Basic Biology IV
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.
The goal of this proposal is to identify novel mechanisms by which human mesenchymal stem cells (MSCs) integrate physical and biochemical signals as they differentiate into cartilage cells, called chondrocytes. To address this problem, the applicant will investigate mechanisms by which physical cues alter MSC response to a specific cell signaling pathway. Experiments will focus on the possible involvement and role of cell surface receptors and chromatin remodeling. The applicant suggests that such studies may lead to a better understanding of how arthritis develops and may inform new therapeutic approaches to repair damaged or degenerating cartilage. Significance and Innovation - Cell replacement therapy is a promising approach for treating osteoarthritis, but it is unclear how the complex data and results of these studies would lead to novel therapeutic approaches. - The proposal addresses a pressing need for better methods to generate functional chondrocytes. - Despite an interesting focus on the intersection of cell signaling and mechanical forces, the proposal is of limited innovation due to much current research and the rapidly expanding body of literature on the importance of physical and mechanical signals in cartilage cell differentiation. - Reviewers considered it unlikely that the proposed study would have a major impact on the field. Feasibility and Experimental Design - Preliminary data are adequate but not compelling. In particular, there was little data supporting the role of epigenetic pathways and the experiments addressing aim 2. - The feasibility of Aim 1 is undermined by the complexity of proposed experiments, which require manipulation of a range of receptors and their isoforms. Results could be influenced or confounded by a number of variables relating to intracellular dynamics, expression levels, and the convergence of other pathways that affect receptors and their behavior. - Several known aspects of the biochemical signal to be investigated are not adequately factored into the experimental design, such as the timing, duration, and potential of the signal to act as a morphogen versus alternative mechanisms. - Reviewers praised the thorough, hypothesis-driven mechanistic approach. Principal Investigator (PI) and Research Team - The PI has strong expertise in mechanobiology, which is the focus area of this proposal. - The PI has assembled a strong multidisciplinary team that is capable of executing the proposed studies. Responsiveness to the RFA - The research proposed is responsive to the RFA.