Programmed cells for targeted articular regenerative medicine

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PROJECT SUMMARY Osteoarthritis (OA) affects over 32 million Americans and is a leading cause of years lost to disability worldwide. OA is characterized by the breakdown of the collagen II-rich matrix of articular cartilage, as well as inflammation of joint tissues such as the synovium. No disease-modifying drugs exist to treat arthritis, leaving surgery as the eventual result for patients with progressive OA. While existing surgical options offer some clinical benefit, outcomes decline over time due to the inability of these approaches to induce robust, sustained regeneration of joint tissues. Cell engineering strategies have been developed to overcome the limitations of surgical treatments. These strategies deploy cells or gene delivery vehicles to supply anabolic and/or anti-inflammatory factors to the joint; however, these rely on unregulated or only generically controlled expression of transgenes that may negatively impact health when expressed for long durations or outside of pathologic target tissues. Here, we propose to leverage synthetic biology tools to confine expression of transgenes to sites characterized by joint degeneration. Our approach builds on our use of a customized cell sense and response platform in regenerative engineering. This artificial cell signaling system enables us to program cells to react to selected features of a microenvironment by implementing defined transcriptional programs. Our prior studies have illustrated that exposed collagen II serves as a diagnostic hallmark of OA. This proposal capitalizes on our recent demonstration that the synthetic receptor platform selectively licenses cells to detect type II collagen and then upregulate expression of chosen transgenes. The overall goal of our work is to establish synthetic receptor-controlled cells as agents to orchestrate cartilage repair and combat the inflammation associated with joint trauma or chronic joint inflammation. This project will characterize the ability of our receptors to drive stem cells to mediate cartilage repair in an in vitro model of arthropathy (Aim 1) and will assess the ability of transplanted synNotch-programmed cells to detect and respond to cartilage degeneration in an in vivo model of post-traumatic OA (Aim 2).