Many human neurological disorders, as diverse as inherited leukodystrophies, periventricular leucomalacia, cerebral palsy, and multiple sclerosis, are characterized by the selective loss of oligodendrocytes, the myelin-forming cells in the central nervous system. In affected patients, an appropriate way to restore function may be to provide them with the relevant replacement cells, the oligodendrocytes. Scientists have already been working on methods to generate replacement oligodendrocytes from human embryonic stem cells (hESCs) or to generate accurate in vitro models of these human neurological diseases using hESCs. A recent breakthrough in stem cell research is the success of generating induced pluripotent stem cells (iPS cells) by in vitro reprogramming of human somatic cells back to a pluripotent state using defined factors. We will build upon this amazing technology to generate new iPS cells directly from adult cells from patients with myelin disorders either by using defined genetic transcription factors or by using small-molecule drugs/defined soluble factors, and test the utilities of these new cells in experimental models in the lab. We will compare the behaviors of the oligodendrocytes derived from these iP cells versus hESCs. Oligodendrocytes are the cell type that is diseased in patients with myelin disorders, so it would be ideal to derive iP cells directly from human oligodendrocytes (“dedifferentiation”) and then to “redifferentiate” them into better in vitro models to study oligodendroglial diseases. Such a “de- and re-differentiation” (hence making a complete “Cellular U-Turn”) approach represents an ideal model of “disease in a dish". Currently very few treatments for any neurological diseases exist, in part because of the lack of suitable in vitro models with which to test therapeutics. The proposal will lead to generation of new cell lines that have important research and clinical application. In vitro reprogramming could provide a way to generate patient-specific stem cells that, in culture, could be turned into the type of cell or tissue needed to cure the patient’s disease or injury. Moreover, genetic defects can be repaired in reprogrammed cells before being transplanted back into the patient’s body. Although both hESC or iPS cell-based therapeutic strategies that can promote remyelination will likely have significant clinical impact, one important advantage of patient-specific self-transplants is that they obviate the need for immunosuppression.
We plan to develop methods to make a complete “Cellular U-Turn” involving “dedifferentiation and redifferentiation” of specialized cell types to study “disease in a dish”. In addition to being integral to understanding the mechanism by which the stem cell program can be reinstated in specialized cells, if successful, this work will provide an important milestone for regenerative medicine. The significance of accomplishing this work is thus at the highest possible level currently for the field. The proposal addresses fundamental biological processes in reprogramming, i.e. reverting specialized cell types back to a more immature cell that can act like a stem cell, and may also pave the way for autologous stem cell-based therapies. We believe the proposed research will benefit Californian in many ways. It will result in development of novel technologies that will be broadly applicable to study stem cells and development of stem cell-based therapies, and will help position us and other Californian scientists at the forefront of stem cell research and medicine. We will make newly generated cell lines readily and freely available to other investigators and companies in the hope of accelerating the pace of discovery. The research relies on products and tools manufactured and sold in the state of California. If successful, research will require a scaled-up version of protocols designed in the proposed studies. This could attract new biotechnology companies in the state, boosting the tax revenue in the state. This in turn will provide new jobs for California residents. This research will increase experience and knowledge of stem cells among residents of California. Establishment of successful cellular therapeutics in California will encourage institutions of higher education to promote science education to fill the jobs created by stem cell research. This will retain California students in the state that are interested in biomedical research and medical careers. It could also attract out-of-state students seeking degrees that will allow them access to careers in stem cell research. This research will contribute to the California education and health care systems by training undergraduate, graduate and postdoctoral students into highly skilled stem cell biologists. It is also envisioned that this will trickle down to the K-12 levels and provide funding to promote science education at all levels.