We would like to congratulate Drs. Bolognin, Antony, and Schwamborn on their excellent publication regarding a 3D human neural cell culture model of PD. We are very excited to see that the 3D Matrigel-based cell culture system accelerates pathogenic cascades in hiPSC-derived PD neurons as we have shown with AD neurons (Choi et al., 2014). In our previous study, we showed that the 3D Matrigel cell culture system accelerated accumulation/aggregation of pathogenic amyloid beta species and also increased the expression of adult neural markers including adult 4-repeat tau isoform, which is crucial for developing robust tau pathology. It is quite interesting that the 3D Matrigel cell culture system also accelerated mitochondrial deficits and neuronal death in human PD iPSC-derived neurons. It is possible that similar mechanisms may play a role. Although α-synuclein aggregation was not detected in Dr. Bolognin’s 3D PD cellular model, we think it will be intriguing to check whether soluble pathogenic proteins, including extracellular alpha-synuclein, selectively accumulate in 3D Matrigel with PD iPSC-derived neurons.
We also agree with Dr. Bolognin that these new 3D human cellular models provide a new research tool to study the pathogenic mechanism of neurodegeneration in a human brain-like environment. However, many challenges lie ahead for comprehensively recapitulating brain conditions during human neurodegeneration: 1) mimicking aging aspects to 3D neural cell culture models; 2) precisely reconstituting brain structures that are damaged during neurodegeneration, as Dr. Bolognin addressed; 3) generating sporadic disease models; 4) adding neuroinflammatory elements. In an attempt to more precisely mimic the disease conditions, our lab, in collaboration with Dr. Cho’s lab at UNCC, recently developed 3D triculture models that mimic neuroinflammation in AD by adding human microglia cells into our 3D neuron-astrocyte AD models (Park et al., 2018). We think it will be interesting to find whether adding neuroinflammatory elements to 3D PD cellular models can further accelerate pathogenic cascades in PD iPSC-derived neurons.
Finally, we would like to briefly comment on implications of the 3D cell culture models for drug discovery. As pointed by Dr. Bolognin, there are many challenges to adapt self-assembling 3D organoid models into high-throughput drug screening system. However, ours and Dr. Bolognin’s 3D culture models can be easily adapted to large-scale drug testing since they do not need complex self-organization of neural stem cells. Although there are many limitations in current 3D neurodegeneration models, we strongly believe that some of the 3D models are already useful enough for drug screening.
-Doo Yeon Kim, Joseph Park, Mehdi Jorfi, Rudolph E. Tanzi
Choi, S.H., Kim, Y.H., Hebisch, M., Sliwinski, C., Lee, S., D'Avanzo, C., Chen, H., Hooli, B., Asselin, C., Muffat, J., et al. (2014). A three-dimensional human neural cell culture model of Alzheimer’s disease. Nature 515, 274–278.
Park, J., Wetzel, I., Marriott, I., Dréau, D., D'Avanzo, C., Kim, D.Y., Tanzi, R.E., and Cho, H. (2018). A 3D human triculture system modeling neurodegeneration and neuroinflammation in Alzheimer's disease. Nat Neurosci 21, 941–951.