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.

抽象的： 我们的器官通过重复的形态结构（例如卵泡，椎骨和绒毛）的功能，与之抗衡 现代制造实现的秩序。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。但是，在发育中的皮肤中，最近 研究表明，分子蓝图的概念是为了考虑细胞的机制 通过身体互动进行自我组织。自组织机制在 构成间充质组织的成纤维细胞集体。在我们的最新作品中，我们发现自我 嵌入细胞外基质（ECM）中的成纤维细胞的组织足以稳健地产生有序 皮肤的结构：润滑前聚集体的网格。这些结果突出了图案生成的力量 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，稳健地启动有序的组织结构。剩下的中心差距正在剖析 单个细胞的生物物理特征会影响细胞 - 细胞配位的动力学，以实现结构化 器官。在我们提出的对这种细胞生态学的研究中，我们旨在了解细胞如何转化能量 以分子量表注入夫妇运动，组织力并在组织中进行交流 形态发生。这个新型的集体牢房行为平台使此询问成为可能 捕获皮肤祖细胞在订购中进行的自组织过程，并 结构连接的组织。我们将研究生物物理特征如何影响自组织和细胞细胞 结果出现的链接。根据我们最近的发现，我们建议研究生物电气 信号传导以确定钙振荡行为是否可以用作使机械的手段 细胞的耦合更健壮。我们还将探测整个细胞集合中发生的能量流 自组织以发现哪种代谢途径用于指导细胞所需的能量流 表达其机械行为。了解力学，电力等物理实体如何 在间充质组织自组织形成期间共同调节能量将为 组织设计和重构以及为药物开发的新途径。