Washington University
School of Medicine

Dept. of Medicine
Pathology & Immunology
Box 8118
660 S. Euclid Ave.
St. Louis, MO 63110

We study the role and regulation of intestinal epithelial stem cells in health and disease. Numerous common, western world maladies (ranging in morbidity from irritable bowel syndrome to colon cancer) target these cells and effect repair, regeneration and transformation of this epithelium. These progenitors compose one of the largest populations of epithelial stem cells in the human body and are the source of the rapid and continuous renewal of the absorptive epithelial lining of the intestine. Our goal is to define their molecular properties and determine how they interact with the surrounding mesenchymal stem cell niche.

We use the mouse intestine (morphologically and developmentally homologous to human intestine) as an in vivo system to model disruptions in both stem cells and their niche. An advantage of intestine for the study of stem cell biology is that both the morphologic features and anatomic location of the epithelial progenitors and their descendant lineages are well established. Thus, well characterized 'micro-geographic' features allow us to collect and analyze specified cell populations using laser capture microdissection (LCM). We use combinations of genetic, pharmacologic and luminal manipulations to test hypotheses about epithelial stem cell function. For example, we have shown that chemically wounding the colon induces activated macrophages to appose epithelial progenitors, thereby supporting proliferation in the stem cell compartment. We are currently investigating the molecular nature of the macrophage-stem cell interaction. In another project, we are pursuing new markers of intestinal epithelial stem cells using the novel genes identified through sequencing micro-cDNA libraries of LCM procured progenitors.

Stappenbeck, T.S., J.C. Mills and J.I. Gordon. (2003) Molecular features of adult mouse small intestinal epithelial progenitors. Proc. Natl. Acad. Sci. USA. 100, 1004-1009.

Stappenbeck, T.S., L.V. Hooper, J.K Manchester, M.H. Wong and J.I. Gordon (2002). Laser capture microdissection of the mouse intestine: Characterizing mRNA and protein expression, and profiling intermediary metabolism in specified cell populations. In: Methods in Enzymology (Laser Capture Microscopy and Microdissection, P.M. Conn, editor) Academic Press. 356, 168-196.

Stappenbeck, T.S., L.V. Hooper and J.I. Gordon. (2002) Developmental regulation of intestinal vasculogenesis by indigenous microbes via Paneth cells. Proc. Natl. Acad. Sci. USA 99, 15451-15451.

Stappenbeck, T.S. and J.I. Gordon (2001). Extranuclear sequestration of phospho- N-terminal kinase and distorted villi produced by activated Rac1 in the intestinal epithelium of chimeric mice. Development 128, 2603-2614.

Stappenbeck, T.S. and J.I. Gordon (2000). Rac1 mutations produce aberrant epithelial differentiation in the developing and adult mouse small intestine. Development 127, 2629-2642.