Mechanisms of myocardial inflammation and fibrogenesis and the role of autophagy in SSc

During the last years, there was a shift in systemic sclerosis (SSc)-related death causes, indicating inflammatory dilated cardiomyopathy (iDCM) as a major cause of death in these patients. Nevertheless, so far little is known about the etiology of iDCM and the mechanisms leading to heart dysfunction in SSc patients.

We are interested to study the role of inflammatory myeloid cell compartment in myocardial fibrogenesis and pathological remodelling. Therefore we aim to determine the origin of cardiac pathological myofibroblasts and their cellular sources in SSc. We are particularly focusing on the cell-to-cell interaction during the process of myocardial inflammation and fibrogenesis, and on the molecular mechanisms that drive this complicated signalling orchestra. 

For this purpose, we are able to use SSc patient blood samples to conduct initial in vitro studies on cell differentiation and cellular function. This knowledge is to be combined with research on Fra-2 transgenic mice, an SSc mouse model that best reflects the vascular and inflammatory phenotype of the disease. 

Sections of mouse heart with the phenotype of inflammatroy dilated cardiomyophathy.
Figures from two recent publications (Kania et al., 2009 Cir Res., Blyszczuk et al., 2013, Cardiov Res.)

Autophagy (initially viewed as a conserved bulk-degradation mechanism) has emerged as a central player in a multitude of immune functions which raises the possibility that autophagy is centrally involved in the pathogenesis of inflammatory-driven organ fibrosis.

We will analyse the TGF-β-dependent activation of canonical and non-canonical pathways in myofibroblasts progenitors on the one hand. On the other hand, the role of TGF-β, angiotensin II and Wnt signalling in the myofibroblast differentiation process will be delineated in vitro, and in vivo. We aim to determine the origin of cardiac pathological myofibroblasts and characterize their cellular sources in SSc Fra-2 transgenic mouse model and in endomyocardial biopsies (EMBs) from SSc patients.

Moreover, we assume that autophagy might be one or the crucial mechanisms during myocardial remodelling leading to cardiac fibrogenesis. Therefore, we will study the presence of autophagy in the heart of Fra-2 tg mice, and in the different myofibroblasts progenitors such as heart fibroblast, heart-inflammatory progenitors and bone marrow-derived progenitors cells after in vitro stimulation with different cytokines including TGF-β. Moreover, autophagy presence will be evaluated within the EMBs and blood-derived myofibroblast progenitors from SSc patients. Afterwards, we assume to find a crosstalk between autophagy and TGF-β/Wnt signalling.

Factors mediating myocardial fibrosis formation in inflammatory dilated cardiomyopathy.
Figures from recent review article (Kania et al., 2013 Swiss Med Wkly)