Dept. of Cell and Developmental Biology
Oregon Health & Science University
The epithelial lining of the intestine is one of the human bodyâs most rapidly proliferating tissues, with complete renewal every 4-8 days. This expansive process is orchestrated by the intestinal stem cell and requires a fine balance between proliferation, differentiation, migration and cell death. Tight regulation of stem cell behavior is required to maintain the architecture and normal function of the tissue, and to prevent manifestation of diseases, such as cancer. The unique secondary structure of the intestinal crypt provides a regulatory niche for the stem cell. However, mechanisms coordinating signaling pathways to instruct stem cell behavior are poorly understood. Cell adhesion complexes are known to direct and regulate cell signaling and subsequent cellular behavior. Intriguingly, the cell adhesion molecule, CD166, was recently described as a cancer stem cell molecule in colorectal cancer. In the normal intestine, CD166 function is unknown. Based upon its relevance in colorectal cancer and its recently described expression within the hematopoietic stem cell niche, I hypothesize that CD166 is expressed within the intestinal stem cell niche and may participate in regulation of stem cell homeostasis. To directly test this hypothesis, we investigated the expression pattern of CD166 in the normal intestine and interrogated stem cell expression within the CD166-positive epithelial population. Further, to understand the normal function of CD166 within the intestinal stem cell niche we explored the impact of loss of CD166 on intestinal stem cell homeostasis. Intriguingly, we determined that CD166 expression within the intestinal crypt was tightly restricted to a domain encompassing both Lgr5-positive progenitor cells and neighboring differentiated Paneth cells. This discrete expression domain is highly suggestive of an important regulatory relationship between the stem cell and neighboring niche cells. Consistent with this concept, we discovered that intestines from CD166-null mice harbored defects in proliferation, Wnt signaling and migration. These results were manifested, in part, by a reduction in stem cell numbers and crypt size. Radiation challenge to the intestine, as a means of testing activation of stem cell proliferation, revealed that CD166-null intestines harbored a delay in a proliferative response. Our findings support the notion that CD166 participates as a regulatory niche molecule in establishing a homeostatic set point in the intestine and in coordinating proliferative response. This important advance has implications for normal epithelial regeneration and cancer. Significantly, targeting CD166 may provide a novel mechanism for disrupting the interaction between the CD166-expressing cancer stem cell and its surrounding microenvironment.
School of Medicine
Levin, Trevor Gilpin, "Role of cell adhesion molecule CD166 in homeostatic maintenance and regeneration of the intestinal stem cell niche" (2011). Scholar Archive. 698.
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