Cell Adhesion Molecule CD166/ALCAM Functions Within the Crypt to Orchestrate Murine Intestinal Stem Cell Homeostasis

Overview

Journal Cell Mol Gastroenterol Hepatol

Specialty Gastroenterology

Date 2017 May 3

PMID 28462380

Citations 21

Authors

Nicholas R Smith

Paige S Davies

Trevor G Levin

Alexandra C Gallagher

Douglas R Keene

Sidharth K Sengupta

Nikki Wieghard

Edward El Rassi

Melissa H Wong

Affiliations

Soon will be listed here.

Abstract

Background & Aims: Intestinal epithelial homeostasis is maintained by active-cycling and slow-cycling stem cells confined within an instructive crypt-based niche. Exquisite regulating of these stem cell populations along the proliferation-to-differentiation axis maintains a homeostatic balance to prevent hyperproliferation and cancer. Although recent studies focus on how secreted ligands from mesenchymal and epithelial populations regulate intestinal stem cells (ISCs), it remains unclear what role cell adhesion plays in shaping the regulatory niche. Previously we have shown that the cell adhesion molecule and cancer stem cell marker, CD166/ALCAM (activated leukocyte cell adhesion molecule), is highly expressed by both active-cycling Lgr5 ISCs and adjacent Paneth cells within the crypt base, supporting the hypothesis that CD166 functions to mediate ISC maintenance and signal coordination.

Methods: Here we tested this hypothesis by analyzing a CD166 mouse combined with immunohistochemical, flow cytometry, gene expression, and enteroid culture.

Results: We found that animals lacking CD166 expression harbored fewer active-cycling Lgr5 ISCs. Homeostasis was maintained by expansion of the transit-amplifying compartment and not by slow-cycling Bmi1 ISC stimulation. Loss of active-cycling ISCs was coupled with deregulated Paneth cell homeostasis, manifested as increased numbers of immature Paneth progenitors due to decreased terminal differentiation, linked to defective Wnt signaling. CD166 Paneth cells expressed reduced Wnt3 ligand expression and depleted nuclear β-catenin.

Conclusions: These data support a function for CD166 as an important cell adhesion molecule that shapes the signaling microenvironment by mediating ISC-niche cell interactions. Furthermore, loss of CD166 expression results in decreased ISC and Paneth cell homeostasis and an altered Wnt microenvironment.

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References

Medema J, Vermeulen L . Microenvironmental regulation of stem cells in intestinal homeostasis and cancer. Nature. 2011; 474(7351):318-26. DOI: 10.1038/nature10212. View

Smith N, Davies P, Silk A, Wong M . Epithelial and mesenchymal contribution to the niche: a safeguard for intestinal stem cell homeostasis. Gastroenterology. 2012; 143(6):1426-30. PMC: 3889478. DOI: 10.1053/j.gastro.2012.10.024. View

Ohneda O, Ohneda K, Arai F, Lee J, Miyamoto T, Fukushima Y . ALCAM (CD166): its role in hematopoietic and endothelial development. Blood. 2001; 98(7):2134-42. DOI: 10.1182/blood.v98.7.2134. View

Ritsma L, Ellenbroek S, Zomer A, Snippert H, de Sauvage F, Simons B . Intestinal crypt homeostasis revealed at single-stem-cell level by in vivo live imaging. Nature. 2014; 507(7492):362-365. PMC: 3964820. DOI: 10.1038/nature12972. View

Biswas S, Davis H, Irshad S, Sandberg T, Worthley D, Leedham S . Microenvironmental control of stem cell fate in intestinal homeostasis and disease. J Pathol. 2015; 237(2):135-45. PMC: 4744721. DOI: 10.1002/path.4563. View

Moon R, Kohn A, De Ferrari G, Kaykas A . WNT and beta-catenin signalling: diseases and therapies. Nat Rev Genet. 2004; 5(9):691-701. DOI: 10.1038/nrg1427. View

