Regulation of the Intestinal Stem Cells During Regeneration

肠干细胞（ISCs）介导肠道损伤后的再生反应， 尽管调控这些必需细胞的机制仍然知之甚少。在 成年Wnt反应性Wnt（+）Lgr 5 + ISCs是肠道维持所必需的，但这些细胞 对损伤非常敏感（例如，照射、炎症、禁食）。相反，储备 休眠的（d）-ISC群体，例如由mTert表达标记的那些，具有高度抗性 损伤并被激活以恢复Lgr 5 + ISCs和组织稳态。我们最近的数据 表明d-ISC（与Lgr 5+细胞不同）维持在Wnt无响应Wnt（-）状态。 类似地，胎儿ISCs在出生前是Wnt（-），并且在围产期成熟为Wnt（+）ISCs。 从子宫内过渡到子宫外生活，以应对未知因素。所有这些 观察表明，从Wnt（-）到Wnt（+）状态的转变是一个关键过程， 再生和发育过程中Lgr 5 + ISCs的产生。我们最近的分析，使用 RNA-seq比较Wnt（-）和Wnt（+）ISC群体，揭示了多重差异。 表达的基因，强调不同的调控途径控制这两个ISC 人口。Wnt（-）状态在d-ISC中是如何维持的，以及它如何影响它们的 再生反应在很大程度上未知。为解决这一问题，我们提出以下建议： 目标1。确定候选调节因子的作用和长寿命d-ISCs的身份; 目标2.确定微生物组和/或其代谢物如何调节ISC存活;以及 目标3。研究人类（h）Tert+细胞在肠道内稳态中的作用。 这些研究试图了解Wnt（-）ISC的调控机制 维持和存活并调节它们向Wnt（+）ISCs的过渡。成功 这些研究的完成可能会为患者带来有针对性的新再生疗法 患有炎症性肠病、短肠综合征、环境性肠病和 由于暴露于辐射和化学疗法而导致的肠毒性。

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.