Characterization of Telomerase Expressing Intestinal Stem Cells

描述（由申请人提供）：长期以来，人们认为，自我更新的组织如骨髓是由缓慢循环的（大部分是静止的）干细胞维持的，干细胞在活化后产生快速循环的祖细胞。最近，已经确定还存在休眠干细胞的亚群（很少循环），其似乎主要作为组织损伤后的有效干细胞发挥作用。相比之下，在正常情况下，休眠的干细胞被认为对组织稳态的贡献很小。相反，持续自我更新的肠上皮似乎在基础条件下由至少两个独立的干细胞群维持，这两个干细胞群要么快速循环，要么缓慢循环。使用两个品系的报告小鼠，我们现在表明，端粒酶表达细胞代表了一种罕见的休眠干细胞群体，对肠道损伤具有高度抵抗力。因此，端粒酶并不代表ISC的通用标志物，而是标记具有有效再生能力的ISC亚群。有趣的是，我们的初步数据表明，表达端粒酶的ISCs引起快速循环的Lgr5+细胞，这表明肠隐窝内的谱系层次结构以及损伤后干细胞可能被替换的潜在机制。该提案旨在进一步确定表达mTert的细胞在肠内稳态和响应损伤中的作用，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提供对ISCs所利用的关键调控途径的深入理解，并可能为患有胃肠道疾病（如炎症性肠病，短肠综合征和肠癌）的患者带来新的治疗策略。

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.