Sangiorgi E, Capecchi M . Bmi1 is expressed in vivo in intestinal stem cells. Nat Genet. 2008; 40(7):915-20. PMC: 2906135. DOI: 10.1038/ng.165. View

Wong M, Rubinfeld B, Gordon J . Effects of forced expression of an NH2-terminal truncated beta-Catenin on mouse intestinal epithelial homeostasis. J Cell Biol. 1998; 141(3):765-77. PMC: 2132757. DOI: 10.1083/jcb.141.3.765. View

Durand A, Donahue B, Peignon G, Letourneur F, Cagnard N, Slomianny C . Functional intestinal stem cells after Paneth cell ablation induced by the loss of transcription factor Math1 (Atoh1). Proc Natl Acad Sci U S A. 2012; 109(23):8965-70. PMC: 3384132. DOI: 10.1073/pnas.1201652109. View

10.

Dalerba P, Dylla S, Park I, Liu R, Wang X, Cho R . Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci U S A. 2007; 104(24):10158-63. PMC: 1891215. DOI: 10.1073/pnas.0703478104. View

11.

Aoki R, Shoshkes-Carmel M, Gao N, Shin S, May C, Golson M . Foxl1-expressing mesenchymal cells constitute the intestinal stem cell niche. Cell Mol Gastroenterol Hepatol. 2016; 2(2):175-188. PMC: 4772878. DOI: 10.1016/j.jcmgh.2015.12.004. View

12.

Munoz J, Stange D, Schepers A, van de Wetering M, Koo B, Itzkovitz S . The Lgr5 intestinal stem cell signature: robust expression of proposed quiescent '+4' cell markers. EMBO J. 2012; 31(14):3079-91. PMC: 3400017. DOI: 10.1038/emboj.2012.166. View

13.

Barker N, Clevers H . Tracking down the stem cells of the intestine: strategies to identify adult stem cells. Gastroenterology. 2007; 133(6):1755-60. DOI: 10.1053/j.gastro.2007.10.029. View

14.

Barker N, van Es J, Kuipers J, Kujala P, van den Born M, Cozijnsen M . Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature. 2007; 449(7165):1003-7. DOI: 10.1038/nature06196. View

15.

Wang F, Scoville D, He X, Mahe M, Box A, Perry J . Isolation and characterization of intestinal stem cells based on surface marker combinations and colony-formation assay. Gastroenterology. 2013; 145(2):383-95.e1-21. PMC: 3781924. DOI: 10.1053/j.gastro.2013.04.050. View

16.

Andreu P, Peignon G, Slomianny C, Taketo M, Colnot S, Robine S . A genetic study of the role of the Wnt/beta-catenin signalling in Paneth cell differentiation. Dev Biol. 2008; 324(2):288-96. DOI: 10.1016/j.ydbio.2008.09.027. View

17.

Kim T, Li F, Ferreiro-Neira I, Ho L, Luyten A, Nalapareddy K . Broadly permissive intestinal chromatin underlies lateral inhibition and cell plasticity. Nature. 2014; 506(7489):511-5. PMC: 4151315. DOI: 10.1038/nature12903. View

18.

Farin H, van Es J, Clevers H . Redundant sources of Wnt regulate intestinal stem cells and promote formation of Paneth cells. Gastroenterology. 2012; 143(6):1518-1529.e7. DOI: 10.1053/j.gastro.2012.08.031. View

19.

Uchida N, Yang Z, Combs J, Pourquie O, Nguyen M, Ramanathan R . The characterization, molecular cloning, and expression of a novel hematopoietic cell antigen from CD34+ human bone marrow cells. Blood. 1997; 89(8):2706-16. View

20.

Tachezy M, Zander H, Gebauer F, Marx A, Kaifi J, Izbicki J . Activated leukocyte cell adhesion molecule (CD166)--its prognostic power for colorectal cancer patients. J Surg Res. 2012; 177(1):e15-20. DOI: 10.1016/j.jss.2012.02.013. View