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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

基本信息

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
项目类别：
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

项目摘要

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.

摘要