The intestinal architecture is composed of a sequential array of zones along the villus-crypt axis in which cellular self-renewal, proliferation, differentiation, and apoptosis is ongoing. Postnatal regeneration of the intestines is driven by intestinal stem cells (ISCs), which have the ability to regenerate by self-renewal and are multipotent, giving rise to four different types of epithelial lineages. Thus far, regulation of this sequential developmental process remains largely unknown. Although ISCs have been reported to be located at the 4th or 5th position from the crypt base, no biological marker is available for recognition and mapping the fate of ISCs. Nor has the cellular component of the ISC niche been identified. We have generated a BMPRIA knockout mutant mouse line to explore the roles of the BMP signal in regulating ISC development. This mutant mouse model develops profuse polyps in the gastrointestinal tract resembling human juvenile polyposis, and with it an increased number of ISCs and progenitor cells. In these mice we have found compartmentalized BMP activity which ties in with the zones of ISCs self-renewal, proliferation, differentiation, and apoptosis. This research proposal is to test our theories that 1) the compartmentalized BMP activity determines the zones in which ISCs undergo sequential development, 2) to isolate and characterize intestinal stem cells using ISC-SM1 which we identified recently through analysis of the Bmprla mutant mice, and 3) to isolate and characterize ISC candidate niche cells using N-cadherin as the surface marker. We believe that the results derived from these studies will provide important insight into understanding the properties of intestinal stem cells and intestinal regeneration. Identification and isolation of both ISCs and their niche cells will not only open a new avenue for studying stem cell behavior in vitro, but will also have clinical implications in the areas of stem cell transplantation and stem cell-based replacement therapy for gastrointestinal diseases.
| Wang, Mei-Lun; Keilbaugh, Sue A; Cash-Mason, Tanesha et al. (2008) Immune-mediated signaling in intestinal goblet cells via PI3-kinase- and AKT-dependent pathways. Am J Physiol Gastrointest Liver Physiol 295:G1122-30 |
| He, Xi C; Yin, Tong; Grindley, Justin C et al. (2007) PTEN-deficient intestinal stem cells initiate intestinal polyposis. Nat Genet 39:189-98 |
