ES cell transplantation for the treatment of Parkinson's disease

Abstract

Cell replacement therapy is one of the methods used for the regeneration of neuronal functions. Transplantation of fetal dopaminergic (DA) neurons can produce symptomatic relief, however, the technical and ethical difficulties in obtaining sufficient and appropriate donor fetal brain tissue have limited the application of this therapy. In the future, neural precursor cells and embryonic stem (ES) cells are expected to be candidates for use as potential donor cells for transplantation. First, we examined the potential of neural precursor cells derived from a 9-week-old human embryo. Two region-specific differences in neural precursor cells were revealed: 1) The precursor cells from the rostral part of the brain tended to proliferate faster than those from the caudal part, and 2) The precursors from the mesencephalon gave rise to more TH-positive neurons than those from the telencephalon. Furthermore, the former TH-positive cells were large, multipolar, and GABA-negative, which suggested that these cells were midbrain DA neurons. In contrast, the latter were small, bipolar, and GABA-positive, suggesting that they were interneurons. Embryonic stem (ES) cells are pluripotent cells that can be expanded without losing their potential to differentiate into a variety of cell types from all three germ layers. Previous studies examining, monkey, and human ES cells have revealed that they are also able to differentiate into neural cells. Furthermore, when grafted into the brain, ES cells survive and can differentiate into functional neurons. These data suggest that ES cells might represent a useful donor source for cell transplantation that may be used to treat neurological disorders such as Parkinson's disease. Next, we generated neurospheres composed of neural precursors from monkey ES cells, which are capable of producing large numbers of DA neurons. We demonstrated that FGF20, preferentially expressed in the substantia nigra, synergistically increased the number of DA neurons in ES cell-derived neurospheres with FGF2 treatment. We analyzed the effect of transplantation of DA neurons generated from monkey ES cells into MPTP-treated monkeys as a primate model of Parkinson's disease. Behavioral studies and functional imaging revealed that the transplanted cells functioned as DA neurons, attenuating the MPTP-induced neurological symptoms.