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SCF/KIT inhibition has a cumulative but reversible effect on the self-renewal of embryonic stem cells and on the survival of differentiating cells.

TitleSCF/KIT inhibition has a cumulative but reversible effect on the self-renewal of embryonic stem cells and on the survival of differentiating cells.
Publication TypeJournal Article
Year of Publication2013
AuthorsFraser L, A Taylor H, Forrester LM
JournalCell Reprogram
Volume15
Issue4
Pagination259-68
Date Published2013 Aug
ISSN2152-4998
KeywordsAdult Stem Cells, Animals, Antibodies, Blocking, Apoptosis, Cell Differentiation, Cell Proliferation, Cell Survival, Cells, Cultured, Embryonic Stem Cells, Gene Knockdown Techniques, JNK Mitogen-Activated Protein Kinases, MAP Kinase Signaling System, Mice, Proto-Oncogene Proteins c-kit
Abstract

The receptor tyrosine kinase c-KIT is expressed in embryonic stem cells (ESCs) and adult stem cells, and many functional studies have demonstrated the importance of the SCF/KIT signaling pathway in adult stem cell maintenance. In this study, we show that a high level of KIT expression in wild-type ESCs correlates with an enhanced self-renewal and that inhibition of KIT signaling in ESCs for extended periods of time has a cumulative but reversible effect on self-renewal. Together these data suggest that continued KIT signaling in some cells within a self-renewing ESC population is required for optimal ESC function. Using a KIT blocking antibody, we recapitulated the phenotype we previously reported for genetically deficient KIT-null cells, demonstrating that SCF/KIT signaling is essential for the survival of differentiating ESCs. Here we show that this phenotype is also reversible. Pharmacological inhibition of JNK also had a cumulative but reversible detrimental effect on the survival of differentiating cells, thus recapitulating the Kit null phenotype and implicating JNK as a downstream mediator of KIT signaling. In contrast, the self-renewal of ESCs was unaffected by prolonged exposure to the JNK inhibitor, suggesting that JNK-independent downstream pathways are involved in KIT-mediated ESC self-renewal whereas KIT-mediated survival of differentiating ESC is likely to be JNK dependent.

DOI10.1089/cell.2013.0015
Alternate JournalCell Reprogram
PubMed ID23768117
Grant List / / Medical Research Council / United Kingdom