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，以改变其命运。这种特性使他们能够制造替代部件，如器官或四肢，以从损伤或疾病中恢复过来。该项目的先前工作和其他研究已经揭示了特化细胞显示干细胞某些特性的广泛倾向；它们产生新的细胞类型作为对损伤的反应。细胞在从一种命运转变到另一种命运的过程中所经历的动态变化可以揭示细胞用来改变它们命运的机制。这些见解将揭示细胞可塑性的基本特征，从而改善人类细胞的再生治疗。然而，由于对体内再生细胞的全球状况分析的限制，很少有研究

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.