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

基本信息

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
项目类别：
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

项目摘要

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发挥功能，如毛囊、椎骨和绒毛，这些结构与现代制造业实现的有序性。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，最近研究表明，为了考虑细胞的机制，分子蓝图的概念应该被抛弃。通过物理相互作用进行自组织。自组织机制在以下领域尤其未知构成间充质组织的成纤维细胞的集合。在我们最新的工作中，我们发现自我嵌入细胞外基质（ECM）的成纤维细胞的组织足以稳健地产生有序的皮肤结构：毛囊前聚集体的网格。这些结果凸显了模式生成能力间充质，细胞 ECM 超结构的形成可能被证明是一种广泛使用的工具有效且稳健地启动有序组织结构。仍然存在的一个核心差距是剖析如何单个细胞的生物物理特征影响细胞间协调的动态，从而能够构建器官。在我们提出的这种细胞生态学研究中，我们的目标是了解细胞如何转换能量以分子尺度注射以耦合运动、组织力并在组织过程中进行交流形态发生。这项调查是通过一种新颖的集体细胞行为平台实现的，该平台成功地捕捉皮肤祖细胞在合并成有序且有序的过程中所经历的自组织过程结构上相连的组织。我们将研究生物物理特征如何影响自组织和细胞间的相互作用由此产生的联系。根据我们最近的发现，我们建议研究生物电确定钙振荡行为是否可以作为产生机械效应的一种手段细胞耦合更加稳健。我们还将探究细胞集体中发生的能量流，因为它们自组织以发现哪些代谢途径可以引导细胞所需的能量流来表达它们的机械行为。了解机械、电力等物理实体如何间充质组织自组织形成过程中能量的共同调节将为组织设计和重建以及药物开发的新途径。