Abstract
The disease biology of frontotemporal lobe dementia (FTD) is complex and not fully understood, with limited translational value appreciated from animal models to date. Human cellular systems that can recapitulate phenotypic features of disease offer promise as translational tools to not only increase our understanding of disease processes but also increase the probability of success of translating novel treatment options to patients. However not all researchers may necessarily have access to well-characterized induced pluripotent stem cell (iPSC)-derived human neurons. As an example, we therefore comprehensively profiled phenotypic features over time in one commercially-available IPSC-derived human neuron cell line. This included systems-level assessments of neurite outgrowth dynamics, neuronal network function, and genome-wide gene expression. By investigating progranulin biology as an example we then demonstrated the utility of these cells as a tool to investigate human disease biology. For example, by using the siRNA-mediated knockdown of the progranulin (GRN) gene, we demonstrated the establishment of an isogenic human cellular model to facilitate translational FTD research. We reproduced findings from rodent neurons by demonstrating that recombinant progranulin (rPGRN) mediated neuroprotection. Contrary to previous rodent data, in our human cellular models, growth factor treatment showed no consistent sensitivity to modulate neurite outgrowth dynamics. Our study further provides the first evidence that rRPGRN modulated neuronal firing and synchrony in human neurons. Taken together, our datasets are a valuable systems-level resource demonstrating the utility of the tested commercially-available human iPSC neurons for investigating basic human neurobiology, translational neuroscience, and drug discovery applications in neurodegenerative and other CNS diseases.
Highlights
While most basic biological studies utilize animal-based models to investigate disease mechanisms and biology, suitable models that allow translation of these findings to human biology are often missing
Culture of Induced pluripotent stem cells (iPSCs)-Derived Neurons iCell GlutaNeurons (GNs; FUJIFILM Cellular Dynamics Inc., FCDI) are human cells differentiated from a master bank of stably induced pluripotent stem cells from normal donors
In this study, we focused our attention on iPSC-derived neuronal cells as a key technology that is commercially available and, would allow independent validation and wide distribution of the presented tools among the science community to open up this technology to researchers that are not proficient in iPSC reprogramming
Summary
While most basic biological studies utilize animal-based models to investigate disease mechanisms and biology, suitable models that allow translation of these findings to human biology are often missing. Induced pluripotent stem cells (iPSCs) can be differentiated into a host of cell types, including neurons (Takahashi et al, 2007) and have been implemented to model common and rare neurological diseases (Park et al, 2008; Ross and Akimov, 2014), including Alzheimer’s disease (AD; Israel et al, 2012) and frontotemporal lobe dementia (FTD; Almeida et al, 2012; Raitano et al, 2015) Such iPSC-derived neuronal models from normal donors and patients are useful but have certain disadvantages. The creation of these cells is time-consuming and requires extensive characterization (Xu and Zhong, 2013); results have been shown to vary substantially between labs (Volpato et al, 2018)
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