Integrated biochemical and mechanical signals regulate multifaceted human embryonic stem cell functions

Author:

Li Dong11,Zhou Jiaxi11,Wang Lu11,Shin Myung Eun11,Su Pei11,Lei Xiaohua2,Kuang Haibin2,Guo Weixiang2,Yang Hong11,Cheng Linzhao3,Tanaka Tetsuya S.11,Leckband Deborah E.1,Reynolds Albert B.4,Duan Enkui2,Wang Fei11

Affiliation:

1. Institute for Genomic Biology, Department of Cell and Developmental Biology, Department of Animal Sciences, and Department of Chemical and Molecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801

2. State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Science, Beijing 100101, China

3. Stem Cell Program, Institute for Cell Engineering, School of Medicine, Johns Hopkins University, Baltimore, MD 21205

4. Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232

Abstract

Human embryonic stem cells (ESCs [hESCs]) proliferate as colonies wherein individual cells are strongly adhered to one another. This architecture is linked to hESC self-renewal, pluripotency, and survival and depends on epithelial cadherin (E-cadherin), NMMIIA (nonmuscle myosin IIA), and p120-catenin. E-cadherin and p120-catenin work within a positive feedback loop that promotes localized accumulation of E-cadherin at intercellular junctions. NMMIIA stabilizes p120-catenin protein and controls E-cadherin–mediated intercellular adhesion. Perturbations of this signaling network disrupt colony formation, destabilize the transcriptional regulatory circuitry for pluripotency, and impair long-term survival of hESCs. Furthermore, depletion of E-cadherin markedly reduces the efficiency of reprogramming of human somatic cells to an ESC-like state. The feedback regulation and mechanical–biochemical integration provide mechanistic insights for the regulation of intercellular adhesion and cellular architecture in hESCs during long-term self-renewal. Our findings also contribute to the understanding of microenvironmental regulation of hESC identity and somatic reprogramming.

Publisher

Rockefeller University Press

Subject

Cell Biology

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