Characterized by continual turnover, the intestine provides an elegant system for the study of adult stem cells - - cells which self-renew and regenerate and, thus, hold great promise for regenerative medicine. Studies have provided important insight regarding the capacity of intestinal stem cells (ISCs) for self-repair or healing as well as ongoing maintenance and differentiation into all the various intestinal cell types. However, considerable research is needed to better understand the different states and functions of subpopulations of ISCs and how these are regulated. In other tissues, such as hair and blood, the quiescent stem cell subpopulation is known to be critical, especially for long-term maintenance of the stem cell pool and for regeneration in response to stress or injury. However, in intestine, it is a matter of debate whether bona fide quiescent ISCs exist and/or where they reside. This research proposes that bona fide quiescent ISCs coexist with active ISCs. The active subpopulation accounts for generation and regeneration of intestinal epithelial lineages, and the quiescent subpopulation functions as a 'reserve'pool to replenish lost active ISCs and damaged tissues. The goal of this research is to further investigate +4 quiescent ISCs, in particular, and to determine potential molecular regulation of quiescent and active ISC subpopulations. Methods to be used will include: surface markers and in vitro culture and in vivo lineage tracing assays to identify and characterize quiescent ISCs under stable and stressed conditions;RNA sequencing to determine how and where certain factors (Frizzled5 and/or 7) mediate signaling (noncanonical and/or canonical Wnt) that govern ISC maintenance, activation, self- renewal and location;and genetic mouse models to study the effect of protein inactivation on quiescent and active ISCs. Understanding signaling regulation of the state and fate of quiescent and active ISCs can uncover potential therapeutic targets for treating intestinal disorders, including cancer. If this goal can be achieved, it will open avenues not only for advancing the study of ISC behavior, but also for treating intestinal disorders in which ISC-driven tissue regeneration is essential and for screening drugs to target cancer stem cells. The ability to identify and isolate and characterize ISCs is critical for therapeutic advancements, especially tissue replacement, and for enhanced understanding of the development, prevention, and cure of intestinal disease.

Public Health Relevance

More than 70 million Americans are affected by a wide range of digestive diseases at an astronomical cost that exceeds $142 billion. Evidence indicates intestinal stem cells (ISCs) are involved in many of these diseases -- from Crohn's to colitis to cancer. This research will increase knowledge of ISC biology, which can be applied to enhance treatment efficacies, improve patient outcomes, and ultimately, reduce the public health burden of digestive diseases.

National Institute of Health (NIH)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZDK1)
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Carrington, Jill L
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Stowers Institute for Medical Research
Kansas City
United States
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Wang, Fengchao; Scoville, David; He, Xi C et al. (2013) Isolation and characterization of intestinal stem cells based on surface marker combinations and colony-formation assay. Gastroenterology 145:383-95.e1-21
Gracz, Adam D; Fuller, Megan K; Wang, Fengchao et al. (2013) Brief report: CD24 and CD44 mark human intestinal epithelial cell populations with characteristics of active and facultative stem cells. Stem Cells 31:2024-30
Magness, Scott T; Puthoff, Brent J; Crissey, Mary Ann et al. (2013) A multicenter study to standardize reporting and analyses of fluorescence-activated cell-sorted murine intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 305:G542-51
Stelzner, Matthias; Helmrath, Michael; Dunn, James C Y et al. (2012) A nomenclature for intestinal in vitro cultures. Am J Physiol Gastrointest Liver Physiol 302:G1359-63
Li, Linheng; Clevers, Hans (2010) Coexistence of quiescent and active adult stem cells in mammals. Science 327:542-5