Epithelial Disruption Drives Mesendoderm Differentiation In human Pluripotent Stem Cells by Enabling TGF-β Protein Sensing

Overview

Journal Nat Commun

Specialty Biology

Date 2023 Jan 21

PMID 36681697

Authors

Thomas Legier

Diane Rattier

Jack Llewellyn

Thomas Vannier

Benoit Sorre

Flavio Maina

Rosanna Dono

Affiliations

Soon will be listed here.

Abstract

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.

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