Regulation of the Intestinal Stem Cells During Regeneration

肠道干细胞(ISCs)介导肠道损伤后的再生反应， 然而，调控这些基本细胞的机制仍然知之甚少。在 肠道维持需要成年的Wnt反应Wnt(+)Lgr5+ISCs，但这些细胞 对损伤(例如，辐射、炎症、禁食)非常敏感。相比之下，储备 休眠的(D)-ISCs群体，例如那些由mTert表达标记的群体，是高度抵抗的 并被激活以恢复Lgr5+ISCs和组织动态平衡。我们最近的数据 表示d-ISCs(与Lgr5+单元不同)保持在WNT无响应WNT(-)状态。 同样，胎儿ISCs在出生前是Wnt(-)，在围产期成熟为Wnt(+)ISCs 对未知因素的反应，从宫内生活过渡到宫外生活。加在一起，这些 观察表明，从WNT(-)状态到WNT(+)状态的转变是 Lgr5+ISCs在再生和发育过程中的生成。我们最近的分析，使用 RNA-seq比较Wnt(-)和Wnt(+)ISC群体，发现多个差异 表达的基因，强调不同的调控途径控制这两个ISC 人口。准确地说，WNT(-)状态是如何在d-ISC中维护的，以及它是如何影响其 再生反应在很大程度上是未知的。为了解决这个问题，我们提出了以下建议： 目的1.确定候选调控因子的作用和长期存活的d-ISCs的特性； 目的2.确定微生物组和/或其代谢物如何调节ISC生存；以及 目的3.探讨人(H)TERT+细胞在肠道动态平衡中的作用。 这些研究试图了解管理WNT(-)ISC的监管机制 维持和生存，并调节其向WNT(+)ISCs的转变。成功者 这些研究的完成可能会为患者带来有针对性的新的再生疗法 患有炎症性肠病、短肠综合征、环境性肠病和 因受到辐射和化疗而引起的肠道毒性。

Intestinal stem cells (ISCs) mediate the regenerative response that follows injury to the gut, though the mechanisms that regulate these essential cells remain poorly understood. In the adult, Wnt-responsive Wnt(+) Lgr5+ ISCs are required for intestinal maintenance, but these cells are exquisitely sensitive to injury (e.g., irradiation, inflammation, fasting). In contrast, a reserve population of dormant (d)-ISCs, such as those marked by mTert expression, are highly resistant to injury and become activated to restore Lgr5+ ISCs and tissue homeostasis. Our recent data indicate that d-ISCs (unlike Lgr5+ cells) are maintained in a Wnt-unresponsive Wnt(-) state. Similarly, fetal ISCs are Wnt(-) before birth and mature into Wnt(+) ISCs during the perinatal transition from intra- to extra-uterine life in response to unknown factors. Together, these observations suggest that the transition from a Wnt(-) to a Wnt(+) state is a crucial process for the generation of Lgr5+ ISCs during regeneration and development. Our recent analyses, using RNA-seq to compare Wnt(-) and Wnt(+) ISC populations, revealed multiple differentially expressed genes, underscoring that distinct regulatory pathways control these two ISC populations. Precisely how the Wnt(-) state is maintained in d-ISCs and how it impacts their regenerative response is largely unknown. To address this, we propose the following: Aim 1. Define the role of candidate regulatory factors and the identity of long-lived d-ISCs; Aim 2. Determine how the microbiome and/or its metabolites regulate ISC survival; and Aim 3. Investigate the role of human (h)Tert+ cells in intestinal homeostasis. These studies seek to understand the regulatory mechanisms that govern Wnt(-) ISC maintenance and survival and regulate their transition into Wnt(+) ISCs. The successful completion of these studies may lead to targeted new regenerative therapies for patients suffering from inflammatory bowel disease, short gut syndrome, environmental enteropathy and intestinal toxicity resulting from exposure to radiation and chemotherapy.