Contribution of ATOH1 +  Cells to the Homeostasis, Repair, and Tumorigenesis of the Colonic Epithelium

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Summary

ATOH1 is a master transcription factor for the secretory lineage differentiation of intestinal epithelial cells (IECs). However, the comprehensive contribution of ATOH1 ⁺ secretory lineage IECs to the homeostasis, repair, and tumorigenesis of the intestinal epithelium remains uncertain. Through our ATOH1 ⁺ cell-lineage tracing, we show here that a definite number of ATOH1 ⁺ IECs retain stem cell properties and can form ATOH1 ⁺IEC-derived clonal ribbons (ATOH1 ⁺ICRs) under completely homeostatic conditions. Interestingly, colonic ATOH1 ⁺ IECs appeared to exhibit their stem cell function more frequently compared with those of the small intestine. Consistently, the formation of ATOH1 ⁺ICRs was significantly enhanced upon dextran sodium sulfate colitis-induced mucosal damage. In addition, colonic ATOH1 ⁺ IECs acquired tumor stem cell-like properties in the azoxymethane-DSS tumor model. Our results reveal an unexpected contribution of colonic ATOH1 ⁺ IECs to maintaining the stem cell population under both homeostatic and pathologic conditions and further illustrate the high plasticity of the crypt-intrinsic stem cell hierarchy.

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Highlights

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Intestinal ATOH1 ⁺ cells can exhibit stem cell properties under homeostatic conditions
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Recruitment of ATOH1 ⁺ cell-derived stem cells is enhanced by inflammation
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Cell-intrinsic NF-kB signaling promotes generation of ATOH1 ⁺ cell-derived stem cells
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ATOH1 ⁺ tumor stem cells contribute to the development of colitis-associated tumors

Abstract

Ishibashi et al. report the contribution of ATOH1 ⁺ intestinal epithelial cells to the maintenance, regeneration, and tumorigenesis in the colon. They find that a definite number of ATOH1 ⁺ intestinal epithelial cells retain stem cell properties under homeostatic conditions. Also, generation of ATOH1 ⁺ cell-derived stem cells is significantly enhanced by the inflammatory environment and contributes to the development of colitis-associated tumors.

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Most cited references 23

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Prominin1 marks intestinal stem cells that are susceptible to neoplastic transformation

Liqin Zhu, Paul Gibson, D. Currle … (2008)

Cancer stem cells (CSC) are remarkably similar to normal stem cells: both self-renew, are multipotent and express common surface markers, e.g., PROMININ-1 (PROM1, CD133)1. What remains unclear is whether CSC are the direct progeny of mutated stem cells, or more mature cells that reacquire stem cell properties during tumor formation. Answering this important question will require knowledge of whether normal stem cells are susceptible to cancer causing mutations; however, this has proved difficult to test since the identity of most adult tissue stem cells is not known. Here, using an inducible-Cre-nuclear(n)LacZ reporter allele knocked into the Prom1 locus (Prom1C-L ), we show that Prom1 is expressed in a variety of developing and adult tissues. Lineage-tracing studies of adult Prom1 +/C-L mice containing the Rosa26YFP reporter allele showed that Prom1+ cells are located at the base of crypts in the small intestine, co-express Lgr52, generate the entire intestinal epithelium, and are therefore likely to be the small intestinal stem cell. Prom1 was reported recently to mark CSC of human intestinal tumors that arise frequently as a consequence of aberrant Wingless (WNT) signaling3-5. Activation of endogenous Wnt signaling in Prom1 +/C-L mice containing a Cre-dependent mutant allele of Beta-catenin (Ctnnb1lox(ex3) ) resulted first in a gross disruption of crypt architecture and a disproportionate expansion of Prom1+ cells at the crypt base. Lineage-tracing demonstrated that the progeny of these cells replaced the mucosa of the entire small intestine with neoplastic tissue that was characterized by focal high-grade intraepithelial neoplasia and crypt adenoma formation. Although all neoplastic cells arose from Prom1+ cells in these mice, only 7% of tumor cells retained Prom1 expression. Our data indicate that Prom1 marks stem cells in the adult small intestine, which are susceptible to transformation into tumors retaining a fraction of mutant-Prom1+ tumor cells.

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Long-lived intestinal tuft cells serve as colon cancer-initiating cells.

