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Signalling pathway crosstalk stimulated by L-proline drives mouse embryonic stem cells to primitive-ectoderm-like cells

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posted on 2023-11-06, 05:27 authored by Hannah Glover, Holly Holliday, Rachel Shparberg, David WinklerDavid Winkler, Margot Day, Michael Morris
The amino acid L-proline exhibits novel growth factor-like properties during development - from improving blastocyst development to driving neurogenesis in vitro. Addition of 400 µM L-proline to self-renewal medium drives naïve mouse embryonic stem cells (ESCs) to early primitive ectoderm-like (EPL) cells - a transcriptionally distinct primed or partially primed pluripotent state. EPL cells retain expression of pluripotency genes, upregulate primitive ectoderm markers, undergo a morphological change, and have increased cell number. These changes are facilitated by a complex signalling network hinging on the Mapk, Fgfr, Pi3k and mTor pathways. Here, we use a factorial experimental design coupled with statistical modelling to understand which signalling pathways are involved in the transition between ESCs and EPL cells, and how they underpin changes in morphology, cell number, apoptosis, proliferation, and gene expression. This approach reveals pathways which work antagonistically or synergistically. Most properties were affected by more than one inhibitor, and each inhibitor blocked specific aspects of the naïve-to-primed transition. These mechanisms underpin progression of stem cells across the in vitro pluripotency continuum and serve as a model for pre-, peri- and post-implantation embryogenesis.

Funding

Bosch Institute and School of Medical Sciences, The University of Sydney.

History

Publication Date

2023-10-26

Journal

Development

Volume

150

Issue

20

Article Number

dev.201704

Pagination

14p.

Publisher

The Company of Biologists

ISSN

1873-5061

Rights Statement

© 2023 The Authors. Published by The Company of Biologists Ltd This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

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