Dual inhibition of Src and GSK3 maintains mouse embryonic stem cells, whose differentiation is mechanically regulated by Src signaling

Stem Cells
Takeshi ShimizuYasuhiro Sawada

Abstract

Recent studies reveal that the mechanical environment influences the behavior and function of various types of cells, including stem cells. However, signaling pathways involved in the mechanical regulation of stem cell properties remain largely unknown. Using polyacrylamide gels with varying Young's moduli as substrates, we demonstrate that mouse embryonic stem cells (mESCs) are induced to differentiate on substrates with defined elasticity, involving the Src-ShcA-MAP kinase pathway. While the dual inhibition of mitogen-activated protein (MAP) kinase and glycogen synthase kinase 3 (GSK3), termed "2i," was reported to sustain the pluripotency of mESCs, we find it to be substrate elasticity dependent. In contrast, Src inhibition in addition to 2i allows mESCs to retain their pluripotency independent of substrate elasticity. The alternative dual inhibition of Src and GSK3 ("alternative 2i") retains the pluripotency and self-renewal of mESCs in vitro and is instrumental in efficiently deriving mESCs from preimplantation mouse embryos. In addition, the transplantation of mESCs, maintained under the alternative 2i condition, to immunodeficient mice leads to the formation of teratomas that include differentiation into three germ layer...Continue Reading

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Citations

Oct 12, 2013·Experimental Cell Research·Seiichiro IshiharaHisashi Haga
Dec 12, 2012·Genes & Cancer·Hiroyuki MatsuiYasuhiro Sawada
Feb 11, 2016·Nature Reviews. Molecular Cell Biology·Leehee WeinbergerJacob H Hanna
Sep 10, 2014·Genesis : the Journal of Genetics and Development·Zhaoyu LinJing Zhao
Aug 21, 2015·Current Opinion in Genetics & Development·Yair S ManorJacob H Hanna
Oct 3, 2015·Cell Stem Cell·Aleksandra A KolodziejczykSarah A Teichmann
Mar 22, 2014·Journal of Cellular Physiology·Alvin Kunyao GuoKeiko Kawauchi
Jun 26, 2015·Stem Cells·Galbha DuggalBjörn Heindryckx
Oct 8, 2013·Biochimica Et Biophysica Acta·Hendrik Marks, Hendrik G Stunnenberg
Nov 3, 2016·Proceedings of the National Academy of Sciences of the United States of America·Naotaka NakazawaMichael P Sheetz
Dec 6, 2016·Molecular BioSystems·M BaranekJ Barciszewski
Dec 28, 2018·Journal of Neurochemistry·Takeshi ShimizuKazuhiro Ikenaka
Oct 18, 2013·American Journal of Physiology. Cell Physiology·Kimberly M Stroka, Konstantinos Konstantopoulos
Nov 14, 2018·Cellular and Molecular Life Sciences : CMLS·Seyedeh-Nafiseh HassaniHossein Baharvand
Apr 7, 2019·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Chinnadurai ManiKomaraiah Palle

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