Crypt base columnar stem cells in small intestines of mice are radioresistant Journal Article

Authors: Hua, G.; Thin, T. H.; Feldman, R.; Haimovitz-Friedman, A.; Clevers, H.; Fuks, Z.; Kolesnick, R.
Article Title: Crypt base columnar stem cells in small intestines of mice are radioresistant
Abstract: Background & Aims: Adult stem cells have been proposed to be quiescent and radiation resistant, repairing DNA double-strand breaks by nonhomologous end joining. However, the population of putative small intestinal stem cells (ISCs) at position +4 from the crypt base contradicts this model, in that they are highly radiosensitive. Cycling crypt base columnar cells (CBCs) at crypt positions +1-3 recently were defined as an alternative population of ISCs. Little is known about the sensitivity of this stem cell population to radiation. Methods: Radiation-induced lethality of CBCs was quantified kinetically in Lgr5-lacZ transgenic mice. γ-H2AX, BRCA1, RAD51, and DNA-PKcs foci were used as DNA repair surrogates to investigate the inherent ability of CBCs to recognize and repair double-strand breaks. 5-ethynyl-2′-deoxyuridine and 5-bromo-2′-deoxyuridine incorporation assays were used to study patterns of CBC growth arrest and re-initiation of cell cycling. Apoptosis was evaluated by caspase-3 staining. Results: CBCs are relatively radioresistant, repairing DNA by homologous recombination significantly more efficiently than transit amplifying progenitors or villus cells. CBCs undergo apoptosis less than 24 hours after irradiation (32% ± 2% of total lethality) or mitotic death at 24-48 hours. Survival of CBCs at 2 days predicts crypt regeneration at 3.5 days and lethality from gastrointestinal syndrome. Crypt repopulation originates from CBCs that survive irradiation. Conclusions: Adult ISCs in mice can cycle rapidly yet still be radioresistant. Importantly, homologous recombination can protect adult stem cell populations from genotoxic stress. These findings broaden and refine concepts of the phenotype of adult stem cells. © 2012 AGA Institute.
Keywords: controlled study; nonhuman; radiation dose; mitosis; mouse; phenotype; animals; mice; animal tissue; homologous recombination; cell survival; dna repair; apoptosis; bone marrow; cell growth; animal experiment; animal model; adult stem cells; caspase 3; cell population; cell assay; radiation injury; brca1 protein; mice, transgenic; stem cell; dna; dna breaks, double-stranded; cell cycle arrest; radiosensitivity; double stranded dna break; cell regeneration; small intestine; cell protection; adult stem cell; histone h2ax; jejunum; intestine injury; rad51 protein; genotoxicity; radiation tolerance; radiation injury repair; crypt cell; cancer treatment; radioresistance; brdu; cell cycle checkpoints; gi syndrome; crypt base columnar cell
Journal Title: Gastroenterology
Volume: 143
Issue: 5
ISSN: 0016-5085
Publisher: Elsevier Inc.  
Date Published: 2012-11-01
Start Page: 1266
End Page: 1276
Language: English
DOI: 10.1053/j.gastro.2012.07.106
PROVIDER: scopus
PMCID: PMC3480544
PUBMED: 22841781
Notes: --- - "Cited By (since 1996): 1" - "Export Date: 3 December 2012" - "CODEN: GASTA" - "Source: Scopus"
Citation Impact
MSK Authors
  1. Zvi Fuks
    419 Fuks
  2. Richard N Kolesnick
    278 Kolesnick
  3. Tin Htwe Thin
    12 Thin
  4. Guoqiang Hua
    17 Hua