Histopathological evaluation of crypt fission during intestinal development
in neonatal mice

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Abstract

Pathological evaluation of juvenile toxicity studies requires the understanding of normal tissue development at different ages. Here, we report the morphological features of the neonatal mouse intestine, focusing on crypt fission. Postnatal day (PND) 7 and 14 mice showed fewer crypts and less mature epithelial morphology compared to PND 21 and 28. Crypt fission occurred in three stages: 1) flattening of the crypt base into a skirt shape, 2) penetration of myofibroblasts into the crypt base center, and 3) complete separation of a single crypt into two daughter crypts. The ratio of crypt fission to total number of crypts was the highest at PND 14 and 7 in the jejunum and colon, respectively. Crypt fission, a key phenomenon for balance or imbalance in epithelial cell hierarchy, including stem and differentiated cells, is related to tissue injury repair and tumorigenesis. Therefore, examining crypt fission can provide valuable insights into current conditions of intestine.

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Most cited references 21

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Wnt5a potentiates TGF-β signaling to promote colonic crypt regeneration after tissue injury.

Hiroyuki Miyoshi, Rieko Ajima, Christine Luo … (2012)

Reestablishing homeostasis after tissue damage depends on the proper organization of stem cells and their progeny, though the repair mechanisms are unclear. The mammalian intestinal epithelium is well suited to approach this problem, as it is composed of well-delineated units called crypts of Lieberkühn. We found that Wnt5a, a noncanonical Wnt ligand, was required for crypt regeneration after injury in mice. Unlike controls, Wnt5a-deficient mice maintained an expanded population of proliferative epithelial cells in the wound. We used an in vitro system to enrich for intestinal epithelial stem cells to discover that Wnt5a inhibited proliferation of these cells. Surprisingly, the effects of Wnt5a were mediated by activation of transforming growth factor-β (TGF-β) signaling. These findings suggest a Wnt5a-dependent mechanism for forming new crypt units to reestablish homeostasis.

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Colonic crypt organization and tumorigenesis.

Adam Humphries, Nicholas A Wright (2008)

An appreciation of colonic crypt organization has become essential to any understanding of tumorigenesis in the colon. Intestinal crypts house tissue-specific, multipotential stem cells, which are located in the niche at the base of the intestinal crypt and are capable of regenerating all intestinal cell types. Recent advances in our understanding of crypt biology, including how mutations in stem cells become fixed and expand within the epithelium, has led to new theories on the origins of colonic adenomas and cancers.

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Intestinal Subepithelial Myofibroblasts Support the Growth of Intestinal Epithelial Stem Cells

Nan Ye Lei, Ziyad Jabaji, Jiafang Wang … (2014)

Intestinal epithelial stem cells (ISCs) are the focus of recent intense study. Current in vitro models rely on supplementation with the Wnt agonist R-spondin1 to support robust growth, ISC self-renewal, and differentiation. Intestinal subepithelial myofibroblasts (ISEMFs) are important supportive cells within the ISC niche. We hypothesized that co-culture with ISEMF enhances the growth of ISCs in vitro and allows for their successful in vivo implantation and engraftment. ISC-containing small intestinal crypts, FACS-sorted single ISCs, and ISEMFs were procured from C57BL/6 mice. Crypts and single ISCs were grown in vitro into enteroids, in the presence or absence of ISEMFs. ISEMFs enhanced the growth of intestinal epithelium in vitro in a proximity-dependent fashion, with co-cultures giving rise to larger enteroids than monocultures. Co-culture of ISCs with supportive ISEMFs relinquished the requirement of exogenous R-spondin1 to sustain long-term growth and differentiation of ISCs. Mono- and co-cultures were implanted subcutaneously in syngeneic mice. Co-culture with ISEMFs proved necessary for successful in vivo engraftment and proliferation of enteroids; implants without ISEMFs did not survive. ISEMF whole transcriptome sequencing and qPCR demonstrated high expression of specific R-spondins, well-described Wnt agonists that supports ISC growth. Specific non-supportive ISEMF populations had reduced expression of R-spondins. The addition of ISEMFs in intestinal epithelial culture therefore recapitulates a critical element of the intestinal stem cell niche and allows for its experimental interrogation and biodesign-driven manipulation.

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Author and article information

Journal

Journal ID (nlm-ta): J Toxicol Pathol

Journal ID (iso-abbrev): J Toxicol Pathol

Journal ID (publisher-id): TOX

Title: Journal of Toxicologic Pathology

Publisher: Japanese Society of Toxicologic Pathology

ISSN (Print): 0914-9198

ISSN (Electronic): 1881-915X

Publication date (Electronic): 23 September 2019

Publication date (Print): January 2020

Volume: 33

Issue: 1

Pages: 39-46

Affiliations

[1 ]Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan

[2 ]Forerunner Pharma Research Co., Ltd., Komaba Open Laboratory, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan

[3 ]Chugai Research Institute for Medical Science, Inc, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan

Author notes

*Corresponding author: M Yamazaki (e-mail: yamazakimsk@ 123456chugai-pharm.co.jp )

Article

Publisher ID: 2019-0032

DOI: 10.1293/tox.2019-0032

PMC ID: 7008202

SO-VID: 86c852e7-ac64-46e2-aae9-52fdbb21d0a6

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This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: https://creativecommons.org/licenses/by-nc-nd/4.0/ ）.

Histopathological evaluation of crypt fission during intestinal development in neonatal mice

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Marine Development

Most cited references 21

Wnt5a potentiates TGF-β signaling to promote colonic crypt regeneration after tissue injury.

Colonic crypt organization and tumorigenesis.

Intestinal Subepithelial Myofibroblasts Support the Growth of Intestinal Epithelial Stem Cells

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