Studying the cellular ecology of organ formation using a novel tissue reconstitution system

使用新型组织重建系统研究器官形成的细胞生态学

• 批准号: 10686610
• 负责人: Amy Elizabeth Shyer
• 金额: $ 152.55万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10686610
• 关键词: Behavior; Behavioral; Behavioral Assay; Bioenergetics; Biomechanics; Biophysics; Calcium; Cells; Communication; Coupling; Ecology; Electricity; Engineering; Extracellular Matrix; Fibroblasts; Functional Regeneration; Gene Expression Profile; Generations; Individual; Knowledge; Link; Mechanics; Mesenchymal; Mesenchyme; Metabolic Pathway; Mission; Modernization; Molecular; Morphogenesis; Morphology; Motion; Organ; Pathway interactions; Pattern; Periodicals; Process; Signal Transduction; Skin; Structure; System; Tissues; Villus; Work; bioelectricity; design; drug development; manufacture; mechanical behavior; molecular scale; novel; progenitor; reconstitution; self organization; spine bone structure; stem cells; tool

Abstract: Our organs function via repetitive morphological structures like follicles, vertebra, and villi that rival the orderliness achieved by modern manufacturing. In recent decades, the generation of these periodic structures has been primarily ascribed to pre-existing gene expression patterns. In the developing skin, however, recent studies suggest that the concept of a molecular blueprint be shed in order to consider mechanisms where cells self-organize through physical interactions. Self-organization mechanisms are especially uncharted in the collectives of fibroblasts that make up mesenchymal tissues. In our latest work, we find that the self- organization of fibroblasts embedded in extracellular matrix (ECM) is sufficient to robustly generate the ordered structures of the skin: a grid of pre-follicle aggregates. These results highlight the pattern-generating power of the mesenchyme, where the formation of cell-ECM supra-structures may prove to be a broadly-used tool to efficiently and robustly initiate ordered tissue structures. A central gap that remains is dissecting how the biophysical features of individual cells impact the dynamics of cell-cell coordination to enable the structuring of organs. In our proposed studies of such cellular ecology, we aim to understand how cells convert energy injected at the molecular scale to couple motion, organize force, and communicate during tissue morphogenesis. This inquiry is made possible by a novel collective cell behavioral platform that successfully captures the self-organizing process that skin progenitors undergo as they coalesce into an ordered and structurally linked tissue. We will investigate how biophysical features impact self-organization and the cell-cell linkages that emerge as a result. Based on our recent findings, we propose to investigate bioelectrical signaling to determine whether calcium oscillatory behavior can serve as a means to make mechanical coupling of cells more robust. We will also probe the energetic flows occurring across the cell collective as they self-organize in order to discover which metabolic pathways serve to guide the energy flows required for cells to express their mechanical behavior. Understanding how physical entities such as mechanics, electricity, and energy are co-regulated during mesenchymal tissue self-organization formation will offer new pathways for tissue design and reconstitution as well as present new avenues for drug development.

摘要： 我们的器官通过重复的形态结构，如卵泡，椎骨和绒毛， 现代制造业所实现的有序。近几十年来，这些周期性结构的产生 主要归因于预先存在的基因表达模式。然而，在发育中的皮肤中， 研究表明，分子蓝图的概念应该被抛弃，以考虑细胞 通过物理互动进行自我组织。自组织机制尤其是未知的， 成纤维细胞的集合体构成间质组织。在我们最新的研究中，我们发现自我- 包埋在细胞外基质（ECM）中的成纤维细胞的组织足以稳健地产生有序的细胞外基质。 皮肤的结构：前毛囊聚集的网格。这些结果突出了 间充质，其中细胞-ECM超结构的形成可能被证明是广泛使用的工具， 有效且稳健地引发有序的组织结构。仍然存在的一个中心缺口是剖析 单个细胞的生物物理特征影响细胞-细胞协调的动力学，以使细胞的结构化成为可能。 机关在我们对这种细胞生态学的研究中，我们的目标是了解细胞如何转换能量 在分子尺度上注射，以耦合运动，组织力量，并在组织过程中进行通信。 形态发生这种研究是通过一种新型的集体细胞行为平台实现的， 捕捉自组织过程，皮肤祖细胞经历，因为他们合并成一个有序的， 结构相连的组织我们将研究生物物理特征如何影响自组织和细胞-细胞 由此产生的联系。基于我们最近的发现，我们建议研究生物电 信号传导以确定钙振荡行为是否可以作为使机械 细胞的耦合更加稳健。我们还将探测发生在整个细胞集体的能量流，因为它们 自我组织，以发现哪些代谢途径有助于引导细胞所需的能量流 来表达它们的机械行为。理解物理实体，如机械，电力， 能量在间充质组织自组织形成过程中共同调节，将为 组织设计和重建以及药物开发的新途径。