Absolute requirement for STAT3 function in small-intestine crypt stem cell survival

Matthews, James, Sansom, O. J. and Clarke, Alan Richard ORCID: https://orcid.org/0000-0002-4281-426X 2011. Absolute requirement for STAT3 function in small-intestine crypt stem cell survival. Cell Death and Differentiation 18 (12) , pp. 1934-1943. 10.1038/cdd.2011.77

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Abstract

The transcription factor signal transducer and activator of transcription 3 (STAT3) is frequently activated in human cancers. Interestingly, STAT3 also maintains the pluripotency and self-renewal of murine embryonic stem cells, and several tissue stem cell types. To investigate whether STAT3 also maintains the small-intestine crypt stem cell, we conditionally inactivated a Floxed Stat3 allele (Stat3fl) in murine small-intestine crypt stem cells. Following Cre recombinase expression, apoptosis increased in Stat3fl/ experimental crypts relative to Stat3wt/ controls before declining. Control Stat3wt/ mice carrying a Flox-STOP LacZ reporter transgene stably expressed LacZ after Cre induction. In contrast, Stat3fl/intestine LacZ expression initially increased modestly, before declining to background levels. Quantitative PCRs revealed a similar transient in recombined Stat3fl allele levels. Long-term bromodeoxyuridine labelling directly demonstrated that functional STAT3 is required for þ4 to þ6 region label-retaining small-intestine stem cell survival. Rapid clearance of recombined Stat3fl/ cells involves apoptosis potentially induced by elevated c-Myc in non-recombined cells and involves elevated p53 expression and caspase 3 activation. Intriguingly, Stat3fl/ intestine recombination triggered dramatically upregulated polycomb transcriptional repressor Bmi1 – potentially accelerating recombined crypt repopulation. In summary, STAT3 activity is absolutely required for small-intestine crypt stem cell survival at both the þ4 to þ6 label-retaining and crypt base columnar cell locations.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences European Cancer Stem Cell Research Institute (ECSCRI)
Subjects:	Q Science > QH Natural history > QH301 Biology Q Science > QP Physiology R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Publisher:	Nature Publishing Group
ISSN:	1350-9047
Last Modified:	20 Oct 2022 09:34
URI:	https://orca.cardiff.ac.uk/id/eprint/32521

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