mTORC2-mediated cell-cell interactions promote BMP4-induced WNT activation and mesoderm differentiation
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
The mechanistic target of rapamycin complex 2 (mTORC2) is essential for embryonic development but its underlying molecular mechanisms remain unclear. Here we show that
disruption of mTORC2 in human embryonic stem cells (hESCs) considerably alters the Rho/Rac signaling dynamics and reduces E-cadherin expression and cell adhesion. Despite this, mTORC2-deficient hESCs maintain self-renewal and expression of pluripotent markers
when cultured in mouse-embryonic fibroblast conditioned medium supplemented with bFGF (MEF-CM). However, these hESCs exhibit significantly impaired mesoderm and endoderm differentiation in response to BMP4 and Activin treatment, respectively, possibly due to reduced WNT activation mediated by cell-cell interactions. Direct activation of the WNT pathway using a GSK3 inhibitor restores mesendoderm differentiation in mTORC2-deficient hESCs. Our study uncovers a novel mechanism by which mTORC2 regulates cell fate determination and highlights a critical link between the intercellular adhesion and the activation of canonical WNT genes.
disruption of mTORC2 in human embryonic stem cells (hESCs) considerably alters the Rho/Rac signaling dynamics and reduces E-cadherin expression and cell adhesion. Despite this, mTORC2-deficient hESCs maintain self-renewal and expression of pluripotent markers
when cultured in mouse-embryonic fibroblast conditioned medium supplemented with bFGF (MEF-CM). However, these hESCs exhibit significantly impaired mesoderm and endoderm differentiation in response to BMP4 and Activin treatment, respectively, possibly due to reduced WNT activation mediated by cell-cell interactions. Direct activation of the WNT pathway using a GSK3 inhibitor restores mesendoderm differentiation in mTORC2-deficient hESCs. Our study uncovers a novel mechanism by which mTORC2 regulates cell fate determination and highlights a critical link between the intercellular adhesion and the activation of canonical WNT genes.
Date Issued
2025-11-11
Date Acceptance
2025-09-19
Citation
Stem Cell Reports, 2025, 20 (11)
ISSN
2213-6711
Publisher
Elsevier
Journal / Book Title
Stem Cell Reports
Volume
20
Issue
11
Copyright Statement
© 2025 The Authors. Published by Elsevier Inc. on behalf of International Society for Stem Cell Research. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
License URL
Publication Status
Published
Article Number
102680
Date Publish Online
2025-10-16