Courtney Houchen, Anna Brandtner, M. D. Lukin … (2014)

Doublecortin-like kinase 1 protein (DCLK1) is a gastrointestinal tuft cell marker that has been proposed to identify quiescent and tumor growth-sustaining stem cells. DCLK1⁺ tuft cells are increased in inflammation-induced carcinogenesis; however, the role of these cells within the gastrointestinal epithelium and their potential as cancer-initiating cells are poorly understood. Here, using a BAC-CreERT-dependent genetic lineage-tracing strategy, we determined that a subpopulation of DCLK1⁺ cells is extremely long lived and possesses rare stem cell abilities. Moreover, genetic ablation of Dclk1 revealed that DCLK1⁺ tuft cells contribute to recovery following intestinal and colonic injury. Surprisingly, conditional knockdown of the Wnt regulator APC in DCLK1⁺ cells was not sufficient to drive colonic carcinogenesis under normal conditions; however, dextran sodium sulfate-induced (DSS-induced) colitis promoted the development of poorly differentiated colonic adenocarcinoma in mice lacking APC in DCLK1⁺ cells. Importantly, colonic tumor formation occurred even when colitis onset was delayed for up to 3 months after induced APC loss in DCLK1⁺ cells. Thus, our data define an intestinal DCLK1⁺ tuft cell population that is long lived, quiescent, and important for intestinal homeostasis and regeneration. Long-lived DCLK1⁺ cells maintain quiescence even following oncogenic mutation, but are activated by tissue injury and can serve to initiate colon cancer.

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Efficient colonic mucosal wound repair requires Trem2 signaling.

Thaddeus S. Stappenbeck, Hiroyuki Miyoshi, Hiroshi Seno … (2009)

The colonic epithelial lining undergoes constant replacement, driven by epithelial stem cells in crypts of Lieberkühn. Stem cells lost because of damage or disease can be replaced by adjacent crypts that undergo fission. The close proximity of an extraordinary number of luminal microbes creates a challenge for this repair process; infection must be prevented while immune system activation and epithelial stem cell genetic damage must be minimized. To understand the factors that modulate crypt/stem cell replacement in the mouse colon, we developed an in vivo acute injury system analogous to punch biopsy of the skin. In contrast to epidermal stem cells, colonic epithelial progenitors did not migrate over the wound bed. Instead, their proliferative expansion was confined to crypts adjacent to wound beds and was delayed to the latter phase of healing. This increased epithelial proliferation was coincident with the infiltration of Trem2 expressing macrophages and increased expression of IL-4 and IL-13 in the wound bed. Interestingly, Trem2(-/-) mice displayed slow and incomplete wound healing of colonic mucosal injuries. We found the latter phase of healing in Trem2(-/-) mice showed a diminished burst of epithelial proliferation, increased expression of IFN-gamma and TNF-alpha, diminished expression of IL-4 and IL-13, and increased markers of classical macrophage activation. Ablation of these cytokines in injured WT and Trem2(-/-) mice demonstrated that their expression ultimately determined the rate and nature of wound healing. These studies show that Trem2 signaling is an important pathway to promote healing of wounds in the colon where stem cell replacement is necessary.

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Author and article information

Contributors

Ryuichi Okamoto

Journal

Journal ID (nlm-ta): Stem Cell Reports

Journal ID (iso-abbrev): Stem Cell Reports

Title: Stem Cell Reports

Publisher: Elsevier

ISSN (Electronic): 2213-6711

Publication date PMC-release: 07 December 2017

Publication date Collection: 09 January 2018

Publication date (Electronic): 07 December 2017

Volume: 10

Issue: 1

Pages: 27-42

Affiliations

[1 ]Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8519, Japan

[2 ]Department of Advanced Therapeutics in GI Diseases, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8519, Japan

[3 ]Center for Stem Cell and Regenerative Medicine, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan

[4 ]Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA

[5 ]Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, 24118 Kiel, Germany

Author notes

[∗ ]Corresponding author rokamoto.gast@ 123456tmd.ac.jp

Article

Publisher ID: S2213-6711(17)30492-7

DOI: 10.1016/j.stemcr.2017.11.006

PMC ID: 5768891

PubMed ID: 29233556

SO-VID: 58b3e577-ed1c-4887-a8c2-14ef9f28e490

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 18 May 2017

Date revision received : 4 November 2017

Date accepted : 5 November 2017

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Contribution of ATOH1 ⁺ Cells to the Homeostasis, Repair, and Tumorigenesis of the Colonic Epithelium

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Stress signalling in stem cells

Most cited references 23

Prominin1 marks intestinal stem cells that are susceptible to neoplastic transformation

Long-lived intestinal tuft cells serve as colon cancer-initiating cells.

Efficient colonic mucosal wound repair requires Trem2 signaling.

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Cited by 24

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