Regulation of distinct pools of intestinal stem cells

不同肠道干细胞库的调节

• 批准号: 9135703
• 负责人: Ophir D Klein
• 金额: $ 5万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-05 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9135703
• 关键词: Address; Antibodies; Basic Science; Blocking Antibodies; Cell Cycle; Cell division; Cells; Cellular Structures; Columnar Cell; Development; Disease; Dose; Enteroendocrine Cell; Environment; Epithelial; Epithelium; Future; Gene Targeting; Genetic; Goblet Cells; Health; Homeostasis; Inflammatory Bowel Diseases; Intestines; Ligands; Light; Location; Malignant Neoplasms; Maps; Metabolic Diseases; Monitor; Mus; Nature; Nuclear; Paneth Cells; Pathway interactions; Physiological; Population; Process; Regenerative Medicine; Regulation; Reporter; Role; Secretory Cell; Signal Pathway; Signal Transduction; Small Intestines; Staining method; Stains; Stem cells; Testing; Therapeutic; Tissues; Transgenes; attenuation; base; cell type; combinatorial; genetic approach; interest; intestinal epithelium; lipoprotein receptor-related protein 6; notch protein; organ regeneration; progenitor; regenerative; research study; self-renewal; stem cell population; translational approach

DESCRIPTION (provided by applicant): The small intestine epithelium renews every 2 to 5 days, making it one of the most regenerative mammalian tissues. Understanding the intestinal stem cells (ISCs) that fuel this renewal is both an important basic science question and an essential starting point for translational approaches in regenerative medicine. Genetic inducible fate mapping (GIFM) studies have identified two principal epithelial stem cell pools in the intestine. One pool consists of columnar Lgr5-expressing cells that cycle rapidly and are present predominantly at the crypt base, and the other consists of cells expressing Bmi1 or other markers that largely reside above the crypt base. We have recently demonstrated (Tian et al, Nature, 2011) that Bmi1-expressing ISCs give rise to Lgr5- expressing ISCs under normal physiological conditions. Importantly, when we specifically ablated Lgr5- expressing ISCs, Bmi1-expressing ISCs were able to maintain epithelial homeostasis in the proximal small intestine. These results, which have been confirmed by several other groups, indicated that Lgr5- and Bmi1- expressing ISCs constitute two distinct, although possibly partially overlapping, populations. An important question is which signaling pathways regulate these different stem cell populations, and a growing body of evidence indicates that Wnt and Notch signaling guide both Lgr5- and Bmi1-expressing stem cell self-renewal. In this application, we propose to employ pathway-specific blocking antibodies to understand the differential and combinatorial effects of Wnt and Notch signaling on self-renewal and lineage fate decisions in ISCs. This unique approach - combining antibody blockade and genetic fate mapping - opens up interesting new avenues beyond the traditional purely genetic approaches. The results of these studies will shed important light on the mechanisms by which ISCs self-renew and differentiate, which will help to understand the roles of these ISCs in homeostasis and disease and will help to lay the groundwork for future attempts at organ regeneration.

描述（由申请人提供）：小肠上皮每 2 至 5 天更新一次，使其成为再生能力最强的哺乳动物组织之一。了解促进这种更新的肠道干细胞（ISC）既是一个重要的基础科学问题，也是再生医学转化方法的重要起点。遗传诱导命运图谱（GIFM）研究已经确定了肠道中两个主要的上皮干细胞池。一个池由表达 Lgr5 的柱状细胞组成，这些细胞循环迅速，主要存在于隐窝基底，另一个池由表达 Bmi1 或主要位于隐窝基底上方的其他标记物的细胞组成。我们最近证明（Tian 等，Nature，2011）表达 Bmi1 的 ISC 在正常生理条件下会产生表达 Lgr5 的 ISC。重要的是，当我们特异性消除表达 Lgr5 的 ISC 时，表达 Bmi1 的 ISC 能够维持近端小肠的上皮稳态。这些结果已得到其他几个小组的证实，表明表达 Lgr5 和 Bmi1 的 ISC 构成两个不同但可能部分重叠的群体。一个重要的问题是哪些信号通路调节这些不同的干细胞群，越来越多的证据表明 Wnt 和 Notch 信号传导引导表达 Lgr5 和 Bmi1 的干细胞自我更新。在此应用中，我们建议采用通路特异性阻断抗体来了解 Wnt 和 Notch 信号传导对 ISC 自我更新和谱系命运决定的差异和组合影响。这种独特的方法——结合抗体阻断和遗传命运图谱——开辟了传统的纯遗传方法之外的有趣的新途径。这些研究的结果将重要地揭示ISC自我更新和分化的机制，这将有助于了解这些ISC在体内平衡和疾病中的作用，并有助于为未来器官再生的尝试奠定基础。