Characterization of Telomerase Expressing Intestinal Stem Cells

表达端粒酶的肠干细胞的表征

• 批准号: 8338043
• 负责人: David T Breault
• 金额: $ 0.21万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8338043
• 关键词: Activities of Daily Living; Acute; Biological Markers; Biology; Bone Marrow; Cell Aging; Cell Maintenance; Cell surface; Cells; Data; Disease; Frequencies; Gene Expression; Genetic; Genetic Markers; Germ Cells; Goals; Hematopoietic stem cells; Homeostasis; Inflammatory Bowel Diseases; Injury; Intestinal Cancer; Intestinal Diseases; Intestines; Ionizing radiation; Lead; Molecular; Mus; Natural regeneration; PTEN gene; Patients; Play; Population; Radiation; Regenerative Medicine; Regulatory Pathway; Reporter; Research Design; Resistance; Role; Short Bowel Syndrome; Signal Transduction; Small Intestines; Stem cells; Syndrome; Telomerase; Tissues; Transgenic Mice; Transgenic Organisms; Work; Wound Healing; base; chemotherapy; gastrointestinal; genetic manipulation; innovation; intestinal crypt; intestinal epithelium; male; novel therapeutics; prevent; public health relevance; regenerative; response; response to injury; self-renewal; stem cell niche; stem cell population; tissue regeneration; treatment strategy; Activities of Daily Living; Acute; Biological Markers; Biology; Bone Marrow; Cell Aging; Cell Maintenance; Cell surface; Cells; Data; Disease; Frequencies; Gene Expression; Genetic; Genetic Markers; Germ Cells; Goals; Hematopoietic stem cells; Homeostasis; Inflammatory Bowel Diseases; Injury; Intestinal Cancer; Intestinal Diseases; Intestines; Ionizing radiation; Lead; Molecular; Mus; Natural regeneration; PTEN gene; Patients; Play; Population; Radiation; Regenerative Medicine; Regulatory Pathway; Reporter; Research Design; Resistance; Role; Short Bowel Syndrome; Signal Transduction; Small Intestines; Stem cells; Syndrome; Telomerase; Tissues; Transgenic Mice; Transgenic Organisms; Work; Wound Healing; base; chemotherapy; gastrointestinal; genetic manipulation; innovation; intestinal crypt; intestinal epithelium; male; novel therapeutics; prevent; public health relevance; regenerative; response; response to injury; self-renewal; stem cell niche; stem cell population; tissue regeneration; treatment strategy

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：长期以来一直认为，通过缓慢循环（主要静止）干细胞来维持诸如骨髓等自我更新组织，而激活后会引起快速循环祖细胞。最近，已经确定，还存在休眠干细胞的亚群（很少循环），这似乎主要是组织损伤后有效的干细胞。在正常条件下，相比之下，休眠的干细胞被认为仅对组织稳态最小贡献。相比之下，在基础条件下，至少两个单独的干细胞种群在迅速循环或缓慢循环的基础条件下，连续的自我更新肠上皮似乎至少由两个独立的干细胞种群维持。使用两种报告菌株的小鼠，我们现在表明表达端粒酶的细胞代表了罕见的休眠干细胞群，对肠道损伤具有高度抗性。因此，端粒酶不代表ISC的通用标记，而是标志着具有有效再生能力的ISC的亚群。有趣的是，我们的初步数据表明，表达端粒酶的ISC会导致迅速的循环LGR5+细胞表明肠道隐窝内的谱系层次结构以及受伤后可以替换干细胞的潜在机制。该提案旨在进一步定义表达MTERT细胞在肠内稳态中的作用，并响应损伤以及检查静止和自我更新的分子基础。这些目标的成功完成将深入了解ISC使用的关键调节途径，并有可能为胃肠道疾病（例如炎症性肠病，短肠综合征和肠癌）患者提供新的治疗策略。 公共卫生相关性：缓慢循环组织干细胞对再生医学和组织修复具有很大的希望，尽管由于缺乏确定的生物标志物，包括肠道在内的许多组织中仍然难以捉摸。我们使用转基因小鼠采用了一种创新策略，该策略允许鉴定，分离和遗传操纵肠道干细胞。这项工作可能会引起针对小肠综合征，炎症性肠病和肠癌等肠道疾病的新型治疗策略。