It has long been held that self-renewing tissues such as bone marrow are maintained by slowly cycling (largely quiescent) stem cells, which upon activation give rise to rapidly cycling progenitor cells. Recently, it has been established that a subpopulation of dormant stem cells (that rarely cycle) are also present, which seem to function primarily as potent stem cells following tissue injury. Under normal conditions, by comparison, dormant stem cells are thought to contribute only minimally to tissue homeostasis. The continuously self-renewing intestinal epithelium, in contrast, appears to be maintained by at least two separate stem cell populations under basal conditions, which are either rapidly cycling or slowly cycling. Using two strains of reporter mice, we now show that telomerase-expressing cells represent a rare population of dormant stem cells that are highly resistant to intestinal injury. As such, telomerase does not represent a universal marker for ISCs but rather marks a subpopulation of ISCs with potent regenerative capacity. Intriguingly, our preliminary data indicate that telomerase-expressing ISCs give rise to rapidly cycling Lgr5+ cells suggesting a lineage hierarchy within the intestinal crypt as well as a potential mechanism by which stem cells may be replaced following injury. This proposal seeks to further define the role of mTert-expressing cell in intestinal homeostasis and in response to injury as well as to examine the molecular basis for quiescence and self-renewal. The successful completion of these goals will provide an in depth understanding of the key regulatory pathways utilized by ISCs and potentially lead to novel therapeutic strategies for patients with gastrointestinal conditions such as inflammatory bowel disease, short bowel syndrome and intestinal cancer.

Public Health Relevance

Slowly cycling tissue stem cells hold great promise for regenerative medicine and tissue repair, though have remained elusive in many tissues including intestine due to a lack of definitive biomarkers. We have employed an innovative strategy using transgenic mice that allows for the identification, isolate and genetic manipulate of intestinal stem cells. This work may give rise to novel therapeutic treatment strategies for intestinal diseases such as small bowel syndrome, inflammatory bowel disease and intestinal cancers.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK084056-02
Application #
8090290
Study Section
Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
Program Officer
Carrington, Jill L
Project Start
2010-07-01
Project End
2015-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
2
Fiscal Year
2011
Total Cost
$356,412
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Richmond, Camilla A; Rickner, Hannah; Shah, Manasvi S et al. (2018) JAK/STAT-1 Signaling Is Required for Reserve Intestinal Stem Cell Activation during Intestinal Regeneration Following Acute Inflammation. Stem Cell Reports 10:17-26
O'Connell, Amy E; Zhou, Fanny; Shah, Manasvi S et al. (2018) Neonatal-Onset Chronic Diarrhea Caused by Homozygous Nonsense WNT2B Mutations. Am J Hum Genet 103:131-137
Dumontet, Typhanie; Sahut-Barnola, Isabelle; Septier, Amandine et al. (2018) PKA signaling drives reticularis differentiation and sexually dimorphic adrenal cortex renewal. JCI Insight 3:
Yan, Kelley S; Gevaert, Olivier; Zheng, Grace X Y et al. (2017) Intestinal Enteroendocrine Lineage Cells Possess Homeostatic and Injury-Inducible Stem Cell Activity. Cell Stem Cell 21:78-90.e6
Stokes, Kyle; Cooke, Abrial; Chang, Hanna et al. (2017) The Circadian Clock Gene BMAL1 Coordinates Intestinal Regeneration. Cell Mol Gastroenterol Hepatol 4:95-114
Pignatti, Emanuele; Leng, Sining; Carlone, Diana L et al. (2017) Regulation of zonation and homeostasis in the adrenal cortex. Mol Cell Endocrinol 441:146-155
Nelms, Bradlee D; Waldron, Levi; Barrera, Luis A et al. (2016) CellMapper: rapid and accurate inference of gene expression in difficult-to-isolate cell types. Genome Biol 17:201
Tao, Liang; Zhang, Jie; Meraner, Paul et al. (2016) Frizzled proteins are colonic epithelial receptors for C. difficile toxin B. Nature 538:350-355
Ariyachet, Chaiyaboot; Tovaglieri, Alessio; Xiang, Guanjue et al. (2016) Reprogrammed Stomach Tissue as a Renewable Source of Functional ? Cells for Blood Glucose Regulation. Cell Stem Cell 18:410-21
Richmond, Camilla A; Shah, Manasvi S; Carlone, Diana L et al. (2016) An enduring role for quiescent stem cells. Dev Dyn 245:718-26

Showing the most recent 10 out of 24 publications