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

Autor: Nikki Wieghard, Nicholas R. Smith, Trevor Levin, Paige S. Davies, Edward El Rassi, Douglas R. Keene, Melissa H. Wong, Alexandra C. Gallagher, Sidharth K. Sengupta
Rok vydání: 2017
Předmět:
0301 basic medicine
Intestinal stem cell homeostasis
qRT-PCR
quantitative reverse transcription polymerase chain reaction
Biology
SEM
standard error of the mean
digestive system
BrdU
bromodeoxyuridine
Intestinal Stem Cell
Lyz
lysozyme
03 medical and health sciences
0302 clinical medicine
Paneth Cell
TA
transit-amplifying
Cancer stem cell
FACS
fluorescence-activated cell sorting
medicine
Homeostasis
Stem Cell Niche
lcsh:RC799-869
CLEM
correlative light and electron microscopy
TEM
transmission electron microscopy
Cell adhesion
ALCAM
Original Research
GFP
green fluorescent protein
Muc2
mucin 2
Hepatology
Cell adhesion molecule
HBSS
Hank’s balanced salt solution
Gastroenterology
Activated-Leukocyte Cell Adhesion Molecule
WT
wild-type
3. Good health
Cell biology
030104 developmental biology
medicine.anatomical_structure
030220 oncology & carcinogenesis
Paneth cell
ISC
intestinal stem cell
lcsh:Diseases of the digestive system. Gastroenterology
CD166
FITC
fluorescein isothiocyanate
Stem cell
IHC
immunohistochemistry
Zdroj: Cellular and Molecular Gastroenterology and Hepatology, Vol 3, Iss 3, Pp 389-409 (2017)
Cellular and Molecular Gastroenterology and Hepatology
ISSN: 2352-345X
DOI: 10.1016/j.jcmgh.2016.12.010
Popis: 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.
Graphical abstract
Databáze: OpenAIRE
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