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

摘要 半月板对健康的膝关节功能起着至关重要的作用。然而，考虑到这一组织在负荷中的中心性 转移和苛刻的物理环境，伤害是常见的，成年人的愈合是有限的。这个 目前缺乏膝关节半月板损伤的再生解决方案，部分原因是我们的 了解半月板组织的细胞起源和发育过程中的调节。趁它好的时候 认识到半月板起源于一个专门的祖细胞群体，它首先定义了形成 滑膜关节(带间细胞)，这些细胞分化的调节和时间，它们的表型 异质性，这些细胞在定义的间隔内产生的矩阵的类型和时间，该矩阵如何 成熟并反馈以影响细胞的功能和命运，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 利用一系列新颖的小鼠模型和微尺度实验技术来研究其起源和 追踪组成成熟半月板的细胞的命运和功能。我们还将定义时间演变 结构和力学特征的发展矩阵，并质疑联合加载和蜂窝的作用 在这一发展范式中，对机械输入的反应。我们的中心假设是一个共同的池子 的半月板前体细胞产生于带间，这些细胞受到微环境的作用 由早期的矩阵组装和活动的机械信号(由关节加载产生)定义的提示，并且 这些输入共同作用，完善和指导半月板成熟，使其成年功能。

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.