Control of neural stem-to-progenitor transitions by Cyclin D family members in ES cells
Mouse embryonic stem (mES) cells are the earliest pluripotent mammalian cell ever described, capable of generating entire viable mice in vivo and producing most, if not all, cell types in vitro. In combination with this pluripotency, an extensive rate of proliferation confers on mES cells the status of an unlimited renewable source of cells. The use of ES-derived cells as therapeutic agents has been previously shown to be possible in mice. Therefore, the recent isolation of human ES (hES) cells has stimulated interest in their potential clinical value. hES cells have became the subject of intensive studies aimed at cell therapies, creating a great hope for curing many degenerative diseases. Among them, Amyotrophic Lateral Sclerosis (ALS) is a neurological disease that attacks and degenerates the motor neurons (MNs) that control voluntary muscles.
Spinal MNs can be generated in vitro from ES cells and used to achieve a functional restoration of motor units after injury in model animal. But the relationship between the stage of neuronal differentiation and the efficiency of in vivo engraftment and differentiation has not been empirically investigated so far. It is very important to extensively study the potentiality of engraftment of cells according to their stage of differentiation, in order to optimize the transplantation process. The MN differentiation pathway is very well characterized, divided in at least three stages, but very little is known about the molecular mechanism regulating the neuronal differentiation process, driving the cells from one stage to an other, or the engraftment capacities and degree of commitment of these different developmental intermediate.
Preliminary observations obtained in the lab led us to consider Cyclin Ds, known as positive regulator of the cell cycle, as makers of different stages in the MN differentiation process. In addition, it has been demonstrated that CyclinD1 is able to modify the activity of transcription factors. We thus have hypothesized that the dynamic expression of Cyclin Ds observed in the CNS could be part of the molecular mechanism involved in the regulation of neuronal specification. Preliminary results confirmed this hypothesis and prompted us to ask if, similarly, the modulation of Cyclin Ds level of expression could be a way to influence ES cells along the in vitro MN differentiation process. The goal of this proposal is to test this hypothesis and determine whether it allows amplification of progenitors at different stages in the MN lineage. Preliminary results will be obtained on mES, for the ease of manipulation, but soon similar experiments will be conducted on hES cells. If our hypothesis is confirmed, the efficiency of engraftment will be analyzed for the different populations, hoping that this will leads to optimize the engraftment process, bringing us closer to a cure for many neurodegenerative diseases.
Amyotrophic lateral sclerosis (ALS), often referred to as "Lou Gehrig's disease," is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord, resulting in muscle weakness and atrophy. Nearly 120,000 cases are diagnosed worldwide each year, with a life expectancy after diagnosis as short as 2-4 years. Replacing the degenerating motor neurons using a renewable cell source such as human embryonic stem cells appears to be one of the most promising treatments for ALS, as well as other neurodegenerative diseases. Unfortunately, if the proof of principle for such treatment has already been demonstrated in rodent, long is the way toward such cure for human. Notably, a drastic improvement for the transplantation process is necessary. With this project, we propose to extensively study the potentiality of engraftment of cells according to their stage of differentiation, in order to optimize the transplantation process. If successful, this study will constitute a huge step toward curing ALS patients as well as many patients whom may require neuronal graft. This will also benefit the State of California and its citizens. It is of primary importance to support innovative research as it will maintain a dynamic environment propitious to attract more qualified people. Mastering such cutting edge technology also represents a important advantage for the State of California and its citizens as it may lead to the development of health care program and possibly biotech companies, which represents an advantage for the local economy.