Inflation comes before the fall: How epithelial stretch drives crypt fission

Expansion of intestinal progenitors and putative stem cells (pISC) occurs early and transiently following ileo-cecal resection (ICR). The mechanism controlling this process is not defined. We hypothesized that glucagon-like peptide-2 (GLP-2) would augment jejunal pISC expansion only when administered to mice immediately after ICR. Since recent reports demonstrated increases in intestinal insulin-like growth factor (IGF)-I following GLP-2 administration, we further hypothesized that increased intestinal IGF-I expression would correlate with pISC expansion following ICR. To assess this, GLP-2 or vehicle was administered to mice either immediately after resection (early) or before tissue harvest 6 wk following ICR (late). Histological analysis quantified proliferation and intestinal morphometrics. Serum levels of GLP-2 were measured by ELISA and jejunal IGF-I mRNA by qRT-PCR. Expansion of jejunal pISC was assessed by fluorescent-activated cell sorting of side population cells, immunohistochemistry for phosphorylated β-catenin at serine 552 (a pISC marker), percent of crypt fission, and total numbers of crypts per jejunal circumference. We found that early but not late GLP-2 treatment after ICR significantly augmented pISC expansion. Increases in jejunal IGF-I mRNA correlated temporally with early pISC expansion and effects of GLP-2. Early GLP-2 increased crypt fission and accelerated adaptive increases in crypt number and intestinal caliber. GLP-2 increased proliferation and intestinal morphometrics in all groups. This study shows that, in mice, GLP-2 promotes jejunal pISC expansion only in the period immediately following ICR. This is associated with increased IGF-I and accelerated adaptive increases in mucosal mass. These data provide clinical rationale relevant to the optimal timing of GLP-2 in patients with intestinal failure.

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Asymmetric crypt fission in sessile serrated lesions

Journal of Clinical Pathology ◽

10.1136/jclinpath-2020-207008 ◽

2020 ◽

pp. jclinpath-2020-207008 ◽

Cited By ~ 1

Author(s):

Carlos A Rubio ◽

Peter T Schmidt

Keyword(s):

Somatic Mutations ◽

Colon Mucosa ◽

Normal Colon ◽

Normal Colon Mucosa ◽

Crypt Fission ◽

Tumour Suppressor Protein ◽

Serrated Lesions ◽

Symmetric Fission ◽

Proliferating Cell ◽

Asymmetric Fission

ObjectiveSessile serrated lesions without dysplasia (SSL-ND) are epitomised by dilated crypts with epithelial serrations and architectural distortions portraying boot-shapes, L-shapes or inverted-T shapes. Recently, crypts in asymmetric fission were detected in SSL-ND. The purpose was to assess the frequency of crypts in asymmetric fission in a cohort of SSL-ND.MethodsThe frequency of crypts in fission was assessed in 60 SSL-ND, the distribution of cell proliferation in 48 SSL-ND and the expression of maspin, a tumour-suppressor protein, in 29 SSL-ND.ResultsOut of the 60 SSL-ND, 40 (66.7%) showed crypts in fission: 39 (65%) SSL-ND had crypts in asymmetric fission and one SSL-ND (1.7%), in symmetric fission (p<0.05). Of 1495 crypts recorded in the 60 SSL-ND, 73 (4.9%) were in asymmetric fission but only one (0.06%), in symmetric fission (p<0.05). Out of the 48 Ki67-immunostained SSL-ND,15 (31%) showed randomly distributed proliferating cell-domains. All 29 SSL-ND revealed maspin-upregulation (including crypts in asymmetric and symmetric fission). In contrast, the normal colon mucosa showed occasional single crypts in symmetric fission, proliferating cell-domains limited to the lower thirds of the crypts, absence of crypts in asymmetric fission and remained maspin negative.ConclusionsSSL-ND thrive with crypts in asymmetric fission displaying randomly distributed proliferating cell-domains and maspin-upregulation. These histo-biological aberrations disclose pathological cryptogenesis and suggest possibly unfolding somatic mutations in SSL-ND. The present findings may open new vistas on the parameters pertinent to the susceptibility of SSL-ND to develop dysplasia and carcinoma.

