Regulation of the Intestinal Stem Cells During Regeneration

再生过程中肠干细胞的调节

• 批准号: 10197117
• 负责人: David T Breault
• 金额: $ 47.45万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10197117
• 关键词: AXIN2 gene; Address; Adult; Biological Models; Biopsy; Birth; Cell Cycle; Cell Maintenance; Cell Survival; Cell physiology; Cells; Chemotherapy and/or radiation; Data; Development; EGR2 gene; Exposure to; Fasting; Fractionation; Gene Expression Profile; Generations; Genes; Genetic Transcription; Germ-Free; Homeostasis; Human; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Injury; Intestines; LGR5 gene; Lead; Life; Maintenance; Mediating; Microbe; Modeling; Molecular; Mus; Natural regeneration; OLFM4 gene; Organism; Pathologic; Pathway interactions; Patients; Perinatal; Phenotype; Physiological; Population; Positioning Attribute; Process; Quantitative Reverse Transcriptase PCR; RNA analysis; Regenerative capacity; Regenerative response; Regulation; Regulatory Pathway; Resistance; Role; Short Bowel Syndrome; Stimulus; Stress; Testing; Tissues; Toxic effect; Transplantation; Uterus; WNT Signaling Pathway; base; crypt cell; cytokine; differential expression; experimental study; fetal; genetic signature; in vivo; inhibitor/antagonist; intestinal homeostasis; irradiation; knock-down; microbial; microbiome; mouse model; regenerative therapy; response; response to injury; severe injury; single-cell RNA sequencing; stem cell biomarkers; stem cell population; stem cell survival; stem cells; stressor; transcription factor; transcriptome; transcriptome sequencing; validation studies; virtual

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.

肠道干细胞（ISC）介导对肠道损伤的再生反应， 尽管调节这些基本细胞的机制仍然很少理解。在 成人，Wnt响应的Wnt（+）LGR5+ ISC是肠道维护所必需的，但是这些细胞 对损伤非常敏感（例如辐射，炎症，禁食）。相反，储备金 休眠（d）-ISC的种群，例如以MTER表达为标志的人群，具有高度抗性 损伤并激活以恢复LGR5+ ISC和组织稳态。我们最近的数据 表明D- ISC（与LGR5+细胞不同）保持在Wnt-无反抗的Wnt（ - ）状态中。 同样，胎儿在出生前是wnt（ - ），在围产期期间成熟到wnt（+）ISC 响应未知因素，从内部寿命转变为外部寿命。在一起，这些 观察表明，从Wnt（ - ）到Wnt（+）状态的过渡是关键的过程 在再生和开发过程中LGR5+ ISC的产生。我们最近的分析，使用 RNA-seq比较Wnt（ - ）和Wnt（+）ISC种群，揭示了多个差异性 表达的基因，强调了不同的调节途径控制这两个ISC 人群。正是如何将Wnt（ - ）状态保持在D-ISC中以及它如何影响其 再生反应在很大程度上未知。为了解决这个问题，我们建议以下内容： 目标1。定义候选监管因素的作用和长寿命D-ISC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；和 目标3。研究人（H）TERT+细胞在肠内稳态中的作用。 这些研究试图了解管理Wnt（ - ）ISC的监管机制 维护和生存，并调节其过渡到Wnt（+）ISC。成功 这些研究的完成可能会导致针对患者的新的再生疗法 患有炎症性肠病，肠道综合征短，环境肠病和 暴露于放射线和化学疗法的肠道毒性。