Integrated biochemical and mechanical signals regulate multifaceted human embryonic stem cell functions.
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.
Li
Dong
D
Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Zhou
Jiaxi
J
Wang
Lu
L
Shin
Myung Eun
ME
Su
Pei
P
Lei
Xiaohua
X
Kuang
Haibin
H
Guo
Weixiang
W
Yang
Hong
H
Cheng
Linzhao
L
Tanaka
Tetsuya S
TS
Leckband
Deborah E
DE
Reynolds
Albert B
AB
Duan
Enkui
E
Wang
Fei
F
D015820:Cadherins / Q000378:metabolism; D051177:Catenins / Q000378:metabolism; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D024507:Nonmuscle Myosin Type IIA / Q000378:metabolism; D015398:Signal Transduction; D000095002:Delta Catenin
D015820:Cadherins; D051177:Catenins; D024507:Nonmuscle Myosin Type IIA; D000095002:Delta Catenin; C000722347:CTNND1 protein, human