Regulation of chondrocyte fate and function by ECM Viscoelasticity

摘要 骨关节炎（OA）是一种主要疾病，在美国，每6名60岁以上的成年人中就有1人患有这种疾病， 通过影响运动和功能来提高生活质量。组织健康和疾病通常由一个 复杂的和非线性的相互作用的细胞内在和系统因素，包括生物化学和生物物理 线索该项目的总体目标是了解ECM（细胞外基质）的变化 粘弹性影响健康中以及在OA的疾病起始和发病过程中的软骨稳态。 我们团队最近的研究已经优雅地证明了ECM粘弹性在细胞生长中控制细胞体积。 软骨细胞即软骨细胞。以前的软骨生物学研究只检查了ECM的影响， 弹性（即"刚度"），粘弹性的作用大多被忽略。我们发现粘弹剂 表现出快速应力松弛或更粘稠的水凝胶可以提供 更有利于人软骨细胞中的合成代谢基因表达，导致ECM产生增加， 促进健康的软骨细胞表型。据观察，根本原因是 软骨细胞在快速松弛凝胶中扩大其体积，这种能力在缓慢松弛凝胶中受到限制。 更有弹性的凝胶。了解健康和人类诱导的最佳ECM粘弹性 多能干细胞来源的软骨细胞可指导理想的软骨组织工程支架制备。 因此，该提案的目的是优化水凝胶的粘弹性以用于工程炎症- 抑制软骨结构。我们将首先在快速松弛中优化软骨结构的开发， 水凝胶在动态机械负载的存在下。其次，这些结构将在人体中进行测试， 和软骨缺损的大鼠模型。第三，我们的目标是了解分子途径， 这是软骨健康和疾病中机械传导和炎症之间关系的基础。 这些研究的实验结果有可能提高软骨的治疗策略 再生和OA仍然未满足临床需求。

Abstract Osteoarthritis (OA) is a major disease affecting 1 in 6 adults above 60 years of age in US that significantly impairs quality-of-life by impacting movement and function. Tissue health and disease is frequently governed by a complex and non-linear interplay of cell-intrinsic and systemic factors including both biochemical and biophysical cues. The overall aim of this project is to understand how the changes in ECM (extra cellular matrix) viscoelasticity affect cartilage homeostasis in health and during disease initiation and pathogenesis in OA. Recent studies by our team have elegantly demonstrated that ECM viscoelasticity governs cell volume in cartilage cells i.e. chondrocytes. Previous studies of cartilage biology had only examined the impact of ECM elasticity (i.e. “stiffness”), and the role of viscoelasticity had been mostly ignored. We found that viscoelastic hydrogels that exhibit fast stress relaxation, or were more viscous, could provide a microenvironment that is more conducive to anabolic gene expression in human chondrocytes resulting in increased ECM production, promoting a healthy chondrocyte phenotype. The underlying cause was observed to be the ability of chondrocytes to expand their volume in the fast relaxing gels, an ability that was restricted in the slow relaxing gels, which are more elastic. Understanding the optimal ECM viscoelasticity for healthy and human induced pluripotent stem cell derived chondrocytes can guide ideal scaffold preparation for cartilage tissue engineering. The aim of this proposal is therefore to optimize hydrogel viscoelasticity for engineering inflammation- suppressive cartilage constructs. We will firstly optimize development of cartilage constructs in fast relaxing hydrogels in the presence of dynamic mechanical loading. Secondly, these constructs will be tested in human and rat models of cartilage defects. Thirdly, we aim to gain an understanding of the molecular pathways underlying the relationship between mechano-transduction and inflammation in cartilage health and disease. The experimental outcomes from these studies have the potential to enhance therapeutic strategies for cartilage regeneration and OA that remain unmet clinical needs.