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Virtual-tissue computer simulations define the roles of cell adhesion and proliferation in the onset of kidney cystic disease
In autosomal dominant polycystic kidney disease (ADPKD), cysts accumulate and progressively impair renal function. Mutations in PKD1 and PKD2 genes are causally linked to ADPKD, but how these mutations drive cell behaviors that underlie ADPKD pathogenesis is unknown. Human ADPKD cysts frequently exp...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5221598/ https://www.ncbi.nlm.nih.gov/pubmed/27193300 http://dx.doi.org/10.1091/mbc.E16-01-0059 |
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author | Belmonte, Julio M. Clendenon, Sherry G. Oliveira, Guilherme M. Swat, Maciej H. Greene, Evan V. Jeyaraman, Srividhya Glazier, James A. Bacallao, Robert L. |
author_facet | Belmonte, Julio M. Clendenon, Sherry G. Oliveira, Guilherme M. Swat, Maciej H. Greene, Evan V. Jeyaraman, Srividhya Glazier, James A. Bacallao, Robert L. |
author_sort | Belmonte, Julio M. |
collection | PubMed |
description | In autosomal dominant polycystic kidney disease (ADPKD), cysts accumulate and progressively impair renal function. Mutations in PKD1 and PKD2 genes are causally linked to ADPKD, but how these mutations drive cell behaviors that underlie ADPKD pathogenesis is unknown. Human ADPKD cysts frequently express cadherin-8 (cad8), and expression of cad8 ectopically in vitro suffices to initiate cystogenesis. To explore cell behavioral mechanisms of cad8-driven cyst initiation, we developed a virtual-tissue computer model. Our simulations predicted that either reduced cell–cell adhesion or reduced contact inhibition of proliferation triggers cyst induction. To reproduce the full range of cyst morphologies observed in vivo, changes in both cell adhesion and proliferation are required. However, only loss-of-adhesion simulations produced morphologies matching in vitro cad8-induced cysts. Conversely, the saccular cysts described by others arise predominantly by decreased contact inhibition, that is, increased proliferation. In vitro experiments confirmed that cell–cell adhesion was reduced and proliferation was increased by ectopic cad8 expression. We conclude that adhesion loss due to cadherin type switching in ADPKD suffices to drive cystogenesis. Thus, control of cadherin type switching provides a new target for therapeutic intervention. |
format | Online Article Text |
id | pubmed-5221598 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-52215982017-01-22 Virtual-tissue computer simulations define the roles of cell adhesion and proliferation in the onset of kidney cystic disease Belmonte, Julio M. Clendenon, Sherry G. Oliveira, Guilherme M. Swat, Maciej H. Greene, Evan V. Jeyaraman, Srividhya Glazier, James A. Bacallao, Robert L. Mol Biol Cell Articles In autosomal dominant polycystic kidney disease (ADPKD), cysts accumulate and progressively impair renal function. Mutations in PKD1 and PKD2 genes are causally linked to ADPKD, but how these mutations drive cell behaviors that underlie ADPKD pathogenesis is unknown. Human ADPKD cysts frequently express cadherin-8 (cad8), and expression of cad8 ectopically in vitro suffices to initiate cystogenesis. To explore cell behavioral mechanisms of cad8-driven cyst initiation, we developed a virtual-tissue computer model. Our simulations predicted that either reduced cell–cell adhesion or reduced contact inhibition of proliferation triggers cyst induction. To reproduce the full range of cyst morphologies observed in vivo, changes in both cell adhesion and proliferation are required. However, only loss-of-adhesion simulations produced morphologies matching in vitro cad8-induced cysts. Conversely, the saccular cysts described by others arise predominantly by decreased contact inhibition, that is, increased proliferation. In vitro experiments confirmed that cell–cell adhesion was reduced and proliferation was increased by ectopic cad8 expression. We conclude that adhesion loss due to cadherin type switching in ADPKD suffices to drive cystogenesis. Thus, control of cadherin type switching provides a new target for therapeutic intervention. The American Society for Cell Biology 2016-11-07 /pmc/articles/PMC5221598/ /pubmed/27193300 http://dx.doi.org/10.1091/mbc.E16-01-0059 Text en © 2016 Belmonte, Clendenon, Oliveira, et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology. |
spellingShingle | Articles Belmonte, Julio M. Clendenon, Sherry G. Oliveira, Guilherme M. Swat, Maciej H. Greene, Evan V. Jeyaraman, Srividhya Glazier, James A. Bacallao, Robert L. Virtual-tissue computer simulations define the roles of cell adhesion and proliferation in the onset of kidney cystic disease |
title | Virtual-tissue computer simulations define the roles of cell adhesion and proliferation in the onset of kidney cystic disease |
title_full | Virtual-tissue computer simulations define the roles of cell adhesion and proliferation in the onset of kidney cystic disease |
title_fullStr | Virtual-tissue computer simulations define the roles of cell adhesion and proliferation in the onset of kidney cystic disease |
title_full_unstemmed | Virtual-tissue computer simulations define the roles of cell adhesion and proliferation in the onset of kidney cystic disease |
title_short | Virtual-tissue computer simulations define the roles of cell adhesion and proliferation in the onset of kidney cystic disease |
title_sort | virtual-tissue computer simulations define the roles of cell adhesion and proliferation in the onset of kidney cystic disease |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5221598/ https://www.ncbi.nlm.nih.gov/pubmed/27193300 http://dx.doi.org/10.1091/mbc.E16-01-0059 |
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