The small intestine bears similar morphology of crypts and villi throughout its length, yet marked regional differences in function are well known. The clinical relevance of these differences is highlighted by the region specific location of many human diseases throughout the bowel. Understanding the mechanisms that result in regional specific intestinal stem cells (ISC) is required to develop therapeutic approaches for restoring regional specific function. Our preliminary data supports the concept that patterning of the intestine occurs early in development and is maintained throughout life at the level of the ISC. Using our recently developed in vitro methods to culture human ISC-derived enteroids (hENO) and conditions that regionally pattern human ES/iPS-derived organoids (HIOs), combined with unique transplantation models, we will determine if intestinal regional identity (rID) is stably maintained by specific transcription factors together with a unique chromatin state within individual ISC. To test this hypothesis, we will define the molecular and cellular carriers of intestinal regional identity, determine whether human hENOs and HIOs maintain stable rID after transplantation and identify the network of molecular determinants of regional identity.

Public Health Relevance

The proposed work utilizes cutting edge technology to characterize the network of molecular determinants of regionalized intestinal stem cells. This work will lead to a deeper understanding of regional influence within intestinal stem cell populations that may contribute to physiological and disease specific difference commonly seen between the proximal and distal intestine.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01DK103117-01
Application #
8773809
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Carrington, Jill L
Project Start
2014-09-01
Project End
2019-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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Sinagoga, Katie L; Wells, James M (2015) Generating human intestinal tissues from pluripotent stem cells to study development and disease. EMBO J 34:1149-63
Watson, Carey L; Mahe, Maxime M; Múnera, Jorge et al. (2014) An in vivo model of human small intestine using pluripotent stem cells. Nat Med 20:1310-4