Stem cell and regeneration regulatory mechanisms in planarians

项目摘要 调节干细胞和祖细胞再生的能力在动物界和 已经吸引了几个世纪的调查。进化选择了参与伤口修复和 组织再生是再生医学的梦想。揭示再生的原理 案例研究生物体应该确定自然促进或限制再生的过程，从而使未来 组织损伤修复治疗方法的发展。浮游生物是扁虫，能够 再生任何缺失的身体部位，包括新的头部。他们的再生能力与轻松结合在一起 让它们成为经典的再生模型。脊椎动物的再生涉及成体茎 被称为新生细胞的细胞，我们之前展示了它可以在单细胞水平上表现出多能性 (CNeoblast)。我们研究的一个主要方向是命运决定在再生中是如何发生的。 广泛的研究表明，命运的选择是在新母细胞(称为专门的新母细胞)中做出的，具有 伤口处的再生(胚泡)是由不同的命运决定的细胞组成的复合体。这 重点介绍了在新生干细胞中选择命运的步骤，以此为中心了解 脊椎动物的再生。我们试图理解再生中的“特异性”，在这种情况下，不同的损伤似乎 导致针对缺失组织的身份量身定做的反应。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，以及我们 命名为目标盲目的再生。在目标盲目的再生中，祖细胞的产生以较低的基础速率发生 足以修复小伤口，不需要组织监测；我们假设组织特定 祖细胞的产生主要由创伤诱导的增殖和位置联合调节 信息。我们的目标是了解位置信息如何在组织中调节干细胞的命运选择。 周转率，并在再生期间动态。我们之前在一种全动物细胞类型上的工作 转录组图谱表明存在100多种成体细胞类型。我们试图了解是什么过程 在新生细胞内，干细胞调节着它们如何做出众多可能的选择中的任何一种。我们会研究 利用空间转录学的命运选择模式，并试图区分高度调控的命运- 特定过程，例如通过外部局部组织线索，以及茎内部更随机的过程 细胞。最后，我们将研究由干细胞产生的成体祖细胞如何带来 再生中的组织结构。我们先前的工作表明，外部线索的迁徙靶向结合了 通过祖细胞与其靶组织的自组织来产生和维持组织模式 再生。我们将研究这些过程的分子基础，这对阐明 了解组织修复和再生的基础。

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.