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：
10589080
负责人：
EIKI KOYAMA
金额：
$ 52.37万
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 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10589080
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 Protein-Lysine 6-Oxidase Regulation Reporter Role Series Specific qualifier value Structure Synovial joint System Techniques Testing Time Tissues cartilaginous crosslink healing insight joint loading mechanical force mechanical properties mechanical signal meniscus injury mouse model novel postnatal 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关节功能中起着至关重要的作用。然而，考虑到该组织在负载中的中心地位由于转移和苛刻的物理环境，成人受伤很常见，愈合也很有限。这目前缺乏针对膝关节半月板损伤的再生解决方案，部分原因是我们的技术存在巨大差距。了解半月板组织在发育过程中的细胞起源和调节。虽然还好认识到半月板起源于一种专门的祖细胞群，该祖细胞群首先定义了形成滑膜关节（区间细胞），这些细胞分化的调节和时间，它们的表型异质性，这些细胞在规定的时间间隔内产生的基质的类型和时间，该基质如何成熟并反馈影响细胞功能和命运，以及主动机械力的作用（开始在关节运动的第一阶段），仍然知之甚少。为了解决这些限制，本提案使用一系列新颖的小鼠模型和微型实验技术来研究起源和追踪构成成熟半月板的细胞的命运和功能。我们还将定义随时间演化的开发矩阵的结构和力学特征，并查询联合载荷和细胞的作用在这种发展范式中对机械输入的反应。我们的中心假设是一个公共池半月板祖细胞产生于带间区，这些细胞受到微环境的作用由早期矩阵组装和主动机械信号（随着关节负载而产生）定义的线索，并且这些输入共同作用，以完善和指导半月板的成熟，从而实现其成年功能。