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Longitudinal Characterization of Transcriptomic, Functional, and Morphological Features in Human iPSC-Derived Neurons and Their Application to Investigate Translational Progranulin Disease Biology
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 increas...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689020/ https://www.ncbi.nlm.nih.gov/pubmed/33281596 http://dx.doi.org/10.3389/fnagi.2020.576678 |
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author | Robin, Gaëlle Evans, J. Corey Hauser, David N. Wren, Paul Zembrzycki, Andreas |
author_facet | Robin, Gaëlle Evans, J. Corey Hauser, David N. Wren, Paul Zembrzycki, Andreas |
author_sort | Robin, Gaëlle |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7689020 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-76890202020-12-03 Longitudinal Characterization of Transcriptomic, Functional, and Morphological Features in Human iPSC-Derived Neurons and Their Application to Investigate Translational Progranulin Disease Biology Robin, Gaëlle Evans, J. Corey Hauser, David N. Wren, Paul Zembrzycki, Andreas Front Aging Neurosci Neuroscience 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. Frontiers Media S.A. 2020-11-12 /pmc/articles/PMC7689020/ /pubmed/33281596 http://dx.doi.org/10.3389/fnagi.2020.576678 Text en Copyright © 2020 Robin, Evans, Hauser, Wren and Zembrzycki. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Neuroscience Robin, Gaëlle Evans, J. Corey Hauser, David N. Wren, Paul Zembrzycki, Andreas Longitudinal Characterization of Transcriptomic, Functional, and Morphological Features in Human iPSC-Derived Neurons and Their Application to Investigate Translational Progranulin Disease Biology |
title | Longitudinal Characterization of Transcriptomic, Functional, and Morphological Features in Human iPSC-Derived Neurons and Their Application to Investigate Translational Progranulin Disease Biology |
title_full | Longitudinal Characterization of Transcriptomic, Functional, and Morphological Features in Human iPSC-Derived Neurons and Their Application to Investigate Translational Progranulin Disease Biology |
title_fullStr | Longitudinal Characterization of Transcriptomic, Functional, and Morphological Features in Human iPSC-Derived Neurons and Their Application to Investigate Translational Progranulin Disease Biology |
title_full_unstemmed | Longitudinal Characterization of Transcriptomic, Functional, and Morphological Features in Human iPSC-Derived Neurons and Their Application to Investigate Translational Progranulin Disease Biology |
title_short | Longitudinal Characterization of Transcriptomic, Functional, and Morphological Features in Human iPSC-Derived Neurons and Their Application to Investigate Translational Progranulin Disease Biology |
title_sort | longitudinal characterization of transcriptomic, functional, and morphological features in human ipsc-derived neurons and their application to investigate translational progranulin disease biology |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689020/ https://www.ncbi.nlm.nih.gov/pubmed/33281596 http://dx.doi.org/10.3389/fnagi.2020.576678 |
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