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Organoid-on-a-chip model of human ARPKD reveals mechanosensing pathomechanisms for drug discovery
Organoids serve as a novel tool for disease modeling in three-dimensional multicellular contexts. Static organoids, however, lack the requisite biophysical microenvironment such as fluid flow, limiting their ability to faithfully recapitulate disease pathology. Here, we unite organoids with organ-on...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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American Association for the Advancement of Science
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9491724/ https://www.ncbi.nlm.nih.gov/pubmed/36129975 http://dx.doi.org/10.1126/sciadv.abq0866 |
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author | Hiratsuka, Ken Miyoshi, Tomoya Kroll, Katharina T. Gupta, Navin R. Valerius, M. Todd Ferrante, Thomas Yamashita, Michifumi Lewis, Jennifer A. Morizane, Ryuji |
author_facet | Hiratsuka, Ken Miyoshi, Tomoya Kroll, Katharina T. Gupta, Navin R. Valerius, M. Todd Ferrante, Thomas Yamashita, Michifumi Lewis, Jennifer A. Morizane, Ryuji |
author_sort | Hiratsuka, Ken |
collection | PubMed |
description | Organoids serve as a novel tool for disease modeling in three-dimensional multicellular contexts. Static organoids, however, lack the requisite biophysical microenvironment such as fluid flow, limiting their ability to faithfully recapitulate disease pathology. Here, we unite organoids with organ-on-a-chip technology to unravel disease pathology and develop therapies for autosomal recessive polycystic kidney disease. PKHD1-mutant organoids-on-a-chip are subjected to flow that induces clinically relevant phenotypes of distal nephron dilatation. Transcriptomics discover 229 signal pathways that are not identified by static models. Mechanosensing molecules, RAC1 and FOS, are identified as potential therapeutic targets and validated by patient kidney samples. On the basis of this insight, we tested two U.S. Food and Drug Administration–approved and one investigational new drugs that target RAC1 and FOS in our organoid-on-a-chip model, which suppressed cyst formation. Our observations highlight the vast potential of organoid-on-a-chip models to elucidate complex disease mechanisms for therapeutic testing and discovery. |
format | Online Article Text |
id | pubmed-9491724 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-94917242022-10-03 Organoid-on-a-chip model of human ARPKD reveals mechanosensing pathomechanisms for drug discovery Hiratsuka, Ken Miyoshi, Tomoya Kroll, Katharina T. Gupta, Navin R. Valerius, M. Todd Ferrante, Thomas Yamashita, Michifumi Lewis, Jennifer A. Morizane, Ryuji Sci Adv Biomedicine and Life Sciences Organoids serve as a novel tool for disease modeling in three-dimensional multicellular contexts. Static organoids, however, lack the requisite biophysical microenvironment such as fluid flow, limiting their ability to faithfully recapitulate disease pathology. Here, we unite organoids with organ-on-a-chip technology to unravel disease pathology and develop therapies for autosomal recessive polycystic kidney disease. PKHD1-mutant organoids-on-a-chip are subjected to flow that induces clinically relevant phenotypes of distal nephron dilatation. Transcriptomics discover 229 signal pathways that are not identified by static models. Mechanosensing molecules, RAC1 and FOS, are identified as potential therapeutic targets and validated by patient kidney samples. On the basis of this insight, we tested two U.S. Food and Drug Administration–approved and one investigational new drugs that target RAC1 and FOS in our organoid-on-a-chip model, which suppressed cyst formation. Our observations highlight the vast potential of organoid-on-a-chip models to elucidate complex disease mechanisms for therapeutic testing and discovery. American Association for the Advancement of Science 2022-09-21 /pmc/articles/PMC9491724/ /pubmed/36129975 http://dx.doi.org/10.1126/sciadv.abq0866 Text en Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited. |
spellingShingle | Biomedicine and Life Sciences Hiratsuka, Ken Miyoshi, Tomoya Kroll, Katharina T. Gupta, Navin R. Valerius, M. Todd Ferrante, Thomas Yamashita, Michifumi Lewis, Jennifer A. Morizane, Ryuji Organoid-on-a-chip model of human ARPKD reveals mechanosensing pathomechanisms for drug discovery |
title | Organoid-on-a-chip model of human ARPKD reveals mechanosensing pathomechanisms for drug discovery |
title_full | Organoid-on-a-chip model of human ARPKD reveals mechanosensing pathomechanisms for drug discovery |
title_fullStr | Organoid-on-a-chip model of human ARPKD reveals mechanosensing pathomechanisms for drug discovery |
title_full_unstemmed | Organoid-on-a-chip model of human ARPKD reveals mechanosensing pathomechanisms for drug discovery |
title_short | Organoid-on-a-chip model of human ARPKD reveals mechanosensing pathomechanisms for drug discovery |
title_sort | organoid-on-a-chip model of human arpkd reveals mechanosensing pathomechanisms for drug discovery |
topic | Biomedicine and Life Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9491724/ https://www.ncbi.nlm.nih.gov/pubmed/36129975 http://dx.doi.org/10.1126/sciadv.abq0866 |
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