Investigating the mechanisms of oocyte-based and factor-based reprogramming
The use of induced Pluripotent Stem Cells (iPSCs) genetically identical to patients has great promise for treating many diseases. However, iPSCs generated by current techniques, even iPSC-derivatives genetically identical to the recipient, express proteins that cause them to be rejected, presenting a major problem for their use for regenerative medical applications. Prior research demonstrated eggs (called oocytes) have the potential to change (reprogram) skin cells in a way that may eliminate this problem. However, use of human oocytes is limited by practical, ethical and legal considerations. Identification of the factors in human oocytes that provide this optimized reprogramming will improve the efficacy of human iPSC-based patient-specific cellular therapies. By identifying, cloning and using these factors to generate fully reprogrammed iPSCs, we will eliminate the requirement for donor human oocytes and permit reprogramming that will eliminate the immune rejection problem. The ultimate objective for this proposal is to develop a method that will fully reprogram human skin cells to an Embryonic Stem Cell (ESC)-like state that will not express proteins that cause iPSCs and their derivatives to be rejected by the patient’s immune system. If successful, the ability to transplant patient-specific reprogrammed skin cells, without immune rejection problems, will significantly advance the use of iPSCs for a wide variety of regenerative medical applications.
Diseases (such as Parkinson’s, diabetes and heart disease), injuries (such as spinal cord injury) and age-related tissue degeneration afflict many people both inside and outside the State of California, resulting in physical, emotional and financial burdens on individuals and on society as a whole. The generation of induced Pluripotent Stem Cells (iPSCs) that are genetically identical to patients has significant promise for future patient-specific cellular therapies for these diseases, injuries and aliments. Effective iPSC therapies have the potential to cure or alleviate the symptoms for literally millions of individuals in the future. However, a major unsolved problem for the use of iPSCs for patient-specific cellular therapies is the expression of immunogenicity genes by the iPSCs differentiated derivatives, leading to their immune rejection, even when using genetically identical cells. This immunogenicity problem fundamentally limits the use of iPSC-based therapies. This proposed research seeks to address this immunogenicity problem by identifying the key factors in human eggs (oocytes) that enable the generation of iPSCs that are not rejected following autologous transplantation. Finally, solving the immunogenicity issue would also provide a significant boost to the stem cell biotechnology industry in the State of California, providing jobs and an additional source of revenue through potential patents and licensing agreements.