Dissecting Pathways of p53-Mediated Inhibition of Cellular Reprogramming
The possibility of generating patient-specific pluripotent stem cells has tremendous utility for treating patients with a wide variety of diseases. Recently, it has become possible to derive cells from patients and to subject them to a process known as cellular reprogramming to form induced pluripotent (iPS) cells specific to that patient. This technology, however, currently has some limitations. First, the reprogramming process is not very efficient. Second, the process required to reprogram cells entails introduction of genes that can promote cancer. Therefore, it is a critical goal to define the mechanisms that control the ability of cells to undergo reprogramming, to provide alternate strategies to generate iPS cells more efficiently and more safely. One approach recently demonstrated to enhance the efficiency of reprogramming is through inactivation of a gene known as p53 in the cells to be reprogrammed. Inactivation of p53 also allows iPS cells to be generated without the introduction of cancer-causing genes. Despite increasing efficiency of iPS cell formation, p53 inactivation also has some limitations, as it can cause chromosomal instability in the cell, contributing to cancer development itself. P53 affects a vast network of proteins in the cell, and therefore, if select components of that network could be targeted instead of p53 itself, it might provide a means to increase the efficiency of reprogramming without causing genetic instability and promoting cancer. Here, we propose to identify mediators of p53 function in limiting reprogramming to determine if it is possible to uncouple this function from its ability to maintain chromosomal stability. In this way, we could devise strategies to achieve an enhancement of reprogramming efficiency without the deleterious consequences of compromising chromosomal stability and promoting cancer. Inactivation of such key p53 reprogramming mediators may also allow generation of iPS cells without introducing cancer-causing genes, as does p53-deficiency. Thus, these experiments may lead to both improved efficiency and safety of reprogramming.
The use of stem cells to regenerate and restore tissues is an important strategy for treating a variety of diseases. However, a limitation of this strategy is the possibility of immune rejection of foreign cells by an individual’s body. Therefore, generation of stem cells specific to a given patient, which will not be rejected by that individual’s body, holds great promise for the treatment of a variety of human diseases. Recent technology called cellular reprogramming allows the conversion of cells derived from an individual into stem cells that can be used for therapeutic purposes. This technology still needs further development, in the sense that it is inefficient and not adequately safe. In this grant we explore the ways in which this process is controlled, with the aim of enhancing the efficiency and safety of this process, to facilitate its therapeutic applications. This technology should benefit Californians of a variety of ages, with a broad spectrum of diseases ranging from neurodegeneration to diabetes.