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WNT3a and WNT5a Transported by Exosomes Activate WNT Signaling Pathways in Human Cardiac Fibroblasts

WNT signaling plays an important role in fibrotic processes in the heart. Recently, exosomes have been proposed as novel extracellular transporters for WNT proteins. In this study, we analyzed whether WNT3a and WNT5a carried by exosomes could activate downstream molecular pathways in human cardiac f...

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Autores principales: Działo, Edyta, Rudnik, Michał, Koning, Roman I., Czepiel, Marcin, Tkacz, Karolina, Baj-Krzyworzeka, Monika, Distler, Oliver, Siedlar, Maciej, Kania, Gabriela, Błyszczuk, Przemysław
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6472055/
https://www.ncbi.nlm.nih.gov/pubmed/30901906
http://dx.doi.org/10.3390/ijms20061436
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author Działo, Edyta
Rudnik, Michał
Koning, Roman I.
Czepiel, Marcin
Tkacz, Karolina
Baj-Krzyworzeka, Monika
Distler, Oliver
Siedlar, Maciej
Kania, Gabriela
Błyszczuk, Przemysław
author_facet Działo, Edyta
Rudnik, Michał
Koning, Roman I.
Czepiel, Marcin
Tkacz, Karolina
Baj-Krzyworzeka, Monika
Distler, Oliver
Siedlar, Maciej
Kania, Gabriela
Błyszczuk, Przemysław
author_sort Działo, Edyta
collection PubMed
description WNT signaling plays an important role in fibrotic processes in the heart. Recently, exosomes have been proposed as novel extracellular transporters for WNT proteins. In this study, we analyzed whether WNT3a and WNT5a carried by exosomes could activate downstream molecular pathways in human cardiac fibroblasts. Exosomes were isolated from conditioned medium of control, WNT3a- and WNT5a-producing L cells by differential ultracentrifugations. Obtained exosomes showed size ranging between 20–150 nm and expressed exosomal markers ALG-2-interacting protein X (ALIX) and CD63. Treatment with WNT3a-rich exosomes inhibited activity of glycogen synthase kinase 3β (GSK3β), induced nuclear translocation of β-catenin, and activated T-cell factor (TCF)/lymphoid enhancer factor (LEF) transcription factors as well as expression of WNT/β-catenin responsive genes in cardiac fibroblasts, but did not coactivate extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and activator protein 1 (AP-1) signaling pathways. In contrast, exosomes produced by WNT5a-producing L cells failed to activate β-catenin-dependent response, but successfully triggered phosphorylation of ERK1/2 and JNK and stimulated IL-6 production. In conclusion, exosomes containing WNT proteins can functionally contribute to cardiac fibrosis by activating profibrotic WNT pathways on cardiac fibroblasts and may represent a novel mechanism of spreading profibrotic signals in the heart.
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spelling pubmed-64720552019-04-26 WNT3a and WNT5a Transported by Exosomes Activate WNT Signaling Pathways in Human Cardiac Fibroblasts Działo, Edyta Rudnik, Michał Koning, Roman I. Czepiel, Marcin Tkacz, Karolina Baj-Krzyworzeka, Monika Distler, Oliver Siedlar, Maciej Kania, Gabriela Błyszczuk, Przemysław Int J Mol Sci Article WNT signaling plays an important role in fibrotic processes in the heart. Recently, exosomes have been proposed as novel extracellular transporters for WNT proteins. In this study, we analyzed whether WNT3a and WNT5a carried by exosomes could activate downstream molecular pathways in human cardiac fibroblasts. Exosomes were isolated from conditioned medium of control, WNT3a- and WNT5a-producing L cells by differential ultracentrifugations. Obtained exosomes showed size ranging between 20–150 nm and expressed exosomal markers ALG-2-interacting protein X (ALIX) and CD63. Treatment with WNT3a-rich exosomes inhibited activity of glycogen synthase kinase 3β (GSK3β), induced nuclear translocation of β-catenin, and activated T-cell factor (TCF)/lymphoid enhancer factor (LEF) transcription factors as well as expression of WNT/β-catenin responsive genes in cardiac fibroblasts, but did not coactivate extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and activator protein 1 (AP-1) signaling pathways. In contrast, exosomes produced by WNT5a-producing L cells failed to activate β-catenin-dependent response, but successfully triggered phosphorylation of ERK1/2 and JNK and stimulated IL-6 production. In conclusion, exosomes containing WNT proteins can functionally contribute to cardiac fibrosis by activating profibrotic WNT pathways on cardiac fibroblasts and may represent a novel mechanism of spreading profibrotic signals in the heart. MDPI 2019-03-21 /pmc/articles/PMC6472055/ /pubmed/30901906 http://dx.doi.org/10.3390/ijms20061436 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Działo, Edyta
Rudnik, Michał
Koning, Roman I.
Czepiel, Marcin
Tkacz, Karolina
Baj-Krzyworzeka, Monika
Distler, Oliver
Siedlar, Maciej
Kania, Gabriela
Błyszczuk, Przemysław
WNT3a and WNT5a Transported by Exosomes Activate WNT Signaling Pathways in Human Cardiac Fibroblasts
title WNT3a and WNT5a Transported by Exosomes Activate WNT Signaling Pathways in Human Cardiac Fibroblasts
title_full WNT3a and WNT5a Transported by Exosomes Activate WNT Signaling Pathways in Human Cardiac Fibroblasts
title_fullStr WNT3a and WNT5a Transported by Exosomes Activate WNT Signaling Pathways in Human Cardiac Fibroblasts
title_full_unstemmed WNT3a and WNT5a Transported by Exosomes Activate WNT Signaling Pathways in Human Cardiac Fibroblasts
title_short WNT3a and WNT5a Transported by Exosomes Activate WNT Signaling Pathways in Human Cardiac Fibroblasts
title_sort wnt3a and wnt5a transported by exosomes activate wnt signaling pathways in human cardiac fibroblasts
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6472055/
https://www.ncbi.nlm.nih.gov/pubmed/30901906
http://dx.doi.org/10.3390/ijms20061436
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