Thaddeus S. Stappenbeck, MD, PhD
I study the role and regulation of intestinal epithelial stem cells and their differentiated progeny in health and disease. Numerous common, western world maladies (including inflammatory bowel disease and 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. We use combinations of genetic, pharmacologic and luminal manipulations to test hypotheses about epithelial stem cell function. We have found that the process of creating replacement intestinal epithelial stem cells after injury requires their interaction with fibroblasts and tissue resident macrophages. We are also found the cellular targets in the intestinal epithelium for the loss of function of an autophagy gene that predisposes humans to a form of inflammatory bowel disease.