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Fibroblast mechanotransduction network predicts targets for mechano-adaptive infarct therapies

Regional control of fibrosis after myocardial infarction is critical for maintaining structural integrity in the infarct while preventing collagen accumulation in non-infarcted areas. Cardiac fibroblasts modulate matrix turnover in response to biochemical and biomechanical cues, but the complex inte...

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Detalles Bibliográficos
Autores principales: Rogers, Jesse D, Richardson, William J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8849334/
https://www.ncbi.nlm.nih.gov/pubmed/35138248
http://dx.doi.org/10.7554/eLife.62856
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author Rogers, Jesse D
Richardson, William J
author_facet Rogers, Jesse D
Richardson, William J
author_sort Rogers, Jesse D
collection PubMed
description Regional control of fibrosis after myocardial infarction is critical for maintaining structural integrity in the infarct while preventing collagen accumulation in non-infarcted areas. Cardiac fibroblasts modulate matrix turnover in response to biochemical and biomechanical cues, but the complex interactions between signaling pathways confound efforts to develop therapies for regional scar formation. We employed a logic-based ordinary differential equation model of fibroblast mechano-chemo signal transduction to predict matrix protein expression in response to canonical biochemical stimuli and mechanical tension. Functional analysis of mechano-chemo interactions showed extensive pathway crosstalk with tension amplifying, dampening, or reversing responses to biochemical stimuli. Comprehensive drug target screens identified 13 mechano-adaptive therapies that promote matrix accumulation in regions where it is needed and reduce matrix levels in regions where it is not needed. Our predictions suggest that mechano-chemo interactions likely mediate cell behavior across many tissues and demonstrate the utility of multi-pathway signaling networks in discovering therapies for context-specific disease states.
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spelling pubmed-88493342022-02-17 Fibroblast mechanotransduction network predicts targets for mechano-adaptive infarct therapies Rogers, Jesse D Richardson, William J eLife Computational and Systems Biology Regional control of fibrosis after myocardial infarction is critical for maintaining structural integrity in the infarct while preventing collagen accumulation in non-infarcted areas. Cardiac fibroblasts modulate matrix turnover in response to biochemical and biomechanical cues, but the complex interactions between signaling pathways confound efforts to develop therapies for regional scar formation. We employed a logic-based ordinary differential equation model of fibroblast mechano-chemo signal transduction to predict matrix protein expression in response to canonical biochemical stimuli and mechanical tension. Functional analysis of mechano-chemo interactions showed extensive pathway crosstalk with tension amplifying, dampening, or reversing responses to biochemical stimuli. Comprehensive drug target screens identified 13 mechano-adaptive therapies that promote matrix accumulation in regions where it is needed and reduce matrix levels in regions where it is not needed. Our predictions suggest that mechano-chemo interactions likely mediate cell behavior across many tissues and demonstrate the utility of multi-pathway signaling networks in discovering therapies for context-specific disease states. eLife Sciences Publications, Ltd 2022-02-09 /pmc/articles/PMC8849334/ /pubmed/35138248 http://dx.doi.org/10.7554/eLife.62856 Text en © 2022, Rogers and Richardson https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Computational and Systems Biology
Rogers, Jesse D
Richardson, William J
Fibroblast mechanotransduction network predicts targets for mechano-adaptive infarct therapies
title Fibroblast mechanotransduction network predicts targets for mechano-adaptive infarct therapies
title_full Fibroblast mechanotransduction network predicts targets for mechano-adaptive infarct therapies
title_fullStr Fibroblast mechanotransduction network predicts targets for mechano-adaptive infarct therapies
title_full_unstemmed Fibroblast mechanotransduction network predicts targets for mechano-adaptive infarct therapies
title_short Fibroblast mechanotransduction network predicts targets for mechano-adaptive infarct therapies
title_sort fibroblast mechanotransduction network predicts targets for mechano-adaptive infarct therapies
topic Computational and Systems Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8849334/
https://www.ncbi.nlm.nih.gov/pubmed/35138248
http://dx.doi.org/10.7554/eLife.62856
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