Quiescent Dclk1+ stem cells in the mouse intestine

小鼠肠道中的静态 Dclk1 干细胞

• 批准号: 8577370
• 负责人: Timothy Cragin Wang
• 金额: $ 32万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8577370
• 关键词: Ablation; Adult; Cell Communication; Cell Count; Cell Differentiation process; Cells; Cilia; Coculture Techniques; Data; Development; Diphtheria Toxin; Electron Microscopy; Embryo; Enteral; Enteric Nervous System; Epithelial; Exhibits; Generations; Genes; Growth; Homeostasis; Human; In Vitro; Inflammation; Injury; Intestines; Label; Laboratories; Life; Longevity; Mediating; Modeling; Mus; Natural regeneration; Nerve; Neural Crest; Neurites; Neuroglia; Neurons; Organ; Organoids; Pathway interactions; Phosphotransferases; Play; Property; Radial; Radiation; Radiation Injuries; Regulation; Reporting; Reserve Stem Cell; Role; Signal Transduction; Stem cells; Stromal Cells; Suggestion; Synapses; System; Testing; Tissues; Toxin; Transgenic Mice; beta catenin; cell type; density; doublecortin protein; gastrointestinal; gastrointestinal transplantation; in vivo; inhibitor/antagonist; insight; intestinal crypt; intestinal homeostasis; mouse model; nerve supply; progenitor; public health relevance; regenerative; relating to nervous system; response; sensor; stem; stem cell niche

DESCRIPTION (provided by applicant): Truly quiescent and long-lived stem cells have been postulated but to date not identified in the gut. Doublecortin-like kinase 1 (Dclk1) was proposed as a stem cell marker in the intestine but was also found to be expressed in intestinal tuft cells. Recently, our group has generated Dclk1- Cre-ERT BAC transgenic mice, and we have shown unequivocally that Dclk1+ tuft cells are long-lived, quiescent stem cells that are derived from Lgr5+ stem cells but induced by nervous innervation. Our hypothesis is that Dclk1+ tuft cells play a role both as part of the intestinal stem cell niche and also as reserve intestinal stem cell, and are generated through extrinsic neural innervation. We will explore this hypothesis through three specific aims. (1) What is the role of nerves in the induction of Dclk1+ tuft cells. We will utilize both in vitro culture systems, and in vivo mouse models, to examine the role of nervous innervation, with a focus on NGF-Trk pathway in mediating the nerve-tuft cell interactions. (2) Does ablation of Dclk1+ progenitors inhibit normal intestinal epithelial homeostasis and growth, and the response to radiation injury? Dclk1-Cre-ERT mice crossed to DTR F/F mice will be treated with diptheria toxin and the regenerative response to radiation assessed using both in vitro and in vivo systems. (3). Does activation of Dclk1+ progenitors result in intestinal proliferation and increased regeneration following radiation injury? Preliminary studies suggestion that deletion of Apc in the Dclk1 lineage, and activation of Wnt signaling, is sufficien to convert Dclk1 tuft cells into active stem cells. We will explore the role of Wnt signaling using both crypt cultures and mouse models. Overall, these studies should provide new insights into the role of Dclk1 progenitors as both niche and stem cells in the intestine, and their contribution to intestinal regeneration.

描述（由申请人提供）：真正静止和长寿的干细胞已被假设，但迄今尚未在肠道中发现。双皮质素样激酶1 （Dclk1）被认为是肠道干细胞标志物，但也被发现在肠簇细胞中表达。