Mechanisms of fetal intestinal stem cell regulation and maturation Regulation of embryonic progenitor cells and adult tissue-specific stem cells has been intensely studied. However, these populations (embryonic progenitor vs. adult stem cell) are often considered to be discrete entities existing within time and space. For example, it is uniformly accepted that fetal intestinal progenitor cells give rise to the adult intestinal epithelum, but some literature suggests that adult intestinal stem cells emerge de novo during crypt formation and are molecularly distinct from their embryonic predecessors. However, our preliminary observations suggest that in the fetal/embryonic intestine, adult intestinal stem cell genes are expressed and maintained in a subset of cells throughout development/differentiation. Based on these results, we hypothesize that the adult stem cell state is not a discrete event, but part of a developmental continuum. That is, a stem/progenitor state is established developmentally in a subset of embryonic intestinal cells that give rise to adult intestinal stem cells. To test our hypothesis we will take advantage of two model systems, the murine model system and human pluripotent stem cell derived intestinal tissue. Combined, these powerful in vivo and in vitro systems will allow us to investigate the genetic and epigenetic ontogeny of intestinal stem cell precursors and adult intestinal stem cells.

Public Health Relevance

Our proposal will explore the idea that adult intestinal stem cells are set aside as a precursor population in the embryonic intestine and we will explore the possibility that an epigenomic and transcriptional signature is acquired early in the fetal intestie and maintained into adult life. These studies may help inform regenerative strategies for underdeveloped or damaged embryonic and neonatal disorders affecting the intestine, such as intestinal atresia and short bowel syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DK103141-02
Application #
8918614
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Carrington, Jill L
Project Start
2014-09-01
Project End
2019-08-31
Budget Start
2015-09-01
Budget End
2016-08-31
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Han, Xu; Lee, Allen; Huang, Sha et al. (2018) Lactobacillus rhamnosus GG prevents epithelial barrier dysfunction induced by interferon-gamma and fecal supernatants from irritable bowel syndrome patients in human intestinal enteroids and colonoids. Gut Microbes :1-18
Srivillibhuthur, Manasa; Warder, Bailey N; Toke, Natalie H et al. (2018) TFAM is required for maturation of the fetal and adult intestinal epithelium. Dev Biol 439:92-101
Dame, Michael K; Attili, Durga; McClintock, Shannon D et al. (2018) Identification, isolation and characterization of human LGR5-positive colon adenoma cells. Development 145:
Tsai, Yu-Hwai; Czerwinski, Michael; Wu, Angeline et al. (2018) A Method for Cryogenic Preservation of Human Biopsy Specimens and Subsequent Organoid Culture. Cell Mol Gastroenterol Hepatol 6:218-222.e7
Spence, Jason R (2018) Taming the Wild West of Organoids, Enteroids, and Mini-Guts. Cell Mol Gastroenterol Hepatol 5:159-160
Cruz-Acuña, Ricardo; Quirós, Miguel; Huang, Sha et al. (2018) Publisher Correction: PEG-4MAL hydrogels for human organoid generation, culture, and in vivo delivery. Nat Protoc :
Cruz-Acuña, Ricardo; Quirós, Miguel; Huang, Sha et al. (2018) PEG-4MAL hydrogels for human organoid generation, culture, and in vivo delivery. Nat Protoc 13:2102-2119
Banerjee, Kushal K; Saxena, Madhurima; Kumar, Namit et al. (2018) Enhancer, transcriptional, and cell fate plasticity precedes intestinal determination during endoderm development. Genes Dev 32:1430-1442
Quiros, Miguel; Nishio, Hikaru; Neumann, Philipp A et al. (2017) Macrophage-derived IL-10 mediates mucosal repair by epithelial WISP-1 signaling. J Clin Invest 127:3510-3520
Hill, David R; Huang, Sha; Nagy, Melinda S et al. (2017) Bacterial colonization stimulates a complex physiological response in the immature human intestinal epithelium. Elife 6:

Showing the most recent 10 out of 28 publications