Recent advances in studies of human embryonic stem cells have indicated the value of using these cells to aid regeneration of skeletal tissues. Mesenchymal stem cells that repair the skeleton suffer age-related impairments. For example, aging reduces the number, and proliferative capacity of mesenchymal stem cells which impairs fracture healing. Hence, delivering cells that have the ability to stimulate and participate in skeletal repair would greatly benefit the elderly population of orthopaedic patients. In addition, arthritis resulting from traumatic injury or aging occurs as a result of destruction of the lining of the articular surface of joints. Currently, treatment options include replacement with an artificial joint, because the cartilage lining the joints lacks an adequate intrinsic population of stem cells for regeneration. While this therapy is effective, the artificial joint is temporary and lasts 10-15 years. A better approach for treating arthritis would be to develop a living replacement joint but this relies on finding the correct cells for bioengineering the new joint. Human embryonic stem cells (hESCs) can be expanded indefinitely in vitro while maintaining their undifferentiated, pluripotent state, and these cells could potentially enhance fracture repair and provide the necessary cells for engineering a living replacement joint. However, using these cells to treat recalcitrant fractures and arthritis requires the ability to control and direct differentiation along appropriate pathways. This ability would provide a virtually limitless supply of donor tissue that has the potential for in vivo transplantation and treatment of musculoskeletal diseases. Our objective is to utilize aspects of embryonic development that are important for formation of cartilage. The majority of the skeleton is derived from an embryonic tissue named mesoderm. Hence, in the First Specific Aim of this study, we will compare mesoderm formation among a variety of different hESC lines. In the Second Specific Aim we will isolate mesenchyme from embryoid bodies and assess the extent to which a regulator of chondrocyte differentiation during development and regeneration of the skeleton. Our results will provide the basis for future studies that are aimed at maximizing and refining chondrocyte differentiation during fracture repair and joint regeneration.
Using human embryonic stem cells for therapeutic purposes requires a thorough understanding of the mechanisms that regulate differentiation of these cells. In our protocol we are proposing to examine mechanisms that underlie differentiation of human embryonic stem cells into cartilage-producing cells. Our results will form the basis for future studies that are designed to generate living artificial joints and therapeutic interventions that will aid orthopaedic patients. Ultimately, these results will benefit people by improving the quality of life of patients with degenerative or traumatic injuries to the skeleton. Developing these therapies will take considerable time, effort, and resources, and providing the means for beginning this research will further stimulate the field of tissue engineering. Due to the close proximity of our research and the biotechnology companies in California, we are in a unique position to produce potential therapies more rapidly than others. As stem cell therapies begin to reach clinical settings the need for production and testing of these approaches will provide economic stimulation an job growth within the biotechnology industry. Lastly, the impact of the success of this research will be felt personally. Skeletal injury and deterioration are painful and debilitating, and in the elderly can be life threatening. Therefore, improving the ability to heal the skeleton will likely affect every resident in California at some point during their life.