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Modeling Cell-Cell Interactions in Parkinson's Disease Using Human Stem Cell-Based Models


Modeling Cell-Cell Interactions in Parkinson's Disease Using Human Stem Cell-Based Models

Katrin Simmnacher et al. Front Cell Neurosci.


Parkinson's disease (PD) is the most frequently occurring movement disorder, with an increasing incidence due to an aging population. For many years, the post-mortem brain was regarded as the gold standard for the analysis of the human pathology of this disease. However, modern stem cell technologies, including the analysis of patient-specific neurons and glial cells, have opened up new avenues for dissecting the pathologic mechanisms of PD. Most data on morphological changes, such as cell death or changes in neurite complexity, or functional deficits were acquired in 2D and few in 3D models. This review will examine the prerequisites for human disease modeling in PD, covering the generation of midbrain neurons, 3D organoid midbrain models, the selection of controls including genetically engineered lines, and the study of cell-cell interactions. We will present major disease phenotypes in human in vitro models of PD, focusing on those phenotypes that have been detected in genetic and sporadic PD models. An additional point covered in this review will be the use of induced pluripotent stem cell (iPSC)-derived technologies to model cell-cell interactions in PD.

Keywords: Parkinson’s disease; disease modeling; dopaminergic neuron; glia; iPSC; inflammation; neurodegeneration; organoid.


Figure 1
Figure 1
The growing induced pluripotent stem cell (iPSC) toolbox for Parkinson’s disease (PD) disease modeling.
Figure 2
Figure 2
Major phenotypes observed in iPSC-derived dopaminergic (DA) neurons. The accumulation and aggregation of α-synuclein in PD models of iPSC derived neurons was shown in the following publications: Byers et al. (2011), Devine et al. (2011), Nguyen et al. (2011), Imaizumi et al. (2012), Reinhardt et al. (2013b), Ryan et al. (2013), Flierl et al. (2014), Woodard et al. (2014), Oliveira et al. (2015), Reyes et al. (2015), Chung et al. (2016), Mazzulli et al. (2016), Heman-Ackah et al. (2017), Kouroupi et al. (2017), Vasquez et al. (2017), Kim et al. (2018), Ludtmann et al. (2018), Prots et al. (2018), Hu et al. (2019), Tagliafierro et al. (2019) and Zambon et al. (2019). The phenotype of aberrant neurite morphology was described in Sánchez-Danés et al. (2012), Reinhardt et al. (2013b), Woodard et al. (2014), Schwab and Ebert (2015), Borgs et al. (2016), Lin et al. (2016), Kouroupi et al. (2017), Sommer et al. (2018) and Korecka et al. (2019). Increased cell death without additional stressors could be detected in Sánchez-Danés et al. (2012) and Bogetofte et al. (2019). Several publications detected increased cell death rate in PD models of iPSC derived neurons adding additional stressors: Byers et al. (2011), Nguyen et al. (2011), Miller et al. (2013), Reinhardt et al. (2013b), Flierl et al. (2014), Ryan et al. (2014), Shaltouki et al. (2015), Chung et al. (2016), Lin et al. (2016) and Sommer et al. (2018).
Figure 3
Figure 3
Cell-cell interactions in the pathogenesis of PD—recent advances using iPSC-derived disease modeling. Opaque arrows depict recent findings made using iPSC-derived cell-cell interaction models; pale arrows show mechanisms that still need investigation via iPSC-derived human disease modeling.

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