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Mechanisms driving stem cell responses to injury in planarians

涡虫干细胞对损伤反应的驱动机制

基本信息

批准号：
10810170
负责人：
Carolyn Elizabeth Adler
金额：
$ 1.02万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10810170
关键词：
Apoptosis Automobile Driving Behavior Biochemistry Cell Cycle Cell Cycle Arrest Cell Differentiation process Cells Chemicals Cues DNA Repair Foundations Future Goals Homeostasis Injury Methods Mitogen-Activated Protein Kinases Molecular Monitor Myocardial Infarction Natural regeneration Organ Pathway interactions Pharmacology Pharyngeal structure Physiological Planarians Platyhelminths Pluripotent Stem Cells Proliferating RNA Interference Radiation Regenerative Medicine Regenerative capacity Role Signal Pathway Signal Transduction Stroke Surgical Injuries Technology Testing Tissues Up-Regulation cell behavior design embryonic stem cell flexibility forkhead protein gene conservation improved lens model organism organ regeneration receptor regenerative approach response response to injury single cell sequencing stem cell differentiation stem cell population stem cell proliferation stem cells tissue regeneration

项目摘要

Abstract Successful regeneration of tissues requires transient increases in stem cell plasticity, proliferation, and differentiation, in order to produce new cells that integrate with preexisting tissues and organs. Pathways governing these critical behaviors have been identified, but how injury signals can trigger stem cell proliferation and differentiation of cells necessary for regeneration remains poorly understood. In most model organisms, regenerative capacity is limited and stem cells are scarce, which has made it difficult to pinpoint the mechanisms regulating stem cell proliferation and differentiation after injury. By contrast, the planarian flatworm Schmidtea mediterranea has abundant stem cells that are activated by injury and fuel continuous regeneration. Like embryonic stem cells, planarian stem cells have the capacity to differentiate into any type of tissue. These pluripotent stem cells can be readily identified, monitored, purified, and thoroughly profiled at the molecular level. We recently made two important discoveries that form the foundation of this proposal. First, injury of any type appears to protect stem cells from lethal radiation, because it halts the cell cycle and fewer stem cells undergo apoptosis. Second, we pioneered a chemical method to selectively remove a single organ, the pharynx. Pharynx regeneration requires the upregulation of the conserved Forkhead transcription factor FoxA in a discrete subset of stem cells immediately after this targeted injury. We find that the mitogen- activated protein kinase (MAPK) pathway is a central driver of these behaviors. MAPK promotes stem cell differentiation in cultured stem cells, but its roles in physiologically-relevant contexts are poorly understood. Together, these findings establish our central hypothesis, which is that injury synchronizes the cell cycle, enabling local cues to channel stem cell differentiation toward discrete cell fates. In Aim 1, we will determine how injury induces cell cycle arrest in stem cells after radiation. We will examine DNA repair and test the function of conserved genes that are upregulated after injury. In Aim 2, we will dissect the mechanisms driving organ-specific regeneration by purification and single-cell sequencing of stem cells proliferating after organ loss, and then testing their function in organ regeneration. In Aim 3, we will identify the upstream receptors that activate MAP kinase signaling in stem cells with combinations of RNAi, pharmacology and biochemistry. This proposal exploits our ability to challenge stem cells with precise insults, providing a lens into the mechanisms that enable flexible stem cell responses during injury and homeostasis. Understanding the molecular mechanisms that govern stem cell behavior in a physiologically-relevant context will inform the design of future strategies for regenerative medicine technologies.

摘要组织的成功再生需要干细胞可塑性、增殖性和分化，以产生与先前存在的组织和器官整合的新细胞。路径控制这些关键行为的机制已经确定，但损伤信号如何触发干细胞增殖而再生所需的细胞分化仍然知之甚少。在大多数模式生物中，再生能力有限，干细胞稀缺，这使得很难准确定位损伤后干细胞增殖和分化的调控机制。与之形成对比的是，爬行动物稻纵卷叶蝉有丰富的干细胞，可被损伤和燃料连续激活再生。像胚胎干细胞一样，脊椎动物干细胞也有能力分化成任何类型的组织。这些多能干细胞可以很容易地识别、监测、纯化和彻底剖析分子水平。我们最近有了两项重要发现，它们构成了这一提议的基础。第一, 任何类型的损伤似乎都能保护干细胞免受致命辐射的伤害，因为它阻止了细胞周期，而且减少了干细胞会发生凋亡。其次，我们开创了一种化学方法，选择性地移除单个器官，咽部。咽再生需要保守的Forkhead转录因子上调在这种靶向损伤后立即在干细胞的离散子集中注射FOXA。我们发现有丝分裂原- 激活的蛋白激酶(MAPK)通路是这些行为的中心驱动因素。MAPK促进干细胞在培养的干细胞中的分化，但它在生理相关环境中的作用还知之甚少。总而言之，这些发现确立了我们的中心假设，即损伤使细胞周期同步，使局部信号能够引导干细胞分化走向离散的细胞命运。在目标1中，我们将确定辐射后损伤如何诱导干细胞细胞周期停滞。我们将检查DNA修复并检测损伤后上调的保守基因的功能。在目标2中，我们将剖析驱动机制器官后增殖干细胞的纯化和单细胞测序的器官特异性再生然后测试它们在器官再生中的功能。在目标3中，我们将识别上游受体通过RNAi、药理学和生物化学的组合激活干细胞中的MAP激酶信号。这提案利用我们通过精确的侮辱来挑战干细胞的能力，为了解这些机制提供了一个镜头使干细胞在受伤和动态平衡期间做出灵活的反应。理解分子在生理相关背景下管理干细胞行为的机制将为未来的设计提供信息再生医学技术的战略。