期刊
FASEB JOURNAL
卷 29, 期 7, 页码 2828-2842出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.14-264010
关键词
irradiation; tissue regeneration; actively cycling ISCs; facultative/reserve ISCs
资金
- University of North Carolina (UNC) Flow Cytometry core facility [P30-CA06086]
- Histology Research Core Facilities of the Center for Gastrointestinal Biology and Disease [P30-DK034987]
- North Carolina Biotechnology Center
- National Cancer Center
- U.S. National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases [R01-DK040247-19, R01-DK091427, R03-DK089126]
- NIH National Institute on Aging Grant [R01-AG041198-01]
- SanteDige Foundation
- Genomics and Bioinformatics core of the UNC Lineberger Comprehensive Cancer Center
- Michael Hooker Microscopy Facility
- Department of Cell Biology and Physiology (UNC)
Insulin-like growth factor 1 (IGF1) has potent trophic effects on normal or injured intestinal epithelium, but specific effects on intestinal stem cells (ISCs) are undefined. We used Sox9-enhanced green fluorescent protein (EGFP) reportermice that permit analyses of both actively cycling ISCs (Sox9-EGFP(Low)) and reserve/facultative ISCs (Sox9-EGFP(High)) to study IGF1 action on ISCs in normal intestine or during crypt regeneration after high-dose radiation-induced injury. We hypothesized that IGF1 differentially regulates proliferation and gene expression in actively cycling and reserve/facultative ISCs. IGF1 was delivered for 5 days using subcutaneously implanted mini-pumps in uninjured mice or after 14 Gy abdominal radiation. ISC numbers, proliferation, and transcriptome were assessed. IGF1 increased epithelial growth in nonirradiated mice and enhanced crypt regeneration after radiation. In uninjured and regenerating intestines, IGF1 increased total numbers of Sox9-EGFP(Low) ISCs and percentage of these cells in M-phase. IGF1 increased percentages of Sox9-EGFP(High) ISCs in S-phase but did not expand this population. Microarray revealed that IGF1 activated distinct gene expression signatures in the 2 Sox9-EGFP ISC populations. In vitro IGF1 enhanced enteroid formation by Sox9-EGFP(High) facultative ISCs but not Sox9-EGFP(Low) actively cycling ISCs. Our data provide new evidence that IGF1 activates 2 ISC populations via distinct regulatory pathways to promote growth of normal intestinal epithelium and crypt regeneration after irradiation.
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