Cargando…
Epithelial disruption drives mesendoderm differentiation in human pluripotent stem cells by enabling TGF-β protein sensing
The processes of primitive streak formation and fate specification in the mammalian epiblast rely on complex interactions between morphogens and tissue organization. Little is known about how these instructive cues functionally interact to regulate gastrulation. We interrogated the interplay between...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9867713/ https://www.ncbi.nlm.nih.gov/pubmed/36681697 http://dx.doi.org/10.1038/s41467-023-35965-8 |
_version_ | 1784876404809138176 |
---|---|
author | Legier, Thomas Rattier, Diane Llewellyn, Jack Vannier, Thomas Sorre, Benoit Maina, Flavio Dono, Rosanna |
author_facet | Legier, Thomas Rattier, Diane Llewellyn, Jack Vannier, Thomas Sorre, Benoit Maina, Flavio Dono, Rosanna |
author_sort | Legier, Thomas |
collection | PubMed |
description | The processes of primitive streak formation and fate specification in the mammalian epiblast rely on complex interactions between morphogens and tissue organization. Little is known about how these instructive cues functionally interact to regulate gastrulation. We interrogated the interplay between tissue organization and morphogens by using human induced pluripotent stem cells (hiPSCs) downregulated for the morphogen regulator GLYPICAN-4, in which defects in tight junctions result in areas of disrupted epithelial integrity. Remarkably, this phenotype does not affect hiPSC stemness, but impacts on cell fate acquisition. Strikingly, cells within disrupted areas become competent to perceive the gastrulation signals BMP4 and ACTIVIN A, an in vitro surrogate for NODAL, and thus differentiate into mesendoderm. Yet, disruption of epithelial integrity sustains activation of BMP4 and ACTIVIN A downstream effectors and correlates with enhanced hiPSC endoderm/mesoderm differentiation. Altogether, our results disclose epithelial integrity as a key determinant of TGF-β activity and highlight an additional mechanism guiding morphogen sensing and spatial cell fate change within an epithelium. |
format | Online Article Text |
id | pubmed-9867713 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-98677132023-01-23 Epithelial disruption drives mesendoderm differentiation in human pluripotent stem cells by enabling TGF-β protein sensing Legier, Thomas Rattier, Diane Llewellyn, Jack Vannier, Thomas Sorre, Benoit Maina, Flavio Dono, Rosanna Nat Commun Article The processes of primitive streak formation and fate specification in the mammalian epiblast rely on complex interactions between morphogens and tissue organization. Little is known about how these instructive cues functionally interact to regulate gastrulation. We interrogated the interplay between tissue organization and morphogens by using human induced pluripotent stem cells (hiPSCs) downregulated for the morphogen regulator GLYPICAN-4, in which defects in tight junctions result in areas of disrupted epithelial integrity. Remarkably, this phenotype does not affect hiPSC stemness, but impacts on cell fate acquisition. Strikingly, cells within disrupted areas become competent to perceive the gastrulation signals BMP4 and ACTIVIN A, an in vitro surrogate for NODAL, and thus differentiate into mesendoderm. Yet, disruption of epithelial integrity sustains activation of BMP4 and ACTIVIN A downstream effectors and correlates with enhanced hiPSC endoderm/mesoderm differentiation. Altogether, our results disclose epithelial integrity as a key determinant of TGF-β activity and highlight an additional mechanism guiding morphogen sensing and spatial cell fate change within an epithelium. Nature Publishing Group UK 2023-01-21 /pmc/articles/PMC9867713/ /pubmed/36681697 http://dx.doi.org/10.1038/s41467-023-35965-8 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Legier, Thomas Rattier, Diane Llewellyn, Jack Vannier, Thomas Sorre, Benoit Maina, Flavio Dono, Rosanna Epithelial disruption drives mesendoderm differentiation in human pluripotent stem cells by enabling TGF-β protein sensing |
title | Epithelial disruption drives mesendoderm differentiation in human pluripotent stem cells by enabling TGF-β protein sensing |
title_full | Epithelial disruption drives mesendoderm differentiation in human pluripotent stem cells by enabling TGF-β protein sensing |
title_fullStr | Epithelial disruption drives mesendoderm differentiation in human pluripotent stem cells by enabling TGF-β protein sensing |
title_full_unstemmed | Epithelial disruption drives mesendoderm differentiation in human pluripotent stem cells by enabling TGF-β protein sensing |
title_short | Epithelial disruption drives mesendoderm differentiation in human pluripotent stem cells by enabling TGF-β protein sensing |
title_sort | epithelial disruption drives mesendoderm differentiation in human pluripotent stem cells by enabling tgf-β protein sensing |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9867713/ https://www.ncbi.nlm.nih.gov/pubmed/36681697 http://dx.doi.org/10.1038/s41467-023-35965-8 |
work_keys_str_mv | AT legierthomas epithelialdisruptiondrivesmesendodermdifferentiationinhumanpluripotentstemcellsbyenablingtgfbproteinsensing AT rattierdiane epithelialdisruptiondrivesmesendodermdifferentiationinhumanpluripotentstemcellsbyenablingtgfbproteinsensing AT llewellynjack epithelialdisruptiondrivesmesendodermdifferentiationinhumanpluripotentstemcellsbyenablingtgfbproteinsensing AT vannierthomas epithelialdisruptiondrivesmesendodermdifferentiationinhumanpluripotentstemcellsbyenablingtgfbproteinsensing AT sorrebenoit epithelialdisruptiondrivesmesendodermdifferentiationinhumanpluripotentstemcellsbyenablingtgfbproteinsensing AT mainaflavio epithelialdisruptiondrivesmesendodermdifferentiationinhumanpluripotentstemcellsbyenablingtgfbproteinsensing AT donorosanna epithelialdisruptiondrivesmesendodermdifferentiationinhumanpluripotentstemcellsbyenablingtgfbproteinsensing |