Abstract
Pluripotent stem cells are regarded as a promising cell source to obtain human dopamine neurons in sufficient amounts and purity for cell replacement therapy. Importantly, the success of clinical applications depends on our ability to steer pluripotent stem cells towards the right neuronal identity. In Parkinson disease, the loss of dopamine neurons is more pronounced in the ventrolateral population that projects to the sensorimotor striatum. Because synapses are highly specific, only neurons with this precise identity will contribute, upon transplantation, to the synaptic reconstruction of the dorsal striatum. Thus, understanding the developmental cell program of the mesostriatal dopamine neurons is critical for the identification of the extrinsic signals and cell-intrinsic factors that instruct and, ultimately, determine cell identity. Here, we review how extrinsic signals and transcription factors act together during development to shape midbrain cell fates. Further, we discuss how these same factors can be applied in vitro to induce, select, and reprogram cells to the mesostriatal dopamine fate.
Highlights
The mesostriatal vmDA subpopulation is often referred to as the A9 group, following the nomenclature of aldehyde fluorescent cell populations identified using the Falck-Hillarp technique, in the rodent brain [13]
Clinical trials have shown a rather modest clinical success and, in some cases, worrying adverse effects [23, 25]. Both the limited benefit and the presence of graft-induced dyskinesias have been attributed to a suboptimal cellular composition of the fetal grafts, other biological and technical factors are important
Serotonin neurons have the capacity to decarboxylate L-dopa and store DA but cannot regulate DA release and reuptake, because they lack DA receptor D2 (DRD2) autoreceptors and DAT. This imbalance has been proposed to underlie the appearance of graft-induced dyskinesia, based on PET studies and on the pharmacological improvement with buspirone (a 5HT1A partial agonist) [30]. The evidence supporting this mechanism in the transplanted patients has been questioned, as dyskinesias should worsen with L-DOPA, which is not the case [33]
Summary
Parkinson disease is characterized by the progressive degeneration of dopamine (DA) neurons in the pars compacta of the substantia nigra (SNc) of the ventral midbrain (vm). The proportion of mesoprefrontal and mesocorticolimbic DA subpopulations in the grafts has not been examined in detail but the presence of calbindin-D28k positive neurons does not appear to cause adverse effects (even if the mesoprefrontal DA neurons do not express DRD2 or DAT). These neurons would not contribute to the synaptic reconstruction of the dorsal striatum [37]. Both for pluripotent stem cells and for reprogrammed cells, acquiring and maintaining the right identity will be a key determinant in the success of future clinical applications
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