Stem cells are the primitive cells that give rise to the different tissue types in the body. In a way, stem cells are the universal cells from which all cells are derived. Their unlimited proliferation and differentiation potential raises the prospect that stem cells could be used as therapeutical tools offering hope for millions who suffer from debilitating diseases and conditions for which there are limited or no treatments including: neurological disease, cardiovascular disease, autoimmune diseases, diabetes, and osteoporosis. Furthermore, stem cells may serve as diagnostic tools, cancer perhaps being one of the most promising areas. But before these potential applications become a reality, we need to have a better understanding of the mechanisms by which human embryonic stem cells renew themselves indefinitely. Our knowledge of the cellular and molecular mechanisms that control self-renewal and pluripotency of human embryonic stem (hES) cells is rather scarce, and most of the information comes from comparisons with their murine counterparts.
Based on published evidence by our group and others and our preliminary results, we hypothesize that the self-renewal of hES cells depends on the establishment of distinct cell populations (compartments). We propose that such cell compartments are specified by a crosstalk between the Notch and Wnt signaling pathways and maintained, at least in part, by regulating the relative activities of p53 and p63 and describe three Specific Aims towards this goal.
The successful completion of the scientific program proposed in this application would be of the highest significance both for our understanding of basic stem cell biology and for the implementation of strategies of regenerative medicine. While our understanding of the network of transcription factors associated with ES cell self-renewal has increased significantly in the recent years, very little is known about the cellular bases of ES cell self-renewal. Our preliminary results indicate that the Notch and Wnt signaling pathways play essential roles for hES cell self-renewal. Here we propose to analyze the specific cell behaviors and compartmentalization dynamics within colonies of undifferentiated hES cells controlled by Notch and Wnt signaling in the context of hES cell self-renewal, and which are the downstream mediators of those effects. Uncovering the specific cell behaviors controlled by extrinsic factors in the context of hES cells will enable us to understand, modulate, and perhaps induce the self-renewal of pluripotent cells.The implications might be far reaching for the implementation of strategies in the fields of diagnosis and treatment of human degenerative diseases.
Statement of Benefit to California:
The long term goal of this research grant proposal is to understand the mechanisms by which human embryonic stem cells renew themselves indefinitely. . Uncovering the molecular factors implicated in self renewal and pluripotency will enable us to understand, modulate, and perhaps induce the self-renewal of pluripotent cells.The implications might be far reaching for the implementation of strategies in the fields of diagnosis and treatment of human degenerative diseases. Neurological and cardiovascular disorders, autoimmune diseases, diabetes, cancer and osteoporosis strike no less than 10 million Californians each year, causing an incalculable personal toll and an annual economic cost of billions of dollars in medical expenses and lost productivity. Thus, one benefit that will be derived from this area of research is the generation of specific tools and methods for reducing medical costs and increasing the quality of life and level of productivity of afflicted Californians. A second key benefit derived from this research grant proposal is the training of new scientists to serve as educators and researchers for the future, many in the burgeoning area of stem cell biology for which the State of California has emerged as a world's leader. Finally, the discoveries derived from innovative and multidisciplinary research on hES cells described in this proposal, are likely to lead to important new areas of intellectual property that are essential for creating high quality jobs in the biotechnology and pharmaceutical industries in California.