Regulation of chondrocyte fate and function by ECM Viscoelasticity

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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.