The existence of intestinal stem cells residing in an interactive niche has been well-accepted as the source of continual self-renewal of the intestinal epithelium. However, while other organ systems have appreciated substantial progress in identifying stem populations and exploiting this knowledge for therapeutic treatment of disease, advances in the intestinal stem cell field have been hampered by the inability to definitively identify, isolate, and grow the stem cell population. Recent identification of a number of putative intestinal stem cell markers displaying distinct expression patterns within the stem cell niche suggests that multiple progenitor pools co-exist. Intriguingly, these intestinal progenitor populations may belong to a stem cell hierarchy analogous to that in the well-characterized hematopoietic system. Defining a similar hierarchy within the intestinal stem cell niche will allow us to prospectively isolate discrete populations, thereby extending our knowledge of intestinal stem cell dynamics. Our long-range research goal is to understand the mechanisms regulating intestinal stem cell behavior in homeostasis and in disease. The studies proposed for this Research Project for the Intestinal Stem Cell Consortium are designed to test the hypothesis that discrete populations of intestinal stem or progenitor cells exist within a hierarchy in both normal tissue, and among cancer stem cells in intestinal cancer. Studies to address these goals are designed to define progenitor populations using protein expression patterns by immunohistochemical analyses and 3-dimensional intestinal crypt reconstruction along with profiling of cell surface antigen expression by fluorescence-activated cell sorting. Further, novel monoclonal antibodies against undifferentiated cells within the crypt will be generated to expand the available resources for effective isolation of intestinal progenitor and stem cells. The ability to isolate discrete pools of intestinal stem cells is critical for advancing our understanding of intestinal biology, which is paramount for understanding, classifying and treating intestinal disease.

Public Health Relevance

The key to unlocking intestinal biology and harnessing this knowledge for treatment of intestinal disease lies in the ability to identify and isolate the adult intestinal stem cell. This project, designed to understand how this cell functions, will provide insight into diseases where these stem cells do not function properly, such as in intestinal cancer. These studies have the potential for improving diagnoses, informing directed treatment, and designing new therapies for intestinal disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
3U01DK085525-05S1
Application #
8699880
Study Section
Special Emphasis Panel (ZDK1-GRB-8 (O1))
Program Officer
Carrington, Jill L
Project Start
2009-09-30
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2013
Total Cost
$50,800
Indirect Cost
$17,813
Name
Oregon Health and Science University
Department
Dermatology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Smith, Nicholas R; Swain, John R; Davies, Paige S et al. (2018) Monoclonal Antibodies Reveal Dynamic Plasticity Between Lgr5- and Bmi1-Expressing Intestinal Cell Populations. Cell Mol Gastroenterol Hepatol 6:79-96
Lueschow, Shiloh R; Stumphy, Jessica; Gong, Huiyu et al. (2018) Loss of murine Paneth cell function alters the immature intestinal microbiome and mimics changes seen in neonatal necrotizing enterocolitis. PLoS One 13:e0204967
Yan, Kelley S; Gevaert, Olivier; Zheng, Grace X Y et al. (2017) Intestinal Enteroendocrine Lineage Cells Possess Homeostatic and Injury-Inducible Stem Cell Activity. Cell Stem Cell 21:78-90.e6
Yan, Kelley S; Janda, Claudia Y; Chang, Junlei et al. (2017) Non-equivalence of Wnt and R-spondin ligands during Lgr5+ intestinal stem-cell self-renewal. Nature 545:238-242
Smith, Nicholas R; Davies, Paige S; Levin, Trevor G et al. (2017) Cell Adhesion Molecule CD166/ALCAM Functions Within the Crypt to Orchestrate Murine Intestinal Stem Cell Homeostasis. Cell Mol Gastroenterol Hepatol 3:389-409
Smith, Nicholas R; Gallagher, Alexandra C; Wong, Melissa H (2016) Defining a stem cell hierarchy in the intestine: markers, caveats and controversies. J Physiol 594:4781-90
Keene, Douglas R; Tufa, Sara F; Wong, Melissa H et al. (2014) Correlation of the same fields imaged in the TEM, confocal, LM, and microCT by image registration: from specimen preparation to displaying a final composite image. Methods Cell Biol 124:391-417
Wang, Fengchao; Scoville, David; He, Xi C et al. (2013) Isolation and characterization of intestinal stem cells based on surface marker combinations and colony-formation assay. Gastroenterology 145:383-95.e1-21
Magness, Scott T; Puthoff, Brent J; Crissey, Mary Ann et al. (2013) A multicenter study to standardize reporting and analyses of fluorescence-activated cell-sorted murine intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 305:G542-51
Smith, Nicholas R; Davies, Paige S; Silk, Alain D et al. (2012) Epithelial and mesenchymal contribution to the niche: a safeguard for intestinal stem cell homeostasis. Gastroenterology 143:1426-30

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