Activated cardiac fibroblasts control contraction of human fibrotic cardiac microtissues by a β-adrenoreceptor-dependent mechanism

Błyszczuk, P., Zuppinger, C., Costa, A., Nurzynska, D., Di Meglio, F., Stellato, M., Agarkova, I., Smith, G. , Distler, O. and Kania, G. (2020) Activated cardiac fibroblasts control contraction of human fibrotic cardiac microtissues by a β-adrenoreceptor-dependent mechanism. Cells, 9(5), 1270. (doi: 10.3390/cells9051270) (PMID:32443848) (PMCID:PMC7290967)

[img]
Preview
Text
221021.pdf - Published Version
Available under License Creative Commons Attribution.

5MB

Abstract

Cardiac fibrosis represents a serious clinical problem. Development of novel treatment strategies is currently restricted by the lack of the relevant experimental models in a human genetic context. In this study, we fabricated self-aggregating, scaffold-free, 3D cardiac microtissues using human inducible pluripotent stem cell (iPSC)-derived cardiomyocytes and human cardiac fibroblasts. Fibrotic condition was obtained by treatment of cardiac microtissues with profibrotic cytokine transforming growth factor β1 (TGF-β1), preactivation of foetal cardiac fibroblasts with TGF-β1, or by the use of cardiac fibroblasts obtained from heart failure patients. In our model, TGF-β1 effectively induced profibrotic changes in cardiac fibroblasts and in cardiac microtissues. Fibrotic phenotype of cardiac microtissues was inhibited by treatment with TGF-β-receptor type 1 inhibitor SD208 in a dose-dependent manner. We observed that fibrotic cardiac microtissues substantially increased the spontaneous beating rate by shortening the relaxation phase and showed a lower contraction amplitude. Instead, no changes in action potential profile were detected. Furthermore, we demonstrated that contraction of human cardiac microtissues could be modulated by direct electrical stimulation or treatment with the β-adrenergic receptor agonist isoproterenol. However, in the absence of exogenous agonists, the β-adrenoreceptor blocker nadolol decreased beating rate of fibrotic cardiac microtissues by prolonging relaxation time. Thus, our data suggest that in fibrosis, activated cardiac fibroblasts could promote cardiac contraction rate by a direct stimulation of β-adrenoreceptor signalling. In conclusion, a model of fibrotic cardiac microtissues can be used as a high-throughput model for drug testing and to study cellular and molecular mechanisms of cardiac fibrosis.

Item Type:Articles
Additional Information:Funding: This research was founded by the Swiss Heart Foundation and Vontobel Foundation.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Smith, Professor Godfrey
Creator Roles:
Smith, G.Formal analysis, Writing – review and editing
Authors: Błyszczuk, P., Zuppinger, C., Costa, A., Nurzynska, D., Di Meglio, F., Stellato, M., Agarkova, I., Smith, G., Distler, O., and Kania, G.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Cells
Publisher:MDPI
ISSN:2073-4409
ISSN (Online):2073-4409
Copyright Holders:Copyright © 2020 by the authors
First Published:First published in Cells 9(5):1270
Publisher Policy:Reproduced under a Creative Commons licence

University Staff: Request a correction | Enlighten Editors: Update this record