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A cancer rainbow mouse for visualizing the functional genomics of oncogenic clonal expansion

Nature Communications ◽

10.1038/s41467-019-13330-y ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 6

Author(s):

Peter G. Boone ◽

Lauren K. Rochelle ◽

Joshua D. Ginzel ◽

Veronica Lubkov ◽

Wendy L. Roberts ◽

...

Keyword(s):

Stem Cell ◽

Somatic Mutations ◽

Clonal Expansion ◽

Field Cancerization ◽

Intratumor Heterogeneity ◽

Colon Cancers ◽

Crypt Fission ◽

Oncogenic Mutations ◽

Rapid Spread ◽

Plausible Mechanism

AbstractField cancerization is a premalignant process marked by clones of oncogenic mutations spreading through the epithelium. The timescales of intestinal field cancerization can be variable and the mechanisms driving the rapid spread of oncogenic clones are unknown. Here we use a Cancer rainbow (Crainbow) modelling system for fluorescently barcoding somatic mutations and directly visualizing the clonal expansion and spread of oncogenes. Crainbow shows that mutations of ß-catenin (Ctnnb1) within the intestinal stem cell results in widespread expansion of oncogenes during perinatal development but not in adults. In contrast, mutations that extrinsically disrupt the stem cell microenvironment can spread in adult intestine without delay. We observe the rapid spread of premalignant clones in Crainbow mice expressing oncogenic Rspondin-3 (RSPO3), which occurs by increasing crypt fission and inhibiting crypt fixation. Crainbow modelling provides insight into how somatic mutations rapidly spread and a plausible mechanism for predetermining the intratumor heterogeneity found in colon cancers.

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Age related differences in intestinal proliferation and crypt fission in the rat small intestine and colon

Gastroenterology ◽

10.1016/s0016-5085(03)81397-5 ◽

2003 ◽

Vol 124 (4) ◽

pp. A278-A279

Author(s):

Nikki Mandir ◽

Anthony J. Fitzgerald ◽

Robert A. Goodlad

Keyword(s):

Small Intestine ◽

Rat Small Intestine ◽

Crypt Fission ◽

Age Related ◽

Intestinal Proliferation

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CD44 and TLR4 mediate hyaluronic acid regulation of Lgr5+ stem cell proliferation, crypt fission, and intestinal growth in postnatal and adult mice

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00123.2015 ◽

2015 ◽

Vol 309 (11) ◽

pp. G874-G887 ◽

Cited By ~ 19

Author(s):

Terrence E. Riehl ◽

Srikanth Santhanam ◽

Lynne Foster ◽

Matthew Ciorba ◽

William F. Stenson

Keyword(s):

Cell Proliferation ◽

Small Intestine ◽

Stem Cell ◽

Hyaluronic Acid ◽

Postnatal Life ◽

Epithelial Proliferation ◽

Stem Cell Proliferation ◽

Crypt Fission ◽

Intestinal Length

Hyaluronic acid, a glycosaminoglycan in the extracellular matrix, binds to CD44 and Toll-like receptor 4 (TLR4). We previously addressed the role of hyaluronic acid in small intestinal and colonic growth in mice. We addressed the role of exogenous hyaluronic acid by giving hyaluronic acid intraperitoneally and the role of endogenous hyaluronic acid by giving PEP-1, a peptide that blocks hyaluronic acid binding to its receptors. Exogenous hyaluronic acid increased epithelial proliferation but had no effect on intestinal length. PEP-1 resulted in a shortened small intestine and colon and diminished epithelial proliferation. In the current study, we sought to determine whether the effects of hyaluronic acid on growth were mediated by signaling through CD44 or TLR4 by giving exogenous hyaluronic acid or PEP-1 twice a week from 3–8 wk of age to wild-type, CD44−/−, and TLR4−/− mice. These studies demonstrated that signaling through both CD44 and TLR4 were important in mediating the effects of hyaluronic acid on growth in the small intestine and colon. Extending our studies to early postnatal life, we assessed the effects of exogenous hyaluronic acid and PEP-1 on Lgr5+ stem cell proliferation and crypt fission. Administration of PEP-1 to Lgr5+ reporter mice from postnatal day 7 to day 14 decreased Lgr5+ cell proliferation and decreased crypt fission. These studies indicate that endogenous hyaluronic acid increases Lgr5+ stem cell proliferation, crypt fission, and intestinal lengthening and that these effects are dependent on signaling through CD44 and TLR4.

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