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Abstract Number: 1045

Myocardial Involvement in SSc: Key Role of Lin-gp38+ Stromal Cells in the Onset of Fibrosis and Defects of the Conduction System

Mara Stellato1, Michal Rudnik 2, Florian Renoux 3, Przemyslaw Blyszczuk 4, Elena Osto 5, Matthias Dewenter 6, Petra Seebeck 7, Elena Pachera 2, Oliver Distler 8 and Gabriela Kania 4, 1Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland, 2Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, Zurich, Zurich, Switzerland, 3Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, Zurich, 4Centre of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland, 5Institute of Clinical Chemistry, University Hospital Zurich, Switzerland, Zurich, Zurich, Switzerland, 6Department of Molecular Cardiology and Epigenetics, University Hospital, Heidelberg, Germany, Heidelberg, Germany, 7Zurich integrative Rodent Physiology, University of Zurich, Switzerland, Zurich, Switzerland, 8Dept. of Rheumatology, University Hospital Zürich, Zürich, Switzerland, Zürich, Switzerland

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: Cardiac fibrosis, Conduction system, Fra-2, Stromal cells and SSc

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Session Information

Date: Monday, November 11, 2019

Session Title: Systemic Sclerosis & Related Disorders – Basic Science Poster

Session Type: Poster Session (Monday)

Session Time: 9:00AM-11:00AM

Background/Purpose: Cardiac fibrosis is a known complication of SSc, associated with increased mortality. During fibrogenesis, fibroblasts differentiate into myofibroblasts and secrete excessive extracellular matrix proteins. Here, we aim to identify the role of a specific fibroblast subset in fibrogenesis and defects of the cardiac electrophysiology in the Fra2 transgenic (tg) mouse model.

Methods: Cardiac function of Fra2 tg and Rag2-/- Fra2 tg mice was assessed by echocardiography, ECG and radiotelemetry. Hearts were analysed by immunohistochemistry (IHC) and IF. The myocardial fibroblast subset represented by stromal (Ter119–CD45–CD31–, hereafter Lin–) gp38+ cells, was sorted and cultured. The phenotype was evaluated by qPCR, α-smooth muscle actin (αSMA) and stress fibre IF, secreted collagens and contraction assay. Proliferation and apoptosis were measured by BrdU incorporation and Caspase 3/7 activity.

Results: Fra2 tg mice displayed increased ejection fraction (p=0.02) and fractional shortening (p=0.02) with decreased left ventricle end-diameter and end-volume in systole (p=0.006, p=0.008) and in diastole (p=0.007, p=0.008) in echocardiography. ECG in conscious mice revealed lower heart rate (HR) (WT 741 ± 33 BPM, tg 644 ± 37 BPM, p< 0.0001) and prolonged QRS, ST and QTc parameters (p=0.001, p=0.01, p=0.01), which may predispose to arrhythmias. Continuous ECG measured by radiotelemetry showed the presence of atrioventricular (AV) blocks that correlated with phenotype severity score (R=0.9, p=0.02). Fibrosis might be responsible for these changes by separating myocardial bundles, causing improper conduction. Indeed, the myocardium of Fra2 tg mice uncovered mild inflammation and interstitial fibrosis with higher expression of collagen- (p=0.03, n=7) and periostin-expressing cells (p=0.001, n=7), increased number of αSMA+ myofibroblasts as well as Lin-gp38+ cells compared to WT mice (1.4% ± 1.4, n=15 and Fra-2 tg: 6% ± 4.5, n=14, p=0.001). Importantly, the majority of myocardial Fra-2 tg gp38+ cells co-expressed αSMA, collagen, ADAM12 and periostin, indicating a myofibroblast-like phenotype. Finally, gp38 expression correlated with collagen deposition (R=0.9, p< 0.0001) measured by Sirius Red staining. In vitro, sorted Lin-gp38+ cells isolated from Fra2 tg mice showed increased αSMA total protein and αSMA fibres that co-localized with stress fibres, resulting in a faster and stronger contraction capability of Fra2 tg cells (p< 0.0001, n=3). Proliferation of Fra2 tg cells was increased compared to WT cells (p=0.007, n=5), while apoptosis was unchanged (p=0.335, n=5). Rag2-/-Fra2 tg mice showed no myocardial fibrosis or Lin-gp38+ cell expansion. ECG parameters of Rag2-/-Fra2 tg mice did not differ from control mice, indicating that inflammation is necessary to acquire the Fra2-driven fibrotic phenotype and defects in the conduction system.

Conclusion: Fra2 overexpression and inflammation drive the differentiation of fibroblasts into myofibroblasts, leading to cardiac fibrosis and defects of the conduction system. This mechanism might be a therapeutic target for SSc patients with disorders of the cardiac conduction system.


Disclosure: M. Stellato, None; M. Rudnik, None; F. Renoux, None; P. Blyszczuk, None; E. Osto, None; M. Dewenter, None; P. Seebeck, None; E. Pachera, None; O. Distler, A. Menarini, 5, Abbvie, Acceleron, 5, Acceleron Pharma, 5, Actelion, 2, 5, 8, Actelion Pharmaceuticals, 2, 5, 8, 9, Amgen, 5, AnaMar, 2, 5, Bayer, 2, 5, 8, 9, Biogen Idec, 2, 5, Blade Therapeutics, 5, Boehringer Ingelheim, 2, 5, 8, 9, Catenion, 5, 9, ChemomAb, 2, 5, ChemomAB, 5, CSL Behring, 5, Ergonex, 5, espeRare Foundation, 2, 5, Genentech/Roche, 2, 5, GlaxoSmithKline, 5, GSK, 2, 5, Holds Patent mir-29 for the treatment of systemic sclerosis, 9, Inventiva, 2, 5, iQvia, 5, Italfarmaco, 2, 5, Italfarmco, 5, Lilly, 2, 5, med, 5, 8, medac, 5, Medac, 2, 5, MedImmune, 2, 5, Medscape, 5, 8, 9, Menarini, 8, Mepha, 8, Mitsubishi Tanabe, 2, 5, Mitsubishi Tanabe Pharma, 2, 5, MSD, 5, 8, Novartis, 2, 5, 8, 9, Patent, 9, Patent issued, 9, Pfizer, 2, 5, 8, Pharmacyclics, 2, 5, Roche, 5, 8, 9, Sanofi, 2, 5, Sinoxa, 2, 5, Target Bio Science, 5, Target BioScience, 5, UCB, 2, 5, 9, UCB in the area of potential treatments of scleroderma and its complications, 2, 5; G. Kania, Bayer, 2, Actelion, 8, Boehringer Ingelheim, 8.

To cite this abstract in AMA style:

Stellato M, Rudnik M, Renoux F, Blyszczuk P, Osto E, Dewenter M, Seebeck P, Pachera E, Distler O, Kania G. Myocardial Involvement in SSc: Key Role of Lin-gp38+ Stromal Cells in the Onset of Fibrosis and Defects of the Conduction System [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/myocardial-involvement-in-ssc-key-role-of-lin-gp38-stromal-cells-in-the-onset-of-fibrosis-and-defects-of-the-conduction-system/. Accessed January 27, 2023.
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