Dopaminergic neurons generated from monkey embryonic stem cells function in a Parkinson primate model

Abstract

Parkinson disease (PD) is a neurodegenerative disorder characterized by loss of midbrain dopaminergic (DA) neurons. ES cells are currently the most promising donor cell source for cell-replacement therapy in PD. We previously described a strong neuralizing activity present on the surface of stromal cells, named stromal cellderived inducing activity (SDIA). In this study, we generated neurospheres composed of neural progenitors from monkey ES cells, which are capable of producing large numbers of DA neurons. We demonstrated that FGF20, preferentially expressed in the substantia nigra, acts synergistically with FGF2 to increase the number of DA neurons in ES cell-derived neurospheres. We also analyzed the effect of transplantation of DA neurons generated from monkey ES cells into 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated (MPTP-treated) monkeys, a primate model for PD. Behavioral studies and functional imaging revealed that the transplanted cells functioned as DA neurons and attenuated MPTP-induced neurological symptoms. IntroductionParkinson disease (PD) is a neurodegenerative disorder characterized by the loss of midbrain dopaminergic (DA) neurons, with subsequent reductions in striatal dopamine levels. While initial pharmacological treatment with L-dihydroxyphenylalanin (L-DOPA) can attenuate symptoms, the efficacy of this treatment gradually decreases over time. The development of motor complications then requires additional treatments, including deep brain stimulation and fetal DA neuron transplantation (1-3). Both studies of animal models and clinical investigations have shown that transplantation of fetal DA neurons can produce symptomatic relief (4-8). The technical and ethical difficulties in obtaining sufficient and appropriate donor fetal brain tissue, however, have limited the application of this therapy.ES cells are self-renewing, pluripotent cells derived from the inner cell mass of the preimplantation blastocyst. These cells have many of the characteristics required of a cell source for cell-replacement therapy, including proliferation and differentiation capacities (9). We previously discovered that a strong neuralizing activity, which we called stromal cell-derived inducing activity (SDIA), is present

Exposure to Organophosphates Reduces the Expression of Neurotrophic Factors in Neonatal Rat Brain Regions: Similarities and Differences in the Effects of Chlorpyrifos and Diazinon on the Fibroblast Growth Factor Superfamily

“…There is growing suspicion that repeated developmental exposures to pesticides that target striatal dopamine projections play a significant role in the later emergence of this neurodegenerative disorder (for review, see Cory-Slechta et al 2005; Landrigan et al 2005). Indeed, the relationship of suppressed fgf20 expression to dopaminergic deficits and thence to Parkinson disease is directly supported by human genetic data (Murase and McKay 2006; Takagi et al 2005; van der Walt et al 2004) and by the specific role of this neurotrophic factor in promoting survival of the very neurons that are lost in Parkinson disease (Damier et al 1999; Yamada et al 1990). …”

“…Across the various stages of development, the FGFs promote and maintain neuronal cell replication and are required for differentiation into the terminal transmitter phenotype (Gage et al 1995; Johe et al 1996). The different FGFs play specific roles in neuronal cell differentiation, neurite outgrowth, and the recovery from damage in regions such as the striatum and hippocampus (Hart et al 2000; Limke et al 2003; Murase and McKay 2006; Ohmachi et al 2000; Ray et al 1993; Takagi et al 2005). The same regions are known targets for the adverse neurodevelopmental effects of organophosphates (Barone et al 2000; Slotkin 1999, 2004, 2005), which disrupt the very same cellular events for which the FGFs provide trophic signals (Axelrad et al 2003; Das and Barone 1999; Howard et al 2005; Song et al 1998).…”

Generation of diverse neural cell types through direct conversion

“…ESC also have great therapeutic potential, in particular for treatment of neurological disorders [25] . ESC have been shown to differentiate into a range of neural cell types, with noted improvements in function following implantation, with examples in models of Parkinson's disease [26,27] , motor neuron disease [28,29] , stroke [30,31] , and spinal cord injury [32,33] . Despite the research and clinical potential of ESC, their use is surrounded by much debate, due to technical obstacles, as well as legal and ethical issues regarding their isolation [34] .…”

Adult human neural stem cell therapeutics: Current developmental status and prospect

“…Dopaminergic neuroblasts for preclinical animal models have been cultured from various different stem cell sources, including ESCs [72][73][74][75][76][77][78][79] , fetal NSCs and precursors of embryonic ventral mesencephalon [80][81][82][83] , adult NSCs from the SVZ [84] , bone marrow stem cells [85] , and fibroblast-derived iPSC cells [86] . Although a small portion of dopaminergic neurons derived from transplanted cells contain disease-specific Lewy bodies 11 to 16 years after transplantation [87,88] , implanted cells remained viable [23,89] .…”