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Open AccessArticle

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

1
Department of Clinical Immunology, Jagiellonian University Medical College, 30-663 Cracow, Poland
2
Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, 8952 Schlieren, Switzerland
3
Department of Chemical and Cell Biology, Leiden University Medical Center, Leiden University, 2300 Leiden, The Netherlands
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(6), 1436; https://doi.org/10.3390/ijms20061436
Received: 4 March 2019 / Revised: 18 March 2019 / Accepted: 19 March 2019 / Published: 21 March 2019
(This article belongs to the Special Issue Focus on Exosome-Based Cell-Cell Communication in Health and Disease)
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Abstract

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. View Full-Text
Keywords: exosomes; WNT3a; WNT5a; cardiac fibroblasts; canonical WNT; non-canonical WNT; cardiovascular diseases exosomes; WNT3a; WNT5a; cardiac fibroblasts; canonical WNT; non-canonical WNT; cardiovascular diseases
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Działo, E.; Rudnik, M.; Koning, R.I.; Czepiel, M.; Tkacz, K.; Baj-Krzyworzeka, M.; Distler, O.; Siedlar, M.; Kania, G.; Błyszczuk, P. WNT3a and WNT5a Transported by Exosomes Activate WNT Signaling Pathways in Human Cardiac Fibroblasts. Int. J. Mol. Sci. 2019, 20, 1436.

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