Thaddeus S. Stappenbeck, Ph.D., M.D.

DEPARTMENT OF Pathology & Immunology
Keywords: functional genomics, mouse models, stem cells, laser capture microdissection, cytoskeleton

We study the role of intestinal epithelial stem cells and their progeny in development and disease (such as inflammatory bowel disease and colon cancer). A critical function of these cells is to generate and continuously maintain an expansive epithelial barrier. In the colon, this occurs under extreme conditions: one side of the barrier contacts microbes that normally reside in the colon at a density of hundreds of billions per milliliter while the opposite surface contacts a robust population of immune and microvascular cells. Our goal is to determine how this barrier rapidly expands during development and is preserved when breached. Our working model is that communication of the epithelial stem cells with the underlying mesenchymal cells (‘the stem cell niche’) drives these processes.

We use the mouse intestine (morphologically and developmentally homologous to human intestine) as an in vivo system model system. To disrupt the epithelial barrier, we use combinations of genetic, pharmacologic, lumenal and physical manipulations (the latter using biopsies visualized with a colonoscope designed for mice). Our studies show these injuries induce niche reorganization that strategically repositions specific cell types (including macrophages and an as yet undefined stromal cell) so they can communicate with the overlying epithelial stem cells and thereby properly modulate barrier function recovery. Interestingly, depending on the nature and severity of the insult, different niche modifications are deployed. We are currently defining the molecular nature of these stem cell/niche interactions under a variety of conditions that damage the colonic epithelial barrier.

In a developmental project, we are investigating the role of growth factors secreted by the epithelial stem cells that control fibroblast differentiation in the stem cell niche. Maintenance of undifferentiated fibroblasts appears to be a key element to supporting the rapid expansion of the gut length early in development.