Human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) have two unique properties that make them invaluable resources for regenerative medicine: they are able to renew themselves indefinitely and to develop into every type of cell in the body. These cells therefore have tremendous potential for the development of patient-specific cell therapies for a variety of diseases. To capitalize on this potential, we must develop methods to ensure that hESCs and hiPSCs can maintain their undifferentiated state when expanded in culture. This requires a deep understanding of gene regulation in stem cells and is the area of focus for this proposal. For a typical gene, DNA is the blueprint, RNA is the messenger, and protein is the final product. Although most studies of gene regulation in stem cells have focused on DNA and proteins, it is now clear that RNA is much more than the ‘middle-man’. We plan to determine whether a particular type of chemical change in RNA, termed methylation, is essential for maintaining hESC/hiPSCs in their undifferentiated state. We will examine how RNA methylation occurs and how it regulates genes that control stem cell differentiation. This is a novel, unexplored area of stem cell biology, and the results of the proposed work could lead to the development of methods to sustain hESC/hiPSCs in culture as an unlimited source for cell therapy.
Our highly innovative and exploratory research will benefit the state of California in several ways. First, human pluripotent stem cells have tremendous potential for the development of patient-specific cell therapies for a variety of diseases, thereby contributing to the health of all Californians. Second, by investigating a novel and fundamental gene regulatory mechanism involving RNA modification in human pluripotent stem cells, the proposed study will further our understanding of pluripotency and cell commitment and advance stem cell biology into a previously unexplored area, thereby maintaining California at the forefront of biomedical research, both nationally and internationally. Third, the proposed work will have direct and tangible benefits to Californian scientific and business communities. The results could provide a foundation for the design of new diagnostics and treatments in regenerative medicine, which will create jobs for Californians with a range of skill levels. In addition, most of the proposed work will be performed at local scientific core facilities using reagents and equipment from local vendors. Finally, local students and postdoctoral fellows who will be trained with the support of CIRM will be the driving force for biomedical research in California in the future.