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Src-family tyrosine kinase activities are essential for differentiation of human embryonic stem cells

Zhang, X and Simerly, C and Hartnett, C and Schatten, G and Smithgall, TE (2014) Src-family tyrosine kinase activities are essential for differentiation of human embryonic stem cells. Stem Cell Research (Part A). 379 - 389. ISSN 1873-5061

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Abstract

© 2014 Authors. Embryonic stem (ES) cells are characterized by pluripotency, defined as the developmental potential to generate cell lineages derived from all three primary germ layers. In the past decade, great progress has been made on the cell culture conditions, transcription factor programs and intracellular signaling pathways that control both murine and human ES cell fates. ES cells of mouse vs. human origin have distinct culture conditions, responding to some tyrosine kinase signaling pathways in opposite ways. Previous work has implicated the Src family of non-receptor protein-tyrosine kinases in mouse ES cell self-renewal and differentiation. Seven members of the Src kinase family are expressed in mouse ES cells, and individual family members appear to play distinct roles in regulating their developmental fate. Both Hck and c-Yes are important in self-renewal, while c-Src activity alone is sufficient to induce differentiation. While these findings implicate Src-family kinase signaling in mouse ES cell renewal and differentiation, the role of this kinase family in human ES cells is largely unknown. Here, we explored Src-family kinase expression patterns and signaling in human ES cells during self-renewal and differentiation. Of the eleven Src-related kinases in the human genome, Fyn, c-Yes, c-Src, Lyn, Lck and Hck were expressed in H1, H7 and H9 hES cells, while Fgr, Blk, Srm, Brk, and Frk transcripts were not detected. Of these, c-Yes, Lyn, and Hck transcript levels remained constant in self-renewing human ES cells vs. differentiated EBs, while c-Src and Fyn showed a modest increase in expression as a function of differentiation. In contrast, Lck expression levels dropped dramatically as a function of EB differentiation. To assess the role of overall Src-family kinase activity in human ES cell differentiation, cultures were treated with inhibitors specific for the Src kinase family. Remarkably, human ES cells maintained in the presence of the potent Src-family kinase inhibitor A-419259 retained the morphology of domed, pluripotent colonies and continued to express the self-renewal marker TRA-1-60 despite culture under differentiation conditions. Taken together, these observations support a role for Src-family kinase signaling in the regulation of human ES cell fate, and suggest that the activities of individual Src-family members are required for the initiation of the differentiation program.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Zhang, X
Simerly, C
Hartnett, C
Schatten, Ggps15@pitt.eduGPS15
Smithgall, TEtsmithga@pitt.eduTSMITHGA
Date: 1 November 2014
Date Type: Publication
Journal or Publication Title: Stem Cell Research
Number: Part A
Page Range: 379 - 389
DOI or Unique Handle: 10.1016/j.scr.2014.09.007
Schools and Programs: School of Medicine > Microbiology and Molecular Genetics
School of Medicine > Obstetrics, Gynecology, and Reproductive Sciences
Refereed: Yes
ISSN: 1873-5061
Date Deposited: 24 Jun 2015 19:41
Last Modified: 05 Feb 2019 17:55
URI: http://d-scholarship.pitt.edu/id/eprint/24661

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