Regulation of chondrocyte fate and function by ECM Viscoelasticity

ECM 粘弹性对软骨细胞命运和功能的调节

• 批准号: 10751895
• 负责人: Nidhi Bhutani
• 金额: $ 61.77万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751895
• 关键词: Acceleration; Adult; Affect; Age Years; Alginates; Biochemical; Bioinformatics; Biology; Biomedical Engineering; Biophysics; Bypass; Calcium; Calcium Channel; Calcium Signaling; Cartilage; Cartilage injury; Cell Volumes; Cells; Chondrocytes; Clinical; Clinical Engineering; Complex; Cues; Data; Defect; Degenerative polyarthritis; Development; Disease; Elasticity; Engineering; Exhibits; Exposure to; Extracellular Matrix; FDA approved; Femur; Gel; Gene Expression; Generations; Genetic; Health; Histologic; Homeostasis; Human; Hydrogels; Immunodeficient Mouse; Impairment; Inflammation; Inflammatory; International; Ion Channel; Joints; Laboratories; Lead; Medical; Methods; Modeling; Molecular; Movement; Nature; Nude Rats; Operative Surgical Procedures; Outcome Study; Pathogenesis; Pathway interactions; Phenotype; Preparation; Production; Publishing; Quality of life; Rattus; Regulation; Relaxation; Research; Role; Signal Pathway; Societies; Stress; Stretching; System; Testing; Therapeutic; Tissue Engineering; Tissues; Transplantation; Viscosity; articular cartilage; biophysical properties; cartilage cell; cartilage development; cartilage regeneration; cartilage repair; clinically relevant; cytokine; differential expression; drug development; efficacy testing; in vitro testing; in vivo; in vivo evaluation; induced pluripotent stem cell; insight; knock-down; mechanical load; mechanical properties; mechanotransduction; new therapeutic target; pharmacologic; receptor; repaired; response; scaffold; subcutaneous; tissue repair; transcription factor; transcriptome sequencing; viscoelasticity; voltage

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.

抽象的 骨关节炎（OA）是一种主要疾病 通过影响运动和功能的生活质量。组织健康和疾病经常受 细胞内和系统因素的复杂和非线性相互作用，包括生化和生物物理 提示。该项目的总体目的是了解ECM的变化如何（额外的蜂窝矩阵） 粘弹性影响软骨稳态在健康中以及OA中的疾病开始和发病机理中。 我们团队的最新研究优雅地证明了ECM粘弹性控制了细胞体积 软骨细胞，即软骨细胞。对软骨生物学的先前研究仅检查了ECM的影响 弹性（即“刚度”）和粘弹性的作用被忽略了。我们发现粘弹性 暴露了快速应力放松或更粘性的水凝胶可以提供一个微环境 在人软骨细胞中对合成代谢基因表达的传导更大，导致ECM产生增加， 促进健康的软骨细胞表型。观察到根本原因是 软骨细胞在快速放松凝胶中扩大体积，这种能力受到缓慢放松的限制 凝胶，更弹性。了解健康和人类诱导的最佳ECM粘弹性 多能干细胞得出的软骨细胞可以指导软骨组织工程的理想支架制备。 因此，该提案的目的是优化用于工程炎症的水凝胶粘弹性 - 抑制软骨结构。我们将首先在快速放松中优化软骨结构的开发 水凝胶在动态机械载荷的情况下。其次，这些结构将在人类中进行测试 和软骨缺陷的大鼠模型。第三，我们旨在了解分子途径 软骨健康和疾病中的机械转移与感染之间的关系。 这些研究的实验结果有可能增强软骨的治疗策略 仍然无法满足的临床需求的再生和OA。