Stem cells sense and respond to a multitude of cues in their surroundings to make intricate cellular decisions. Relative to well-studied biochemical cues, we are just learning how cells interpret physical cues. We know even less about the way that cells calibrate their response to biochemical cues based on their physical surroundings. We will investigate fundamental mechanisms by which stem cells integrate biochemical and physical cues. The importance of such mechanisms is particularly clear in cartilage – from development to disease. For example, 20 million Americans are diagnosed with osteoarthritis, a debilitating joint disease that is triggered by traumatic injury or genetic predisposition. Though abundant evidence suggests that these pathways converge to exacerbate arthritic cartilage degeneration, the mechanisms are unclear. Understanding these mechanisms may provide insight that will lead to the development of therapies to prevent or reverse cartilage degeneration, or to improve the success of stem cell-based therapies for cartilage repair. Therefore, our long-term goal is to understand mechanisms by which stem cells and chondrocytes integrate physical and biochemical cues, how these mechanisms are disrupted in arthritis, and how they can be harnessed to repair damaged cartilage. By focusing on pathways important to many tissues and diseases, this research will help to resolve fundamental and clinically relevant questions in stem cell biology and in arthritis.
Statement of Benefit to California:
Approximately 6 million Californians have some form of arthritis, a disabling and painful joint disease in which cartilage deteriorates. This disease costs California nearly $32 billion each year. Consequently, development of improved arthritis therapies to repair cartilage could benefit the health of up to 27% of the California population and prevent $8 billion in lost wages. At a fundamental level, this project investigates cues that direct human mesenchymal stem cells to make cartilage. While this stem cell source is appealing for cartilage repair, several obstacles have limited its clinical application. We have identified a novel combination of biochemical and physical cues that overcomes a number of these obstacles. By investigating the mechanisms by which these cues promote cartilage cell differentiation, this research may identify more therapeutically feasible ways to direct mesenchymal stem cells to repair articular cartilage damaged by arthritis. In addition, identification of these mechanisms will elucidate the way cells interact with their physical surroundings, insight that has implications for the development, disease and regeneration of many tissue types. For example, physical cues that promote a specific cell fate decision can be engineered into biomaterials used to deliver stem cells to any target tissue. These advances could ultimately improve the health of California citizens, while creating opportunities for California biotechnology companies.