An In Vitro Partial Lesion Model of Differentiated Human Mesencephalic Neurons: Effect of Pericyte Secretome on Phenotyp
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An In Vitro Partial Lesion Model of Differentiated Human Mesencephalic Neurons: Effect of Pericyte Secretome on Phenotypic Markers Abderahim Gaceb 1
&
Marco Barbariga 1 & Gesine Paul 1,2
Received: 14 January 2020 / Accepted: 13 May 2020 # The Author(s) 2020
Abstract Parkinson’s disease (PD) is characterised by the progressive degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta. Post-mortem data suggests that the loss of DA markers may long precede the cell death, leaving a window to rescue the DA phenotype. Screening for potential neuroprotective or restorative therapies, however, requires that partial lesions of DA neurons can be modelled in vitro. In order to establish a partial lesion model of DA neurons in vitro, we evaluated the effects of different exposure times to 1-methyl-4-phenylpyridinium (MPP+) and 6-hydroxydopamine (6-OHDA) on the cell survival and DA marker expression using DA neurons derived from the Lund human mesencephalic (LUHMES) cell line. We show that 24-h incubation with 50 μM of MPP+ or 6-h incubation with 100 μM of 6-OHDA leads to a significant decrease in the protein expression of DA markers without affecting overall cell death, consistent with a mild DA lesion. Using conditioned medium of human brain–derived pericytes stimulated with platelet-derived growth factor BB (PDGF-BB), we demonstrate a significant upregulation of DA markers. In conclusion, we provide an experimental model of an in vitro DA neuron partial lesion suitable to study different molecules and their potential neuroprotective or neurorestorative effects on the DA phenotype. We provide evidence that the secretome of brain pericytes stimulated via PDGF-BB/PDGFRβ affects DA marker expression and may represent one possible mechanism contributing to the neurorestoration previously observed in PD by this growth factor. Keywords Brain pericytes . Dopaminergic neurons . Partial lesion . Secretome . Platelet-derived growth factor BB . Neurorestoration
Introduction Parkinson’s disease (PD) is a slowly progressive neurodegenerative disease characterised by the continuous and progressive degeneration of several neuronal subtypes (Jellinger 1991). The most affected cells are the dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc), a cell Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12031-020-01589-6) contains supplementary material, which is available to authorized users. * Abderahim Gaceb [email protected] 1
Translational Neurology Group, Department of Clinical Science, Wallenberg Neuroscience Center and Wallenberg Center for Molecular Medicine, Lund University, Sölvegatan 19, 22184 Lund, Sweden
2
Department of Neurology, Scania University Hospital, 22185 Lund, Sweden
type that has become the primary target for neuroprotective and neurorestorative approaches. The cause of DA neuron death is still debated and may depend on impaired protein degradation systems, synaptic dysfunction, endoplasmic reticulum stress, DNA damage,
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