The underlying molecular mechanism for epithelial pathology in inflammatory bowel disease. Inflammatory bowel disease (IBD) afflicts more than one million Americans and imposes a ten-fold increased risk for colorectal cancer (CRC). Although great strides have been made for treatment, disease etiology and the molecular basis of its fundamental pathology remains unknown. Understanding molecular pathogenesis is the critical foundation for translational research in developing effective therapeutic approaches for managing this disease. Several key developmental signaling pathways, including Wnt and Notch, have been implicated in maintaining normal intestinal homeostasis by balancing stem cell self-renewal, proliferation and cell fate decision. The IBD epithelial pathogenesis suggests that there is a dysregulation of Wnt and Notch pathways, however a causal relationship has not been established. Our laboratory is linking epithelial IBD-associated pathology to perturbations in these developmental signaling pathways. Specifically we are investigating whether suppression of Wnt signaling results in the "crypt dropout" phenotype. Our preliminary data suggests that the proliferative Wnt signal is greatly suppressed in patients and mice with IBD. These studies will provide insight into the molecular mechanism underlying the basic pathology of inflammatory bowel disease.

The implication of circulating bone marrow-derived stem cells and cell fusion on tumor progression. Our laboratory has shown that circulating BMDCs fuse with intestinal stem cells upon tissue injury, inclusive of intestinal tumorigenesis. We now extend these studies to identify the cellular mediators of fusion, the underlying mechanism, and the long-term fate to the cell fusion hybrids. We have currently identified the macrophage population as a key bone marrow derived cell population in this fusion process. Our studies are now focused upon determine the fate of the cell fusion hybrids in participating to intestinal pathogenesis, as we examine genomic instability of the fusion hybrids, the ability of these cells to express macrophage genes under certain contexts, and the contribution of these cells to tumorigenesis. Our studies offer an exciting alternative view of how epithelia regenerate and have the potential to explain how chronic injury can lead to promote malignant tumors.

Identification of markers for intestinal stem cells and intestinal cancer stem cells. The cancer stem cell theory for why many cancers may recur after treatment presents a novel target for cancer therapeutics. However, the notion that cancer stem cells arise from mutations in tissue stem cells suggests that these two cell populations may share similar features and targetable epitopes. We have taken a systematic approach to defining surface antigens on these two populations by generating novel monoclonal antibodies. Our studies will establish a link between these two populations and may provide novel epitopes that are unique to the cancer stem cell that can be used for targeted therapy.

Role of Wnt signaling in regulating the morphogenesis of the intestinal epithelial stem cell niche. Wnt signaling plays an important role in maintaining epithelial proliferation and differentiation in the stem cell niche of the intestine and has been implicated in extension conversion of the organ during development. To gain insight into the importance of Wnt signaling in establishing the proliferation to differentiation gradient in the intestine in the context of tissue regeneration after injury, we turned to the earliest establishment of this gradient, in development of the stem cell niche during crypt morphogenesis. To determine the role of Wnt signaling in establishing the stem cell niche during intestinal development, we are conducting experiments to temporally manipulate the canonical Wnt signaling pathway ( -catenin mediated) using genetically engineered mice. We are currently comparing temporally induced ablation of Apc, an intracellular regulator of -catenin, induced ablation of -catenin, and induced expression of a dominant negative Tcf-4 molecule (DNTcf-4). To fully examine the role of Wnt signaling in the intestine, we are also examining the role of the non-canonical Wnt signaling pathway using a lentiviral mediated delivery approach for over-expressing these ligands in the intestinal mesenchyme. These studies provide insight into how the epithelial stem cell niche is regulated during development and will provide insight into how this niche can be regenerated after epithelial injury.

Selected publications:

Davies PS, Dismuke, AD, Powell AE, Carroll KH, and Wong MH. Wnt signaling regulates proliferation of murine early progenitor cells in the intestine and is differentially stimulated in response to injury. (2008) BMC Gastroenterol, 8:57.

Jiang S, Bailey AS, Goldman DC, Swain JR, Wong MH, Streeter P, and Fleming WH. (2008) Hematopoietic stem cells contribute to lymphatic endothelium. PLoS ONE 3:e3812.

Davies PS, Powell AE, and Wong MH. Inflammation and proliferation act synergistically to mediate intestinal cell fusion. Submitted to PLOS One.

Dismuke AD, Kohn AD, Moon RT, and Wong MH. Lentiviral mediated transgene expression can potentiate intestinal mesenchymal-epithelial signaling. In review at Biologic Procedures.

Levin, TS, Powell AE, Dismuke AD, Davies PS, Swain JS, Glynn CS and Wong MH. Characterization of the intestinal cancer stem cell marker, CD166/ALCAM, in the human and mouse gastrointestinal tract. Submitted to Stem Cells.

Rizvi AZ, Swain JS, Bailey AS, Davies PS, Decker AD, Willenbring H, Grompe M, Fleming WH, and Wong MH. (2006) Bone marrow-derived cells fuse with normal and transformed intestinal progenitor cells. PNAS USA, 103:6321-5.

Wong MH, Huelsken J, Birchmeier W, and Gordon JI. (2002) Stimulation of Lef-1/b-catenin mediated signaling in the developing mouse intestinal epithelium results in loss of stem cells and effects the establishment of the stem cell hierarchy. J. Biol. Chem., 277:15843-15850.

Hooper LV, Wong MH, Thelin A, Falk PG, and Gordon JI. (2001) Molecular components of intestinal function and maturation modulated by a normal resident bacterium. Science, 291:881-884.



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