphingoid bases (sphingosine and dihydrosphingosine) and sphingoid base-1-phosphates (sphingosine-1-phosphate and dihydrosphingosine-1-phosphate) and results in the in utero death of ≈50% of embryos at E12.5 whereas Acer2 deficiency in either the mother or fetus has no such effects. Acer2 deficiency causes hemorrhages from the maternal vasculature in the junctional and/or labyrinthine zones in E12.5 placentas. Moreover, hemorrhagic but not non-hemorrhagic Acer2-deficient placentas exhibit an expansion of parietal trophoblast giant cells with a concomitant decrease in the area of the fetal blood vessel network in the labyrinthine zone, suggesting that Acer2 deficiency results in embryonic lethality due to the atrophy of the fetal blood vessel network in | 15253 LI et aL.

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Section: Discussionmentioning

confidence: 96%

Maternal and fetal alkaline ceramidase 2 is required for placental vascular integrity in mice

Lin

et al. 2020

The FASEB Journal

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“…In the mouse, trophoblast stem cells (TSCs) can be derived by culturing extraembryonic ectoderm in the presence of FGF4, heparin and mouse embryonic fibroblasts (or supplementation of TGF-ß1/Activin) and can readily serve as an in vitro experimental platform 5 . Notably, the timing of developmental events 6,7 , organization of cell types 6,8 and trophoblast gene expression profiles 6,[9][10][11] differ greatly between the mouse and human. In addition, the conditions that drive mouse TSC derivation fail to support the differentiation of human TSCs 12 .…”

Section: Introduction (Main Text Not Including Abstract Methods Refmentioning

confidence: 99%

“…An alternative approach to obtaining trophoblast cell lines has been to isolate primary trophoblasts from early first trimester placental tissue 22 . It is postulated that a TSC niche resides in the early human first trimester placenta 8,[22][23][24] , where these cells are a proliferative, less differentiated progenitor cell population that gives rise to both villous cytotrophoblasts that fuse to form the syncytia as well as extravillous trophoblast (EVT) progenitor cells at the cell column tips 25 .…”

Section: Introduction (Main Text Not Including Abstract Methods Refmentioning

confidence: 99%

Derivation of macaque trophoblast stem cells

Schmidt

Meyer

Wiepz

et al. 2020

Preprint

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200 words max) Nonhuman primates are excellent models for studying human placentation as experimental manipulations in vitro can be translated to in vivo pregnancy. Our objective was to develop macaque trophoblast stem cells (TSC) as an in vitro platform for future assessment of primate trophoblast development and function. Macaque TSC lines were generated by isolating first trimester placental villous cytotrophoblasts followed by culture in TSC medium to "reprogram" the cells to a proliferative state. TSCs grew as mononuclear colonies, whereas upon induction of syncytiotrophoblast (ST) differentiation multinuclear structures appeared, indicative of syncytium formation. Chorionic gonadotropin secretion was >4,000-fold higher in ST culture media compared to TSC media. Characteristic trophoblast hallmarks were defined in TSCs and ST including expression of C19MC miRNAs and macaque placental nonclassical MHC class I molecule, Mamu-AG. TSC differentiation to extravillous trophoblasts (EVTs) with or without the ALK-5 inhibitor A83-01 resulted in differing morphologies but similar expression of Mamu-AG and CD56 as assessed by flow cytometry, hence further refinement of relevant EVT markers is needed. Our preliminary characterization of macaque TSCs suggests that these cells represent a proliferative, self-renewing TSC population capable of differentiating to STs in vitro thereby establishing an experimental model of primate placentation.

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“…Subsequently, the ExE form the chorion layer which gives rise to the labyrinth including two syncytiotrophoblast layers, while the EPC develops into the spongiotrophoblast layer [ 1 ]. The balanced differentiation of various trophoblast cell types is a prerequisite for normal placentation [ 3 , 4 ]. The achaete-scute complex homolog-like 2 ( Ascl2 , also Mash2 ), one member of the basic helix–loop–helix (bHLH) family, has been shown to play a critical role during EPC development.…”

Section: Introductionmentioning

confidence: 99%

Hyperactivated Wnt-β-catenin signaling in the absence of sFRP1 and sFRP5 disrupts trophoblast differentiation through repression of Ascl2

Bao

Liu

et al. 2020

BMC Biol

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Background Wnt signaling is a critical determinant for the maintenance and differentiation of stem/progenitor cells, including trophoblast stem cells during placental development. Hyperactivation of Wnt signaling has been shown to be associated with human trophoblast diseases. However, little is known about the impact and underlying mechanisms of excessive Wnt signaling during placental trophoblast development. Results In the present work, we observed that two inhibitors of Wnt signaling, secreted frizzled-related proteins 1 and 5 (Sfrp1 and Sfrp5), are highly expressed in the extraembryonic trophoblast suggesting possible roles in early placental development. Sfrp1 and Sfrp5 double knockout mice exhibited disturbed trophoblast differentiation in the placental ectoplacental cone (EPC), which contains the precursors of trophoblast giant cells (TGCs) and spongiotrophoblast cells. In addition, we employed mouse models expressing a truncated β-catenin with exon 3 deletion globally and trophoblast-specifically, as well as trophoblast stem cell lines, and unraveled that hyperactivation of canonical Wnt pathway exhausted the trophoblast precursor cells in the EPC, resulting in the overabundance of giant cells at the expense of spongiotrophoblast cells. Further examination uncovered that hyperactivation of canonical Wnt pathway disturbed trophoblast differentiation in the EPC via repressing Ascl2 expression. Conclusions Our investigations provide new insights that the homeostasis of canonical Wnt-β-catenin signaling is essential for EPC trophoblast differentiation during placental development, which is of high clinical relevance, since aberrant Wnt signaling is often associated with trophoblast-related diseases.

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Mechanisms of early placental development in mouse and humans

Cited by 346 publications

References 190 publications

Maternal and fetal alkaline ceramidase 2 is required for placental vascular integrity in mice

Maternal and fetal alkaline ceramidase 2 is required for placental vascular integrity in mice

Derivation of macaque trophoblast stem cells

Hyperactivated Wnt-β-catenin signaling in the absence of sFRP1 and sFRP5 disrupts trophoblast differentiation through repression of Ascl2

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