Pluripotent stem cells can by definition give rise to all cells of an organism and also self-renew. These properties have long been evident in embryonic stem cells isolated from early stage embryos of many species, and then maintained in culture with the aid of exogenous factors that promote proliferation in the absence of differentiation. Advances in isolating and propagating human embryonic stem cell lines have spurred enthusiasm for applying these cells to studies of disease mechanisms, to screening of more effective drugs, and to development of new therapies for disease or and injury. However, progress has been hindered by continuing ethical debates over the theoretical fates of such embryos. Therefore, there is high interest in alternative technology to reprogram differentiated somatic cells to a pluripotent-like state that has the potential to ultimately circumvent dependence on embryos. This has already been demonstrated to varying degrees of efficacy, but each of the current strategies has significant limitations. The objective of this proposal is to establish robust, efficient and high-throughput processes for reprogramming donor somatic cells into pluripotent stem-like cells. An important component of this effort will be to extend these processes through cell derivation and maintenance in a way that could expedite the banking of pluripotent cell lines that may have future clinical utility. Our approaches are both pragmatic and novel. Thus, we will focus on optimizing, comparing and then extending the capabilities of several established reprogramming strategies. Our goals are to (1) test the hypothesis that providing a qualitatively and quantitatively more potent reprogramming stimulus can improve reprogramming efficiency; (2) test the hypothesis that optimizing the source of primary human somatic cells can improve reprogramming efficiency; (3) test the hypothesis that the efficiency of derivation and recovery of pluripotent cell lines can be improved by providing a more permissive and supportive environment for cells during the nuclear remodeling and reprogramming process; ( 4) lay the initial foundation for establishing a large homozygous pluripotent stem cell bank that can meet most potential clinical needs by incorporating the optimized methods into a cGMP-compliant process at the earliest opportunity.
Statement of Benefit to California:
Severe injuries and degenerative diseases are leading contributors to healthcare-related costs that affect all Californians. The potential to derive new types of therapeutics from pluripotent stem cells could revolutionize healthcare by providing more effective and perhaps curative treatments. California is a major hub for research and development on stem cells. In recent years, thought-leaders in this field from around the country have relocated to California universities and biotech companies. Major investments in early-stage companies by venture capital firms and pharmaceutical companies have been announced to rapidly exploit and develop discoveries made by academic researchers. If CIRM-funded research continues to spur progress, this area of biotechnology has the potential to grow substantially. This will help to fulfill CIRM’s goals of increasing the availability of new stem cell-based therapies and diagnostics to citizens, create new jobs and keep the state at the forefront of the biotech industry.