Lateral confined growth of cells activates Lef1 dependent pathways to regulate cell-state transitions

Long-term sustained mechano-chemical signals in tissue microenvironment regulate cell-state transitions. In recent work, we showed that laterally confined growth of fibroblasts induce dedifferentiation programs. However, the molecular mechanisms underlying such mechanically induced cell-state transi...

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Bibliographic Details
Published in:Scientific reports 2022-10, Vol.12 (1), p.17318-17318, Article 17318
Main Authors: Yuan, Luezhen, Roy, Bibhas, Ratna, Prasuna, Uhler, Caroline, Shivashankar, G. V.
Format: Article
Language:English
Subjects:
631/114
631/532
631/80
beta Catenin - genetics
beta Catenin - metabolism
Cell activation
Cell differentiation
Cell Differentiation - genetics
Fibroblasts
Humanities and Social Sciences
Lymphoid Enhancer-Binding Factor 1 - genetics
Lymphoid Enhancer-Binding Factor 1 - metabolism
Mechanotransduction
Mechanotransduction, Cellular
Microenvironments
Molecular modelling
multidisciplinary
NF-κB protein
Science
Science (multidisciplinary)
Signal Transduction
Smad4 protein
Transcription Factors - metabolism
β-Catenin
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Summary:Long-term sustained mechano-chemical signals in tissue microenvironment regulate cell-state transitions. In recent work, we showed that laterally confined growth of fibroblasts induce dedifferentiation programs. However, the molecular mechanisms underlying such mechanically induced cell-state transitions are poorly understood. In this paper, we identify Lef1 as a critical somatic transcription factor for the mechanical regulation of de-differentiation pathways. Network optimization methods applied to time-lapse RNA-seq data identify Lef1 dependent signaling as potential regulators of such cell-state transitions. We show that Lef1 knockdown results in the down-regulation of fibroblast de-differentiation and that Lef1 directly interacts with the promoter regions of downstream reprogramming factors. We also evaluate the potential upstream activation pathways of Lef1, including the Smad4, Atf2, NFkB and Beta-catenin pathways, thereby identifying that Smad4 and Atf2 may be critical for Lef1 activation. Collectively, we describe an important mechanotransduction pathway, including Lef1, which upon activation, through progressive lateral cell confinement, results in fibroblast de-differentiation .
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-022-21596-4