Hes1 Desynchronizes Differentiation of Pluripotent Cells by Modulating STAT3 Activity

Overview

Journal Stem Cells

Publisher Oxford University Press

Specialties Cell Biology
Reproductive Medicine

Date 2013 May 8

PMID 23649667

Citations 21

Authors

Xinzhi Zhou

Andrew J H Smith

Anna Waterhouse

Guillaume Blin

Mattias Malaguti

Chia-Yi Lin

Rodrigo Osorno

Ian Chambers

Sally Lowell

Affiliations

Soon will be listed here.

Abstract

Robust development of the early embryo may benefit from mechanisms that ensure that not all pluripotent cells differentiate at exactly the same time: such mechanisms would build flexibility into the process of lineage allocation. This idea is supported by the observation that pluripotent stem cells differentiate at different rates in vitro. We use a clonal commitment assay to confirm that pluripotent cells commit to differentiate asynchronously even under uniform differentiation conditions. Stochastic variability in expression of the Notch target gene Hes1 has previously been reported to influence neural versus mesodermal differentiation through modulation of Notch activity. Here we report that Hes1 also has an earlier role to delay exit from the pluripotent state into all lineages. The early function of Hes1 to delay differentiation can be explained by an ability of Hes1 to amplify STAT3 responsiveness in a cell-autonomous manner. Variability in Hes1 expression therefore helps to explain why STAT3 responsiveness varies between individual ES cells, and this in turn helps to explain why pluripotent cells commit to differentiate asynchronously.

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References

Kamakura S, Oishi K, Yoshimatsu T, Nakafuku M, Masuyama N, Gotoh Y . Hes binding to STAT3 mediates crosstalk between Notch and JAK-STAT signalling. Nat Cell Biol. 2004; 6(6):547-54. DOI: 10.1038/ncb1138. View

de la Pompa J, Wakeham A, Correia K, Samper E, Brown S, Aguilera R . Conservation of the Notch signalling pathway in mammalian neurogenesis. Development. 1997; 124(6):1139-48. DOI: 10.1242/dev.124.6.1139. View

Niwa H, Yamamura K, Miyazaki J . Efficient selection for high-expression transfectants with a novel eukaryotic vector. Gene. 1991; 108(2):193-9. DOI: 10.1016/0378-1119(91)90434-d. View

Ying Q, Nichols J, Evans E, Smith A . Changing potency by spontaneous fusion. Nature. 2002; 416(6880):545-8. DOI: 10.1038/nature729. View

Yoshiura S, Ohtsuka T, Takenaka Y, Nagahara H, Yoshikawa K, Kageyama R . Ultradian oscillations of Stat, Smad, and Hes1 expression in response to serum. Proc Natl Acad Sci U S A. 2007; 104(27):11292-7. PMC: 1899192. DOI: 10.1073/pnas.0701837104. View

Tesar P, Chenoweth J, Brook F, Davies T, Evans E, Mack D . New cell lines from mouse epiblast share defining features with human embryonic stem cells. Nature. 2007; 448(7150):196-9. DOI: 10.1038/nature05972. View

Banaszynski L, Chen L, Maynard-Smith L, Ooi A, Wandless T . A rapid, reversible, and tunable method to regulate protein function in living cells using synthetic small molecules. Cell. 2006; 126(5):995-1004. PMC: 3290523. DOI: 10.1016/j.cell.2006.07.025. View

Smith A, Heath J, Donaldson D, Wong G, Moreau J, Stahl M . Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides. Nature. 1988; 336(6200):688-90. DOI: 10.1038/336688a0. View

Chambers I, Silva J, Colby D, Nichols J, Nijmeijer B, Robertson M . Nanog safeguards pluripotency and mediates germline development. Nature. 2007; 450(7173):1230-4. DOI: 10.1038/nature06403. View

10.

Peerani R, Onishi K, Mahdavi A, Kumacheva E, Zandstra P . Manipulation of signaling thresholds in "engineered stem cell niches" identifies design criteria for pluripotent stem cell screens. PLoS One. 2009; 4(7):e6438. PMC: 2713412. DOI: 10.1371/journal.pone.0006438. View

11.

Toyooka Y, Shimosato D, Murakami K, Takahashi K, Niwa H . Identification and characterization of subpopulations in undifferentiated ES cell culture. Development. 2008; 135(5):909-18. DOI: 10.1242/dev.017400. View

12.

Hatakeyama J, Kageyama R . Notch1 expression is spatiotemporally correlated with neurogenesis and negatively regulated by Notch1-independent Hes genes in the developing nervous system. Cereb Cortex. 2006; 16 Suppl 1:i132-7. DOI: 10.1093/cercor/bhj166. View

13.

Hall J, Guo G, Wray J, Eyres I, Nichols J, Grotewold L . Oct4 and LIF/Stat3 additively induce Krüppel factors to sustain embryonic stem cell self-renewal. Cell Stem Cell. 2009; 5(6):597-609. DOI: 10.1016/j.stem.2009.11.003. View

14.

Wallace H, Marques-Kranc F, Richardson M, Luna-Crespo F, Sharpe J, Hughes J . Manipulating the mouse genome to engineer precise functional syntenic replacements with human sequence. Cell. 2007; 128(1):197-209. DOI: 10.1016/j.cell.2006.11.044. View

15.

Brons I, Smithers L, Trotter M, Rugg-Gunn P, Sun B, Chuva de Sousa Lopes S . Derivation of pluripotent epiblast stem cells from mammalian embryos. Nature. 2007; 448(7150):191-5. DOI: 10.1038/nature05950. View

16.

Tang F, Barbacioru C, Bao S, Lee C, Nordman E, Wang X . Tracing the derivation of embryonic stem cells from the inner cell mass by single-cell RNA-Seq analysis. Cell Stem Cell. 2010; 6(5):468-78. PMC: 2954317. DOI: 10.1016/j.stem.2010.03.015. View

17.

Morii E, Tsujimura T, Jippo T, Hashimoto K, Takebayashi K, Tsujino K . Regulation of mouse mast cell protease 6 gene expression by transcription factor encoded by the mi locus. Blood. 1996; 88(7):2488-94. View

18.

Schumann R, Kirschning C, Unbehaun A, Aberle H, Knope H, Lamping N . The lipopolysaccharide-binding protein is a secretory class 1 acute-phase protein whose gene is transcriptionally activated by APRF/STAT/3 and other cytokine-inducible nuclear proteins. Mol Cell Biol. 1996; 16(7):3490-503. PMC: 231344. DOI: 10.1128/MCB.16.7.3490. View

19.

Niwa H, Ogawa K, Shimosato D, Adachi K . A parallel circuit of LIF signalling pathways maintains pluripotency of mouse ES cells. Nature. 2009; 460(7251):118-22. DOI: 10.1038/nature08113. View

20.

Katoh M, Katoh M . Integrative genomic analyses on HES/HEY family: Notch-independent HES1, HES3 transcription in undifferentiated ES cells, and Notch-dependent HES1, HES5, HEY1, HEY2, HEYL transcription in fetal tissues, adult tissues, or cancer. Int J Oncol. 2007; 31(2):461-6. View