Using High-Dimensional Omics Data to Identify Therapeutic Strategies for Promoting Tissue Repair and Regeneration

Project Overview

Osteoarthritis is a painful and debilitating joint disease that affects more than 300 million people worldwide. Joint trauma is a major contributing factor for osteoarthritis, and in humans, about 50% of joint injuries will progress to post-traumatic osteoarthritis (PTOA). Military service members and firefighters are disproportionately at risk of developing PTOA as they are more likely to have risk factors including traumatic joint injuries and repetitive movement. Current PTOA treatment options are limited, focusing on surgical procedures to restore the joint anatomy and reduce pain. Therefore, research advancing the current state of diagnostics, prevention, and treatment of injury-induced joint degeneration would greatly improve the health of millions of PTOA patients.

In this study, we characterized the cellular and molecular changes occurring in the joint following injury at a single-cell resolution. This detailed transcriptional profiling of cells from uninjured and injured joints at multiple timepoints allowed us to identify discriminative molecular markers for various connective tissue-forming and immune cell subtypes in a healthy joint for the first time and determine injury-induced molecular changes in these cells that could contribute to PTOA. This study also identified multiple immune subtypes with a potential joint-protective function. Additionally, we developed a pipeline for gene expression-based drug repurposing to identify FDA-approved drugs with the potential to prevent/slow down joint degeneration after injury. Findings from this study expand our knowledge of joint biology and open new avenues for developing improved diagnostic and preventive strategies for mitigating the long-term damaging effects of joint trauma.

Mission Impact

Our research supported and leveraged Lawrence Livermore National Laboratory's (LLNL's) core competencies in bioscience and bioengineering to advance human health. We also leveraged LLNL's capabilities in high-performance computing, simulation and data science to advance the Director's initiative in predictive biology: enabling a new, precision approach to data- and simulation-driven threat characterization, diagnosis, and intervention development. This study significantly improved our fundamental understanding of cellular responses to joint injury and revealed several new promising therapeutic targets and biomarkers for PTOA.

Publications, Presentations, and Patents

Sebastian, A., et al. 2021. "Single-Cell RNA-Seq Reveals Transcriptomic Heterogeneity and Post-Traumatic Osteoarthritis-Associated Early Molecular Changes in Mouse Articular Chondrocytes," Cells. doi: 10.3390/cells10061462. LLNL-JRNL-820854.

Sebastian, A., et al 2021. "Defining articular chondrocyte heterogeneity and injury-induced molecular responses at single cell level." ORS Annual Meeting 2021. LLNL-ABS-814776.

McCool, J., et al. 2021. "Single Cell RNA Sequencing Highlights Unique Subpopulations of Cells in the Knee Joints of MRL/MpJ Superhealers."ORS Annual Meeting 2021. LLNL-PRES-818478.

McCool, J., et al. 2021. "Isolation of Murine Articular Chondrocytes for Single Cell RNA or Bulk RNA Sequencing Analysis," Methods in Molecular Biology (in press). LLNL-BOOK-824156.

Wilson, S., et al. 2021. "Gene Expression-Based Drug Repurposing for Post-Traumatic Osteoarthritis." ORS Annual Meeting 2021. LLNL-POST-818304.

McCool, J., et al. 2021. "Identification of Chondrocyte Sub-populations Using Single-Cell RNA Sequencing to Determine Injury Induced Cellular and Molecular Changes of C57Bl6 and MRL/MpJ Arthritic Knee Joints."ASBMR Annual Meeting 2021. LLNL-POST-826854.

Wilson, S., et al. 2021. "Predictive Analytics for Repurposing Drugs in Search of Novel Post-Traumatic Osteoarthritis Treatment Options." ASBMR Annual Meeting 2021. LLNL-ABS-827056.

Sebastian, A., et al. 2020. Global Gene Expression Analysis Identifies Age-Related Differences in Knee Joint Transcriptome during the Development of Post-Traumatic Osteoarthritis in Mice. Int J Mol Sci. doi: 10.3390/ijms21010364. LLNL-JRNL-797902.