Abstract
Human induced pluripotent stem (iPS) cells have the potential to give rise to a new era in Parkinson’s disease (PD) research. As a unique source of midbrain dopaminergic (DA) neurons, iPS cells provide unparalleled capabilities for investigating the pathogenesis of PD, the development of novel anti-parkinsonian drugs, and personalized therapy design. Significant progress in developmental biology of midbrain DA neurons laid the foundation for their efficient derivation from iPS cells. The introduction of 3D culture methods to mimic the brain microenvironment further expanded the vast opportunities of iPS cell-based research of the neurodegenerative diseases. However, while the benefits for basic and applied studies provided by iPS cells receive widespread coverage in the current literature, the drawbacks of this model in its current state, and in particular, the aspects of differentiation protocols requiring further refinement are commonly overlooked. This review summarizes the recent data on general and subtype-specific features of midbrain DA neurons and their development. Here, we review the current protocols for derivation of DA neurons from human iPS cells and outline their general weak spots. The associated gaps in the contemporary knowledge are considered and the possible directions for future research that may assist in improving the differentiation conditions and increase the efficiency of using iPS cell-derived neurons for PD drug development are discussed.
Highlights
Human induced pluripotent stem cells have the potential to give rise to a new era in Parkinson’s disease (PD) research
HU treatment of human mesencephalic DA neurons derived from induced pluripotent stem (iPS) cells of patients with sporadic PD was shown to induce an array of phenotypic traits associated with neuodegeneration
DA neurons generated from iPS cells of PD patients, Spathis et al showed that BRF110 increases the expression level of genes associated with dopamine synthesis and promotes cell survival under the oxidative stress conditions
Summary
The midbrain dopaminergic (DA) neurons are of particular interest for modern molecular biology due to their selective death in Parkinson’s disease (PD), a widespread incurable neurodegenerative disease. A9 DA neurons [7], while the expression of Otx and Nolz is restricted to A10 group in the adult midbrain [7,8] These genes were shown to distinguish A9 and A10 progenitors already at the early stages of brain development, raising the possibility for their selective generation from pluripotent stem cells (PSC) in vitro [7]. Dopamine degradation by monoamine oxidase, cyclooxygenase, and tyrosinase is associated with generation of reactive oxygen species, and the non-enzymatic dopamine oxidation produces toxic quinone compounds [23] To sustain their functioning during the whole human lifespan, DA neurons possess the remarkable resistance to the oxidative stress. The high energy demands for maintaining this activity in A9 cells impose additional burden upon electron-transfer chain and may contribute to increased vulnerability of these cells mitochondrial stress [26]
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