Cell Stem Cell
Volume 28, Issue 6, 3 June 2021, Pages 1023-1039.e13
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Article
Capturing human trophoblast development with naive pluripotent stem cells in vitro

https://doi.org/10.1016/j.stem.2021.03.013Get rights and content
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Highlights

  • Trophectoderm can be generated from naive human pluripotent stem cells

  • Human trophoblast stem cells represent post-implantation cytotrophoblast

  • Trajectory of trophoblast from pre- to post-implantation is drawn by our model

  • ACE is essential for specification and maintenance of cytotrophoblast stem cells

Summary

Trophoblasts are extraembryonic cells that are essential for maintaining pregnancy. Human trophoblasts arise from the morula as trophectoderm (TE), which, after implantation, differentiates into cytotrophoblasts (CTs), syncytiotrophoblasts (STs), and extravillous trophoblasts (EVTs), composing the placenta. Here we show that naïve, but not primed, human pluripotent stem cells (PSCs) recapitulate trophoblast development. Naive PSC-derived TE and CTs (nCTs) recreated human and monkey TE-to-CT transition. nCTs self-renewed as CT stem cells and had the characteristics of proliferating villous CTs and CTs in the cell column of the first trimester. Notably, although primed PSCs differentiated into trophoblast-like cells (BMP4, A83-01, and PD173074 [BAP]-treated primed PSCs [pBAPs]), pBAPs were distinct from nCTs and human placenta-derived CT stem cells, exhibiting properties consistent with the amnion. Our findings establish an authentic paradigm for human trophoblast development, demonstrating the invaluable properties of naive human PSCs. Our system provides a platform to study the molecular mechanisms underlying trophoblast development and related diseases.

Keywords

amnion
cytotrophoblast
early pregnancy
extraembryonic tissue
implantation
primed pluripotent stem cells
naive pluripotent stem cells
trophectoderm
trophoblast
placenta

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