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Glucose absorption drives cystogenesis in a human organoid-on-chip model of polycystic kidney disease

In polycystic kidney disease (PKD), fluid-filled cysts arise from tubules in kidneys and other organs. Human kidney organoids can reconstitute PKD cystogenesis in a genetically specific way, but the mechanisms underlying cystogenesis remain elusive. Here we show that subjecting organoids to fluid sh...

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Autores principales: Li, Sienna R., Gulieva, Ramila E., Helms, Louisa, Cruz, Nelly M., Vincent, Thomas, Fu, Hongxia, Himmelfarb, Jonathan, Freedman, Benjamin S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9789147/
https://www.ncbi.nlm.nih.gov/pubmed/36564419
http://dx.doi.org/10.1038/s41467-022-35537-2
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author Li, Sienna R.
Gulieva, Ramila E.
Helms, Louisa
Cruz, Nelly M.
Vincent, Thomas
Fu, Hongxia
Himmelfarb, Jonathan
Freedman, Benjamin S.
author_facet Li, Sienna R.
Gulieva, Ramila E.
Helms, Louisa
Cruz, Nelly M.
Vincent, Thomas
Fu, Hongxia
Himmelfarb, Jonathan
Freedman, Benjamin S.
author_sort Li, Sienna R.
collection PubMed
description In polycystic kidney disease (PKD), fluid-filled cysts arise from tubules in kidneys and other organs. Human kidney organoids can reconstitute PKD cystogenesis in a genetically specific way, but the mechanisms underlying cystogenesis remain elusive. Here we show that subjecting organoids to fluid shear stress in a PKD-on-a-chip microphysiological system promotes cyst expansion via an absorptive rather than a secretory pathway. A diffusive static condition partially substitutes for fluid flow, implicating volume and solute concentration as key mediators of this effect. Surprisingly, cyst-lining epithelia in organoids polarize outwards towards the media, arguing against a secretory mechanism. Rather, cyst formation is driven by glucose transport into lumens of outwards-facing epithelia, which can be blocked pharmacologically. In PKD mice, glucose is imported through cysts into the renal interstitium, which detaches from tubules to license expansion. Thus, absorption can mediate PKD cyst growth in human organoids, with implications for disease mechanism and potential for therapy development.
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spelling pubmed-97891472022-12-25 Glucose absorption drives cystogenesis in a human organoid-on-chip model of polycystic kidney disease Li, Sienna R. Gulieva, Ramila E. Helms, Louisa Cruz, Nelly M. Vincent, Thomas Fu, Hongxia Himmelfarb, Jonathan Freedman, Benjamin S. Nat Commun Article In polycystic kidney disease (PKD), fluid-filled cysts arise from tubules in kidneys and other organs. Human kidney organoids can reconstitute PKD cystogenesis in a genetically specific way, but the mechanisms underlying cystogenesis remain elusive. Here we show that subjecting organoids to fluid shear stress in a PKD-on-a-chip microphysiological system promotes cyst expansion via an absorptive rather than a secretory pathway. A diffusive static condition partially substitutes for fluid flow, implicating volume and solute concentration as key mediators of this effect. Surprisingly, cyst-lining epithelia in organoids polarize outwards towards the media, arguing against a secretory mechanism. Rather, cyst formation is driven by glucose transport into lumens of outwards-facing epithelia, which can be blocked pharmacologically. In PKD mice, glucose is imported through cysts into the renal interstitium, which detaches from tubules to license expansion. Thus, absorption can mediate PKD cyst growth in human organoids, with implications for disease mechanism and potential for therapy development. Nature Publishing Group UK 2022-12-23 /pmc/articles/PMC9789147/ /pubmed/36564419 http://dx.doi.org/10.1038/s41467-022-35537-2 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Li, Sienna R.
Gulieva, Ramila E.
Helms, Louisa
Cruz, Nelly M.
Vincent, Thomas
Fu, Hongxia
Himmelfarb, Jonathan
Freedman, Benjamin S.
Glucose absorption drives cystogenesis in a human organoid-on-chip model of polycystic kidney disease
title Glucose absorption drives cystogenesis in a human organoid-on-chip model of polycystic kidney disease
title_full Glucose absorption drives cystogenesis in a human organoid-on-chip model of polycystic kidney disease
title_fullStr Glucose absorption drives cystogenesis in a human organoid-on-chip model of polycystic kidney disease
title_full_unstemmed Glucose absorption drives cystogenesis in a human organoid-on-chip model of polycystic kidney disease
title_short Glucose absorption drives cystogenesis in a human organoid-on-chip model of polycystic kidney disease
title_sort glucose absorption drives cystogenesis in a human organoid-on-chip model of polycystic kidney disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9789147/
https://www.ncbi.nlm.nih.gov/pubmed/36564419
http://dx.doi.org/10.1038/s41467-022-35537-2
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