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.
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.
|Deane, James A; Ong, Y Rue; Cain, Jason E et al. (2016) The mouse endometrium contains epithelial, endothelial and leucocyte populations expressing the stem cell marker telomerase reverse transcriptase. Mol Hum Reprod 22:272-84|
|Ariyachet, Chaiyaboot; Tovaglieri, Alessio; Xiang, Guanjue et al. (2016) Reprogrammed Stomach Tissue as a Renewable Source of Functional Î² Cells for Blood Glucose Regulation. Cell Stem Cell 18:410-21|
|Richmond, Camilla A; Shah, Manasvi S; Carlone, Diana L et al. (2016) Factors regulating quiescent stem cells: insights from the intestine and other self-renewing tissues. J Physiol 594:4805-13|
|Richmond, Camilla A; Shah, Manasvi S; Carlone, Diana L et al. (2016) An enduring role for quiescent stem cells. Dev Dyn 245:718-26|
|D'Addio, Francesca; La Rosa, Stefano; Maestroni, Anna et al. (2015) Circulating IGF-I and IGFBP3 Levels Control Human Colonic Stem Cell Function and Are Disrupted in Diabetic Enteropathy. Cell Stem Cell 17:486-98|
|Richmond, Camilla A; Shah, Manasvi S; Deary, Luke T et al. (2015) Dormant Intestinal Stem Cells Are Regulated by PTEN and Nutritional Status. Cell Rep 13:2403-11|
|San Roman, Adrianna K; Tovaglieri, Alessio; Breault, David T et al. (2015) Distinct Processes and Transcriptional Targets Underlie CDX2 Requirements in Intestinal Stem Cells and Differentiated Villus Cells. Stem Cell Reports 5:673-81|
|Gierut, Jessica J; Lyons, Jesse; Shah, Manasvi S et al. (2015) Oncogenic K-Ras promotes proliferation in quiescent intestinal stem cells. Stem Cell Res 15:165-71|
|Freedman, Bethany D; Kempna, Petra Bukovac; Carlone, Diana L et al. (2013) Adrenocortical zonation results from lineage conversion of differentiated zona glomerulosa cells. Dev Cell 26:666-73|
|Richardson, Gavin D; Breault, David; Horrocks, Grace et al. (2012) Telomerase expression in the mammalian heart. FASEB J 26:4832-40|
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