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Development. 2019 Dec 16;146(24). pii: dev180620. doi: 10.1242/dev.180620.

Naïve human pluripotent stem cells respond to Wnt, Nodal and LIF signalling to produce expandable naïve extra-embryonic endoderm.

Author information

1
Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen N, Denmark.
2
Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen N, Denmark joshua.brickman@sund.ku.dk.

Abstract

Embryonic stem cells (ESCs) exist in at least two states that transcriptionally resemble different stages of embryonic development. Naïve ESCs resemble peri-implantation stages and primed ESCs the pre-gastrulation epiblast. In mouse, primed ESCs give rise to definitive endoderm in response to the pathways downstream of Nodal and Wnt signalling. However, when these pathways are activated in naïve ESCs, they differentiate to a cell type resembling early primitive endoderm (PrE), the blastocyst-stage progenitor of the extra-embryonic endoderm. Here, we apply this context dependency to human ESCs, showing that activation of Nodal and Wnt signalling drives the differentiation of naïve pluripotent cells toward extra-embryonic PrE, or hypoblast, and these can be expanded as an in vitro model for naïve extra-embryonic endoderm (nEnd). Consistent with observations made in mouse, human PrE differentiation is dependent on FGF signalling in vitro, and we show that, by inhibiting FGF receptor signalling, we can simplify naïve pluripotent culture conditions, such that the inhibitor requirements closer resemble those used in mouse. The expandable nEnd cultures reported here represent stable extra-embryonic endoderm, or human hypoblast, cell lines.This article has an associated 'The people behind the papers' interview.

KEYWORDS:

Embryonic stem cells; FGF signalling; Human; Hypoblast; Naïve pluripotency; Primitive endoderm

PMID:
31740534
DOI:
10.1242/dev.180620

Conflict of interest statement

Competing interestsThe authors declare no competing or financial interests.

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