There is emerging evidence that distinct populations of actively cycling and quiescent intestinal stem cells (ISCs) co-exist within the small intestine epithelium and function cooperatively in tissue renewal. This proposal explores the hypothesis that these ISC populations are regulated by distinct sets of extracellular signals involved in organ size control and oxygen-sensing. This hypothesis is evaluated by three Specific Aims: (1) to explore the Hippo signaling pathway, implicated in controlling organ size, in regulating the regenerative responses of active and quiescent ISC populations, (2) to examine metabolic regulation of active and quiescent ISCs by the oxygen-sensing pathway, and (3) to determine the molecular signatures of active versus quiescent ISCs by comparative gene expression profiling.
These Specific Aims will be achieved by employing rigorous mouse genetics to examine ISCs in vivo within their stem cell niches and validated ex vivo clonogenic culture techniques that allow for sustained proliferation and multi-lineage differentiation of single isolated ISCs. Achievement of these Aims should provide insight into the molecular differences between active and quiescent ISCs at the transcriptional level and their differential regulation by diverse pathways governing organ size and metabolism.
The intestinal epithelium undergoes rapid and continuous renewal supported by intestinal stem cells and serves as a model tissue to study stem cell biology. Our proposal aims to understand the regulation of distinct populations of intestinal stem cells that are actively proliferating versus dormant. An improved understanding of the stem cell populations and their regulation may lead to new approaches to regeneration of intestine for therapy of intestinal diseases.
| Pont, Adam R; Yan, Kelley S (2018) Intestinal Crypts Assume the Fetal Position in Response to Injury. Cell Stem Cell 23:158-159 |
| 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 |
| Middelhoff, Moritz; Westphalen, C Benedikt; Hayakawa, Yoku et al. (2017) Dclk1-expressing tuft cells: critical modulators of the intestinal niche? Am J Physiol Gastrointest Liver Physiol 313:G285-G299 |
| Janda, Claudia Y; Dang, Luke T; You, Changjiang et al. (2017) Surrogate Wnt agonists that phenocopy canonical Wnt and ?-catenin signalling. Nature 545:234-237 |
| Yan, Kelley S; Janda, Claudia Y; Chang, Junlei et al. (2017) Non-equivalence of Wnt and R-spondin ligands during Lgr5+ intestinal stem-cell self-renewal. Nature 545:238-242 |
| Mah, Amanda T; Yan, Kelley S; Kuo, Calvin J (2016) Wnt pathway regulation of intestinal stem cells. J Physiol 594:4837-47 |
| Yan, Kelley S; Kuo, Calvin J (2015) Ascl2 reinforces intestinal stem cell identity. Cell Stem Cell 16:105-6 |
| Chan, Charles K F; Seo, Eun Young; Chen, James Y et al. (2015) Identification and specification of the mouse skeletal stem cell. Cell 160:285-98 |
| DiMarco, Rebecca L; Su, James; Yan, Kelley S et al. (2014) Engineering of three-dimensional microenvironments to promote contractile behavior in primary intestinal organoids. Integr Biol (Camb) 6:127-142 |
| 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 |
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