Stem cell and regeneration regulatory mechanisms in planarians

涡虫的干细胞和再生调节机制

• 批准号: 10406655
• 负责人: PETER REDDIEN
• 金额: $ 48.75万
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-21 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10406655
• 关键词: Address; Adult; Animals; Architecture; Atlases; Body part; Case Study; Cell Differentiation process; Cells; Cues; Dreams; Evolution; Future; Growth; Head; Heart; Injury; Investigation; Maintenance; Malignant Neoplasms; Molecular; Names; Natural regeneration; Organism; Pattern; Planarians; Platyhelminths; Process; Production; Public Health; Regenerative Medicine; Research; Specific qualifier value; Specificity; Stochastic Processes; System; Tissues; Work; adult stem cell; base; blastema; blind; cell regeneration; cell type; pluripotency; progenitor; regeneration model; regenerative; repaired; response; restoration; self organization; stem cell fate; stem cell self renewal; stem cells; therapeutic development; tissue regeneration; tissue repair; transcriptome; transcriptomics; wound; wound healing

Project Summary The capacity to regulate stem and progenitor cells for regeneration is widespread in the animal kingdom and has attracted investigation for centuries. Evolution has selected for mechanisms involved in wound repair and tissue regrowth that are the dreams of regenerative medicine. Uncovering the principles of regeneration in case study organisms should identify processes that naturally promote or limit regeneration, enabling future development of therapeutic approaches to tissue damage repair. Planarians are flatworms capable of regenerating any missing body part, including new heads. Their regenerative powers have combined with ease of experimentation to make them a classic regeneration model. Planarian regeneration involves adult stem cells called neoblasts, which we previously showed can display pluripotency at the single cell level (cNeoblasts). A major direction of our research addresses how fate specification occurs in regeneration. Extensive work indicates that fate choices are made within the neoblasts (called specialized neoblasts), with the regeneration outgrowth at the wound (a blastema) being a composite of different fate-specified cells. This highlights the step of fate-choice in neoblast stem cells as central for understanding the mechanistic basis for planarian regeneration. We seek to understand "specificity" in regeneration, in which diverse injuries appear to result in responses tailored to the identity of missing tissue. We aim to distinguish between the possible existence of surveillance systems indicating the presence or absence of differentiated cell types and what we named target-blind regeneration. In target-blind regeneration, progenitor production occurs at a low basal rate sufficient for repair from small wounds, without needing tissue surveillance; we hypothesize tissue-specific progenitor production is primarily regulated by wound-induced proliferation combined with positional information. We aim to understand how positional information regulates stem cell fate choice during tissue turnover, and dynamically during regeneration. Our prior work on a planarian whole-animal cell-type transcriptome atlas indicates the existence of over 100 adult cell types. We seek to understand what processes within neoblast stem cells regulate how they make any one of so many possible choices. We will study the pattern of fate choices using spatial transcriptomics and seek to distinguish between a highly regulated fate- specification process, such as by extrinsic local tissue cues, and a more stochastic process internal to the stem cells. Finally, we will investigate how adult progenitors generated from stem cells bring about the restoration of tissue architecture in regeneration. Our prior work indicates that migratory targeting by extrinsic cues combines with self-organization of progenitors with their target tissue to generate and maintain tissue pattern in regeneration. We will study the molecular bases for these processes, which will be critical to elucidate for understanding the basis for tissue repair and regeneration.

项目摘要 调节干细胞和祖细胞再生的能力在动物界广泛存在， 几个世纪以来一直吸引着调查。进化选择了参与伤口修复的机制， 组织再生是再生医学的梦想。揭示再生的原则， 案例研究生物应确定自然促进或限制再生的过程， 开发组织损伤修复的治疗方法。Planarians是扁形虫， 再生任何缺失的身体部位包括新的头部它们的再生能力与 让它们成为经典的再生模式。涡虫再生涉及成体茎 一种叫做新成细胞的细胞，我们之前已经证明它可以在单细胞水平上显示出多能性 （cNeoblast）。我们研究的一个主要方向是解决再生过程中命运的具体化。 大量的研究表明，命运的选择是在neoblasts（称为专门的neoblasts）内做出的， 伤口处的再生产物（芽基）是不同命运特异性细胞的复合物。这 强调了在新生干细胞中命运选择的步骤，作为理解 真涡虫再生我们试图理解再生的“特异性”，其中不同的损伤似乎 导致针对缺失组织的身份定制的响应。我们的目标是区分可能的 监测系统的存在表明分化细胞类型的存在或不存在， 名为目标盲再生在靶盲再生中，祖细胞产生以低基础速率发生 足以修复小伤口，无需组织监测;我们假设组织特异性 祖细胞的产生主要受创伤诱导的增殖和位置的调节， 信息.我们的目标是了解位置信息如何调节组织中干细胞的命运选择， 在再生过程中的动态变化。我们之前对一种整动物细胞类型的研究 转录组图谱表明存在超过100种成体细胞类型。我们试图了解 在新生儿干细胞中，它们调节着如何做出如此多的选择。我们会研究 使用空间转录组学的命运选择模式，并试图区分高度调控的命运- 规范过程，如通过外部的局部组织线索，和一个更随机的过程内部的茎 细胞最后，我们将研究从干细胞产生的成体祖细胞是如何恢复造血功能的。 再生中的组织结构我们先前的工作表明，迁移目标的外部线索结合 随着祖细胞与其靶组织的自组织， 再生我们将研究这些过程的分子基础，这对于阐明 了解组织修复和再生的基础。