Working Paper Article Version 1 This version is not peer-reviewed

WNT/β-catenin Signaling Promotes TGF-β-mediated Activation of Human Cardiac Fibroblasts by Enhancing IL-11 Production

Version 1 : Received: 28 July 2021 / Approved: 29 July 2021 / Online: 29 July 2021 (13:15:00 CEST)

A peer-reviewed article of this Preprint also exists.

Działo, E.; Czepiel, M.; Tkacz, K.; Siedlar, M.; Kania, G.; Błyszczuk, P. WNT/β-Catenin Signaling Promotes TGF-β-Mediated Activation of Human Cardiac Fibroblasts by Enhancing IL-11 Production. Int. J. Mol. Sci. 2021, 22, 10072. Działo, E.; Czepiel, M.; Tkacz, K.; Siedlar, M.; Kania, G.; Błyszczuk, P. WNT/β-Catenin Signaling Promotes TGF-β-Mediated Activation of Human Cardiac Fibroblasts by Enhancing IL-11 Production. Int. J. Mol. Sci. 2021, 22, 10072.

Journal reference: Int. J. Mol. Sci. 2021, 22, 10072
DOI: 10.3390/ijms221810072

Abstract

Cardiac fibrosis is a pathological process associated with development of heart failure. TGF-β and WNT signaling have been implicated in pathogenesis of cardiac fibrosis, however little is known about molecular cross-talk between these two pathways. The aim of this study was to examine the effect of exogenous canonical WNT3a and non-canonical WNT5a in TGF-β-activated human cardiac fibroblasts. We found that WNT3a and TGF-β induced -catenin-dependent response, whereas WNT5a prompted AP-1 activity. TGF-β triggered profibrotic signature in cardiac fibroblasts, and co-stimulation with WNT3a or co-activation of the β-catenin pathway with GSK3β inhibitor CHIR99021 enhanced collagen I and fibronectin production and development of active contractile stress fibers. In the absence of TGF-β, neither WNT3a nor CHIR99021 exerted profibrotic response. On a molecular level, in TGF-β-activated fibroblasts WNT3a enhanced phosphorylation of TAK1 and production and secretion of IL-11 but showed no effect on Smad pathway. Neutralization of IL-11 activity with the blocking anti-IL-11 antibody effectively reduced profibrotic response of cardiac fibroblasts activated with TGF-β and WNT3a. In contrast to canonical WNT3a, co-activation with non-canonical WNT5a suppressed TGF-β-induced production of collagen I. In conclusion, WNT/β-catenin signaling promotes TGF-β-mediated fibroblast-to-myofibroblast transition by enhancing IL-11 production. Thus, the uncovered mechanism broadens our knowledge on molecular basis of cardiac fibrogenesis and defines novel therapeutic targets for fibrotic heart diseases.

Keywords

cardiac fibroblasts; WNT3a; WNT5a; beta-catenin; TGF-beta signalling; IL-11; cardiac fibrosis

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