Thaddeus S. Stappenbeck, Ph.D., M.D.
Pathology and Immunology
Developmental, Regenerative and Stem Cell Biology Program
Molecular Cell Biology Program
Molecular Microbiology and Microbial Pathogenesis Program
Organs such as the lung and intestine with large surface areas, critical for their absorptive capacity, must also maintain an effective barrier to the outside world. My lab focuses on emerging aspects of innate mucosal immunology that maintain homeostasis and correct injuries at these interfaces. A major focus of the lab is the single layer of epithelial lining cells that forms the absorptive barrier in mucosa-lined organs. An important concept that has grown out of our work, mostly through analysis of mouse models using genetic, pharmacologic, and physical injury is that the decisions made by the epithelium are driven in large part by communication apically through contact with microbes and baso-laterally through contact with their underlying immune and stromal cell populations. We have recently developed novel methods to culture, expand and differentiate epithelial stem cells from mucosal surfaces of mice and humans. These new experimental systems now allow us to study the interactions of epithelial cells with microbes and other host cells to uncover the details of these conversations. Importantly, we can now perform these studies with human cells taken from biopsy specimens which will facilitate translational studies of specific human diseases such as inflammatory bowel disease where mucosal homeostasis is not maintained.
Examples of current projects in the lab that are examining this paradigm: 1) the delineation of how specific commensal bacteria and their gene products trigger inflammation in a genetically susceptible host, 2) understanding the mechanism of how viral infection alters epithelial cell turnover, 3) determining how genes involved in the genetic susceptibility of inflammatory bowel disease function in the epithelium during and how their altered function can lead to disease. One surprise here is that proteins in the autophagy pathway play an important role in epithelial secretion of mucus and antimicrobial proteins in both lung airways and gut. 4) We also study how the host shapes intestinal microbial communities through secretion of IgA and antimicrobial proteins. 5) We are defining previously unrecognized cells and structures that play a key role in repair. We are interested in the first cellular responders to mucosal damage in the form of wound associated epithelial (WAE) cells as well as expanded active stem cells the form wound channels which are precursors to new crypt formation.
Miyoshi H, Ajima R, Luo CT, Yamaguchi TP, Stappenbeck TS. Wnt5a potentiates TGF-β signaling to promote colonic crypt regeneration after tissue injury. Science 2012 338:108
Manieri NA, Drylewicz MR, Miyoshi H, Stappenbeck TS. Igf2bp1 is required for full induction of Ptgs2 mRNA in colonic mesenchymal stem cells in mice. In press. Gastroenterology. 2012 143:110-121.
Malvin NP, Seno, H, Stappenbeck TS: Colonic epithelial response to injury requires Myd88 signaling in macrophages. Mucosal Immunology. 2012 Mar;5(2):194-206.
Bloom SM, Bijanki VN, Nava GM, Sun L, Dunne WM, Allen PM, Stappenbeck TS. Commensal Bacteroides species induce colitis in host-genotype-specific fashion in a mouse model of inflammatory bowel disease Cell Host and Microbe. 2011 9:380-403
Nava GM, Friedrishsen HJ, Stappenbeck TS, Spatial organization of the intestinal microbiota in the mouse ascending colon. ISME J. 2011 5:627-638.
Cadwell K, Patel KK, Maloney NS, Liu TC, Ng AC, Storer CE, Head RD, Xavier R, Stappenbeck TS*, Virgin HW*. Virus-Plus-Susceptibility Gene Interaction Determines Crohn`s Disease Gene Atg16L1 Phenotypes in Intestine. Cell. 2010 Jun 25;141(7):1135-1145. (*Co-corresponding author)
Walker MR, Brown SL, Riehl TE, Stenson WF, Stappenbeck TS. Growth factor regulation of prostaglandin-endoperoxide synthase 2 (Ptgs2) expression in colonic mesenchymal stem cells. J Biol Chem. 2010 Feb 12;285(7):5026-39.
Seno H, Miyoshi H, Brown SL, Geske MJ, Colonna M, Stappenbeck TS. Efficient colonic mucosal wound repair requires Trem2 signaling. Proc Natl Acad Sci U S A. 2009 106:256-61.
Stappenbeck TS, Miyoshi H. The role of stromal stem cells in tissue regeneration and wound repair. Science. 2009 324:1666-9.
Cadwell K, Liu JY, Brown SL, Miyoshi H, Loh J, Lennerz JK, Kishi C, Kc W, Carrero JA, Hunt S, Stone CD, Brunt EM, Xavier RJ, Sleckman BP, Li E, Mizushima N, Stappenbeck TS*, Virgin HW 4th*. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature. 2008 456:259-63. (*Co-corresponding author)
Last Updated: 8/5/2013 11:55:22 AM