In Vitro Generation of Normal and Neoplastic Intestinal Stem Cells
The approximately 25 feet of adult intestine is essential for nutrient absorption, secretion of hormones, and as a barrier to infection. Disorders of the intestine including inflammatory bowel disease, mesenteric ischemia, congenital syndromes and trauma, all significantly interfere with intestinal function and in severe cases result in “short-gut” syndromes and effective intestinal failure. Supportive measures are utilized including total parenteral nutrition, in which patients receive all of their nutrition intravenously, or even intestinal transplantation. One goal of the proposed work is to induce human embryonic stem (hES) cells to be reliably converted to intestinal stem cells in culture, for eventual therapy of these disorders. This will be accomplished by addition of hormones, of candidate genes, and by placing the hESC into a nutritive “niche” that promotes intestinal stem cell genesis and function. The generation of human intestinal stem cells from hESC will provide novel therapeutic approaches to the numerous conditions resulting in effective intestinal failure, for which currently available therapies are decidedly suboptimal.
A second goal of the proposal is to generate and study colon cancer stem cells from the same intestinal cultures, to better understand the biology of colon cancer and to catalyze the rational development of therapies thereof. Previous studies of cancer stem cells have not allowed their study within a native environment, which will be performed here using our methodology. These studies will reveal temporal patterns of colon cancer progression, identify therapeutic/diagnostic targets, and validate an system for the evaluation of new colon cancer therapeutics.
The proposed research will develop new human embryonic stem cell-based technologies enabling the robust propagation of intestinal tissue its associated stem cells, and cancerous derivatives outside of the human body, in laboratory culture. These studies have implications for the treatment of disabling conditions of the intestinal tract including inflammatory bowel disease, mesenteric ischemia, congentital intestinal disorders and cancer.