Mapping the Trajectory of Cell Fate Transitions

描述(由申请人提供)：能够戏剧性再生的生物体维持具有灵活性或可塑性的成年细胞，以改变它们的命运。这一功能使构建替换部件，如器官或四肢，能够从损伤或疾病中恢复。该项目之前的工作和其他研究表明，特化细胞具有广泛的倾向，表现出干细胞的某些特性；它们会产生新的细胞类型，以应对伤害。细胞在从一种命运过渡到另一种命运的过程中所经历的动态变化，可能会揭示细胞用来改变自己命运的机制。这些洞察力将揭示细胞可塑性的基本特征，这些特征可能会改善人类细胞的再生治疗。然而，由于在分析体内再生细胞的全球状态方面的局限性，几乎没有 了解细胞如何从一种状态遍历到另一种状态。该实验计划建议提供细胞在再生过程中过渡到新命运的全面视图。这项研究使用了植物，因为模型系统提供了一个难得的机会来模拟细胞的可塑性。此外，调节可塑性的机制在植物和动物中都很保守，植物熟练的再生能力将说明细胞改变其身份的全部潜力。该提案利用了一个强大的模型系统，该系统允许对再生组织进行连续成像，并分析单细胞在穿越命运时的转录内容。该系统包括每个细胞命运的活性基因清单，允许进行定量分析，以跟踪细胞再生时的复杂身份。因此，完整的分析将生成一个再生细胞轨迹的模型，以解决关于再生的基本问题：参与再生的高度可塑性细胞的起源是什么？再生细胞是否表现出类似干细胞的增殖行为？命运的转变是否需要失去所有的身份，达到“地面”状态或更年轻的发展阶段(去分化)？或者，细胞会直接穿越到新的命运吗？结果将指向可以有针对性地提高再生效率的过程。描绘细胞的完整转录动力学并将其投射到再生组织的图像上的创新广泛适用于许多发育模型系统。因此，总的来说，拟议的工作对再生领域具有广泛的影响。 公共卫生相关性：治疗性再生的一个重要目标是提高现有细胞取代受损细胞的能力。尽管植物和动物不同，但它们拥有共同的机制，控制细胞转换身份的能力。该项目的目标是在高度再生的植物中使用一个强大的系统来了解细胞如何改变其身份，目的是为再生医学的新方法提供见解。

DESCRIPTION (provided by applicant): Organisms capable of dramatic regeneration maintain adult cells that have the flexibility, or plasticity, to change their fate. This feature enables thm build replacement parts, like organs or limbs, to recover from damage or disease. Previous work on the project and other studies have revealed a broad propensity for specialized cells to display some properties of stem cells; they give rise to new cell types in response to injury. The dynamic changes that cells undergo during the transition from one fate to another could reveal the mechanisms that cells employ to enable them to switch their fates. Such insights will reveal basic features of cellular plasticity that could improve regeneration therapy in human cells. However, due to limitations in analyzing the global status of regenerating cells in vivo, little is known about how cells make the traversal from one state to another. The experimental plan proposes to provide a comprehensive view of cells as they transition to new fates during regeneration. The study utilizes plants because the model system provides a rare opportunity to model cellular plasticity. In addition, the mechanisms that regulate plasticity are well conserved across plants and animals and the plant's adept ability to regenerate will illustrate the full potential of cells to change their identity. The proposal takes advantage of a powerful model system that permits continual imaging of regenerating tissue and the analysis of the transcriptional contents of single cells as they traverse fates. This system includes an inventory of active genes for each cell fate, permitting quantitative analyses to track the complex identity of cells as they regenerate. Thus, the complete analysis will generate a model of the trajectory of regenerating cells in order to address basic questions about regeneration: What is the origin of the highly plastic cells that participate in regeneration? Do regenerating cells show proliferative behavior that resembles stem cells? Do fate transitions require losing all identity and reaching a "ground" state or younger developmental stage (dedifferentiation)? Or, do cells traverse directly to new fates? The results will point to processes that can be targeted to make regeneration more efficient. The innovation of profiling the complete transcriptional dynamics of cells and projecting them onto images of regenerating tissue is widely applicable to many developmental model systems. Thus, overall, the proposed work has broad impact on the field of regeneration. PUBLIC HEALTH RELEVANCE: One important goal in therapeutic regeneration is to enhance the ability of existing cells to replace damaged cells. Despite their differences, plants and animals share mechanisms that control a cell's ability to switch identities. The goal of the projec is to use a powerful system in the highly regenerative plant to understand how a cell can change its identity with the aim to provide insights for new approaches in regenerative medicine.