Somatic cell age and memory in the generation of iPS cells

Pluripotent stem cells can give rise to any cell type of the body and hold enormous promise for regenerative medicine. Pluripotent stem cells, such as embryonic stem (ES) cells, are derived from very young human embryos. It is of great interest to derive pluripotent stem cells from adult cells. In this way, one could potentially model in vitro genetic diseases that afflict patients. In addition, cells derived from patient-specific stem cells would not be rejected upon transplantation back into the patient. A methodology for generating induced pluripotent stem (iPS) cells from adult cells has recently been reported. It involves the forced activation of specific genes in the adult cells. This method is very recent: it was first reported in 2006 and only six groups, including our lab, have to date published work describing it. The published literature documents how remarkably similar to ES cells iPS cells are. However, they are not identical, and a major difference is that ES cells are derived from young embryonic cells, whereas iPS cells are derived from older differentiated cells. Furthermore, the method remains very inefficient, has been used with a limited number of adult cell types and needs to be improved in important ways. It will be essential to address the question of how the age or type of the original cell affects the resulting iPS cells. We propose to generate new iPS cells in order to test two hypotheses: 1) that younger cells may generate better quality iPS cells than older cells. If this hypothesis is true, it will be important to understand what are the critical factors that distinguish young versus old cells in their ability to generate iPS cells. From a practical point of view, it may be important to generate iPS cells at a young age and store them for future use, or to manipulate adult cells in additional ways to assure the quality and safety of the resulting iPS cells. 2) that a “memory” of the original cell may persist in iPS cells. If this hypothesis is true, it will be important to understand how that memory is maintained, and to investigate how it may affect the quality and/or safety of iPS cells. In practice, this may mean that certain cell types may be a better starting point for the generation of iPS cells. Our lab has developed improved methods for generation of iPS cells. We are using cells of different types and ages to generate iPS cells, and will be able to compare them. Our laboratory also has extensive experience with studies of the basic biology of pluripotent stem cells, and we will make use of that expertise in the proposed work. The proposed research is expected to provide the community of stem cell researchers with new pluripotent stem cells from diverse cell types, and to make important contributions towards the development of safe clinical applications of iPS cells.