Charles Arber, Jamie Toombs, Christopher Lovejoy, Natalie S. Ryan, Ross W. Paterson, Nanet Willumsen, Eleni Gkanatsiou, Erik Portelius, Kaj Blennow, Amanda Heslegrave, Jonathan M. Schott, John Hardy, Tammaryn Lashley, Nick C. Fox, Henrik Zetterberg, Selina Wray
This paper (Arber et al. 2019) describes the occurrence of different Amyloid beta peptides generated by human cells with different Amyloid Precursor Protein (APP) or Presenilin 1 mutations, related to Alzheimer’s disease. Although the primary aim of the paper is not to compare 2D versus 3D set up of these neural cultures, this is a small point in this paper illustrated in figures S1 and 2. As part of the 3Dbionet online journal club, this discussion will thus focus on the comparison between 2D and 3D cell cultures and will not address the rest of this very original, innovative and timely paper.
I was disappointed to see that the 2D versus 3D cultures comparison in terms of differentiation was minimal. Although the same pluripotent cell lines are used for both 2D and 3D set ups, the neural differentiation protocols used are not the same. 2D cultures used the Shi protocol (Shi, Kirwan, and Livesey 2012) whereas 3D cerebral organoid cultures used the Lancaster protocol (Lancaster and Knoblich 2014). It is evident protocols need to be different as some point in the 2D and 3D culture set up, but for strong comparison, the latest the divergence, the better. The neural induction protocols should be similar up to the neural ectoderm stage at least, once organoids start to self-organise. Why not dissociate early organoids to plate cells in 2D? Although the paper presents juxtaposed images of different neural and cortical markers staining, there is no (semi-) quantification of these data. Moreover, the paper analyses cells at 100 days post neural induction, for both 2D and 3D cultures, without providing evidence that differentiation and maturation occurred at the same rate and time in 2D and 3D cell cultures. The only protein directly compared between 2D and 3D cultures is the APP which peptides analysed in this paper are cleaved from. The protein levels of APP are indeed similar between 2D and 3D cultures but without data on proportion of neurons, astrocytes, neuronal subtypes or mature functional neurons, it is difficult to interpret the similar levels of APP.
Nonetheless, with this comparison, this paper attempts to address a crucial point of 3D and organoid neural cultures research: the current lack of validation and benchmarking of 3D and organoid cultures against both 2D neural cultures and human tissue. How do 3D and organoids cultures compare to 2D cultures and brain tissue? Very few papers have addressed this so far (for example (Zhang et al. 2014; Lee et al. 2016; Yan et al. 2018)). Human iPSC-derived 2D neural cultures have delivered so much knowledge on the molecular and cellular mechanisms related to neurodegenerative diseases that not benchmarking the new 3D and organoids methods to them would be equivalent to going back to the drawing board. Moreover, benchmarking to human brain tissue is an obvious necessary step in the validation of the 3D and organoids methods that not many have taken. This might be due to the difficulty in accessing live human brain tissue, however, only a fraction of available resected brain tissue is indeed used for pre-clinical research (Vargas-Caballero et al. 2016) and more should be done to use the available neurosurgical samples (Ahmed et al. [http://dx.doi.org/10.1136/jnnp-2019-ABN.101]). Benchmarking the methods of 3D neural and cerebral organoids cultures will hopefully allow these innovative techniques to continue to deliver new mechanistic knowledge (as reviewed in (Arber, Lovejoy, and Wray 2017; Siney et al. 2018) for example) and accelerate the finding of new treatments for neurodegenerative diseases.
Arber, C., C. Lovejoy, and S. Wray. 2017. 'Stem cell models of Alzheimer's disease: progress and challenges', Alzheimers Res Ther, 9: 42.
Arber, C., J. Toombs, C. Lovejoy, N. S. Ryan, R. W. Paterson, N. Willumsen, E. Gkanatsiou, E. Portelius, K. Blennow, A. Heslegrave, J. M. Schott, J. Hardy, T. Lashley, N. C. Fox, H. Zetterberg, and S. Wray. 2019. 'Familial Alzheimer's disease patient-derived neurons reveal distinct mutation-specific effects on amyloid beta', Mol Psychiatry.
Lancaster, M. A., and J. A. Knoblich. 2014. 'Generation of cerebral organoids from human pluripotent stem cells', Nat Protoc, 9: 2329-40.
Lee, H. K., C. Velazquez Sanchez, M. Chen, P. J. Morin, J. M. Wells, E. B. Hanlon, and W. Xia. 2016. 'Three Dimensional Human Neuro-Spheroid Model of Alzheimer's Disease Based on Differentiated Induced Pluripotent Stem Cells', PLoS One, 11: e0163072.
Shi, Y., P. Kirwan, and F. J. Livesey. 2012. 'Directed differentiation of human pluripotent stem cells to cerebral cortex neurons and neural networks', Nat Protoc, 7: 1836-46.
Siney, Elodie J., Ksenia Kurbatskaya, Shreyasi Chatterjee, Preeti Prasannan, Amrit Mudher, and Sandrine Willaime-Morawek. 2018. 'Modelling neurodegenerative diseases in vitro: Recent advances in 3D iPSC technologies', AIMS Cell and Tissue Engineering, 2: 1-23.
Vargas-Caballero, M., S. Willaime-Morawek, D. Gomez-Nicola, V. H. Perry, D. Bulters, and A. Mudher. 2016. 'The use of human neurons for novel drug discovery in dementia research', Expert Opin Drug Discov, 11: 355-67.
Yan, W., W. Liu, J. Qi, Q. Fang, Z. Fan, G. Sun, Y. Han, D. Zhang, L. Xu, M. Wang, J. Li, F. Chen, D. Liu, R. Chai, and H. Wang. 2018. 'A Three-Dimensional Culture System with Matrigel Promotes Purified Spiral Ganglion Neuron Survival and Function In Vitro', Mol Neurobiol, 55: 2070-84.
Zhang, D., M. Pekkanen-Mattila, M. Shahsavani, A. Falk, A. I. Teixeira, and A. Herland. 2014. 'A 3D Alzheimer's disease culture model and the induction of P21-activated kinase mediated sensing in iPSC derived neurons', Biomaterials, 35: 1420-8.
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