Aging and Renewal of iPS Cells During Reprogramming, Propagation and Differentiation
The recent discovery of human embryonic stem (ES) cells offers great promise to medicine by allowing for the first time, the potential to produce of any of the cell types of the human body. In the future, this could lead to a host of new therapies in the treatment of diseases of the blood, vascular, heart, nervous, endocrine, muscle, skeletal, and other systems of the human body. However, transplant rejection has long been considered to be one of the great obstacles in successfully implementing these new therapies in the emerging field of regenerative medicine. The recent discovery that cells from the body, such as skin cells, can be returned to an ES-like state simply by the expression of 4 genes (induced pluripotent stem (iPS) cell technology) has revolutionized the field of regenerative medicine by showing a path to make patient-specific cells with the potential of ES cells to differentiate into all the cell types of the body.
While iPS technology can restore an ES-like functionality to a patient’s own cell, our preliminary results show that this technology may not reliably restore a youthful proliferative lifespan to the cells. This apparent defect relates to the length of the linear ends of the DNA strands, a region of the DNA called the “telomere”. Telomere length determines how many times body cells can divide, and our initial results indicate that iPS technology may lead to cells that are prematurely old (short telomeres). This problem would be predicted to severely limit the ability of companies to scale up product from iPS cells and could similarly limit the therapeutic usefulness and potentially even the safety of such cells in humans.
We propose a detailed study of telomere lengths during iPS and the testing of alterations in the procedure targeted toward correcting this problem. We describe a program of research aimed at measuring telomeres in a variety of iPS conditions using a novel system where the initial cells are genetically identical to ES cells, allowing for a careful measurement of telomere lengths during the iPS process. We then propose to modify specific conditions in the iPS process based on the understanding of the mechanisms that regulate telomere length. The final goal of the proposed research is to design and implement improvements in the iPS process that allows telomeres to lengthen back to an embryonic length. The successful restoration of youthful telomere length in iPS protocols would enable iPS-derived cells to have sufficient replicative lifespan to withstand expansion and purification during commercial manufacture, as well as provide robust cells of many kinds with potentially enormous benefits to patients in need of cell-based therapies, in particular an aging population facing age-related degenerative disease.
New technologies in regenerative medicine offer the opportunity to develop novel therapies for a broad spectrum of life-threatening conditions. Additionally, these new technologies may offer solutions for chronic degenerative diseases, thereby potentially saving the people of the State of California enormous expenditures annually. The realization of this opportunity is dependent on technological advances, such as the development of technologies to deal with obstacles in the clinical utility of such technologies, such as transplant rejection. A recently-developed technology called “induced pluripotent stem (iPS) cell technology offers a relatively simple solution to transplant rejection by allowing scientists to transform an easily-accessible cell type, such as skin cells, back to cells similar to embryonic stem (ES) cells that have the ability to become any of the cell types of the human body. The use of iPS technology circumvents the transplant rejection issue and offers the exciting prospect of making patient-specific cells of many different types for a myriad of human therapeutic applications.
We propose a program of research that aims to solve one critical problem of iPS technology relating to the resetting of cell lifespan to aged cells. We show data to indicate that existing technologies have limitations that could restrict the commercial scalability of product from iPS cells and negatively impact patient safety. Safety is critical to the development of any new drug candidate and is even more essential when considering cellular therapies where cells can persist in the body for years. Thus, the primary benefit of our proposed project of generating well-characterized cell lines with a normal cell lifespan is to provide more effective and safer cell therapies. By providing California researchers a means to improve iPS technology in the manner described, we will help overcome the cell lifespan bottleneck that is currently blocking the successful translation of iPS stem cell research to clinical applications. A key beneficial outcome of our project will be to shorten the time it takes to get stem cell therapies from the research laboratory and into the hands of physicians to treat patients suffering from degenerative diseases and injuries. By accelerating the translation of research to drug approval, more Californians that are currently in need of treatment will have the opportunity to benefit from stem cell therapies and Californians will see a more rapid return on their investment in the form of reduced health care costs.