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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Greenwel, Patricia
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cincinnati Children's Hospital Medical Center
United States
Zip Code
Rankin, Scott A; McCracken, Kyle W; Luedeke, David M et al. (2018) Timing is everything: Reiterative Wnt, BMP and RA signaling regulate developmental competence during endoderm organogenesis. Dev Biol 434:121-132
Lee, Kang Kug; McCauley, Heather A; Broda, Taylor R et al. (2018) Human stomach-on-a-chip with luminal flow and peristaltic-like motility. Lab Chip 18:3079-3085
Poling, Holly M; Wu, David; Brown, Nicole et al. (2018) Mechanically induced development and maturation of human intestinal organoids in vivo. Nat Biomed Eng 2:429-442
Wells, James M; Watt, Fiona M (2018) Diverse mechanisms for endogenous regeneration and repair in mammalian organs. Nature 557:322-328
Mahe, Maxime M; Brown, Nicole E; Poling, Holly M et al. (2017) In Vivo Model of Small Intestine. Methods Mol Biol 1597:229-245
McCracken, Kyle W; Wells, James M (2017) Mechanisms of embryonic stomach development. Semin Cell Dev Biol 66:36-42
McCauley, Heather A; Wells, James M (2017) Pluripotent stem cell-derived organoids: using principles of developmental biology to grow human tissues in a dish. Development 144:958-962
McCracken, Kyle W; Aihara, Eitaro; Martin, Baptiste et al. (2017) Wnt/?-catenin promotes gastric fundus specification in mice and humans. Nature 541:182-187
MĂșnera, Jorge O; Sundaram, Nambirajan; Rankin, Scott A et al. (2017) Differentiation of Human Pluripotent Stem Cells into Colonic Organoids via Transient Activation of BMP Signaling. Cell Stem Cell 21:51-64.e6
Workman, Michael J; Mahe, Maxime M; Trisno, Stephen et al. (2017) Engineered human pluripotent-stem-cell-derived intestinal tissues with a functional enteric nervous system. Nat Med 23:49-59

Showing the most recent 10 out of 16 publications