Mechanical Regulation of Cell Fate and Multi-Scale Function in the Developing Meniscus

半月板发育中细胞命运和多尺度功能的机械调节

基本信息

批准号：
10359683
负责人：
EIKI KOYAMA
金额：
$ 51.85万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10359683
关键词：
Address Adult Back Cell Differentiation process Cell Extracts Cell Fate Control Cell physiology Cells Cues Custom Data Set Dense Connective Tissue Deterioration Development Devices Environment Evaluation Excision Extracellular Matrix Extracellular Matrix Proteins Feeds Fostering Functional Regeneration Heterogeneity In Situ In Situ Hybridization Injury Intervention Joints Knee Knowledge Label Lasers Mechanics Meniscus structure of joint Microfluidics Motion Mus Nature Patients Phenotype Physical environment Play Population Process Property Protein-Lysine 6-Oxidase Regulation Reporter Role Series Structure Structure-Activity Relationship Synovial joint System Techniques Testing Time Tissues cartilaginous crosslink healing insight joint loading mechanical force mechanical properties mechanical signal meniscus injury mouse model novel progenitor regenerative regenerative approach residence response sciatic nerve stem cells

项目摘要

Abstract The meniscus plays a vital role in healthy knee function. However, given the centrality of this tissue in load transfer and the demanding physical environment, injury is common and healing in adults is limited. The current lack of regenerative solutions for knee meniscus injury arises, in part, from the significant gap in our understanding of the cellular origins and regulation of meniscus tissue during development. While it is well appreciated that the meniscus arises from a specialized progenitor cell population that first defines the forming synovial joint (interzone cells), the regulation and timing of the differentiation of these cells, their phenotypic heterogeneity, the type and timing of matrix that these cells produce within defined intervals, how this matrix matures and feeds back to influence cell function and fate, and the role of active mechanical forces (that begin during the first stages of joint motion), remain poorly understood. To address these limitations, this proposal uses a series of novel mouse models and micro-scale experimental techniques to investigate the origin and track the fate and function of cells that comprise the mature meniscus. We will also define the time-evolving structural and mechanical features of the developing matrix, and query the role of joint loading and cellular response to mechanical inputs in this developmental paradigm. Our central hypothesis is that a common pool of meniscal progenitor cells arises from the interzone, that these cells are acted on by microenvironmental cues defined by early matrix assembly and active mechanical signals (that arise with joint loading), and that these inputs act together to refine and direct meniscus maturation, enabling its adult function.

抽象的半月板在健康的膝盖功能中起着至关重要的作用。但是，鉴于该组织在负载中的中心性转移和苛刻的身体环境，损伤是常见的，成人的治愈是有限的。这目前缺乏膝盖弯月板损伤的再生解决方案，部分原因是我们的显着差距了解发育过程中半月板组织的细胞起源和调节。虽然很好感谢弯月面是由专门的祖细胞种群引起的，该细胞首先定义形成滑膜关节（间区间细胞），这些细胞分化的调节和时间，其表型这些单元在定义的间隔内产生的异质性，矩阵的类型和时机，该矩阵如何成熟并反馈以影响细胞功能和命运，以及主动机械力的作用（开始在联合运动的第一阶段），仍然了解不足。为了解决这些限制，该提案使用一系列新型的小鼠模型和微尺度实验技术来研究起源和跟踪构成成熟弯月面的细胞的命运和功能。我们还将定义时间不断发展发育矩阵的结构和机械特征，并查询关节载荷和细胞的作用对此发育范式中机械输入的响应。我们的中心假设是一个共同的池半月板祖细胞的产生是由间区域产生的，这些细胞由微环境作用提示由早期矩阵组件和主动机械信号（通过关节载荷产生）定义，并且这些输入共同起作用，以完善和直接弯月面的成熟，从而实现其成人功能。