Research Group Gabriela Kania

Cardiac fibrosis is marked by excessive extracellular matrix (ECM) protein deposition in the myocardial interstitium, serving as a common endpoint for numerous heart diseases and a precursor to heart failure. It is particularly prevalent in autoimmune conditions like systemic sclerosis (SSc), where it severely worsens clinical outcomes. Pro-fibrotic factors, such as transforming growth factor-β, activate cardiac fibroblasts, driving their proliferation, differentiation, and increased ECM production. Recent transcriptomic studies have revealed the heterogeneity of cardiac fibroblast populations at single-cell resolution, while proteomic analyses have provided a closer understanding of their functional phenotypes. Integrating various omics technologies with advanced in vitro and in vivo models will deepen our understanding of the molecular mechanisms underlying cardiac fibrosis, paving the way for the identification of diagnostic markers and the development of targeted antifibrotic therapies.

Funding: Swiss National Science Foundation, Novartis Stiftung, Olga Mayenfisch Stiftung, Swiss Life Jubiläumsstiftung, Gebauer Stiftung, Vontobel Stiftung.

Pulmonary Arterial Hypertension (PAH) is a frequent complication of systemic sclerosis (SSc) and can progress to right ventricular (RV) dysfunction, ultimately leading to heart failure with a poor prognosis. Historically, the RV has been underappreciated, with cardiology research focusing predominantly on the left ventricle (LV), as the RV’s role in overall cardiac hemodynamics was not well understood. As a result, the RV was often referred to as the „forgotten chamber,“ perceived as merely a passive conduit for blood flow into the pulmonary circulation. However, advancements in cardiac imaging have provided clinicians with tools to better evaluate the RV, increasing recognition of the need for biventricular assessment, particularly in conditions like inflammatory dilated cardiomyopathy (DCM). RV involvement is common in DCM, and RV dysfunction has emerged as a significant negative prognostic factor in heart failure. Despite this progress, the study of the RV remains a relatively young field, necessitating deeper investigation into its pathophysiology, epidemiology, and the mechanisms driving RV dysfunction.

Funding: Swiss National Science Foundation, Novartis Stiftung, Olga Mayenfisch Stiftung, Swiss Life Jubiläumsstiftung.

Aging and chronic inflammation are deeply interconnected biological processes that play a critical role in the onset and progression of various diseases, including rheumatic autoimmune disorders like systemic sclerosis and rheumatoid arthritis. These conditions, which predominantly manifest between the ages of 40 and 60, are strongly influenced by the inflammatory environment that becomes more prevalent with age. Persistent, low-grade inflammation, termed “inflamm-aging,” has been recognized as a hallmark of aging and is closely associated with the decline in overall health during this stage of life. Our research focuses on unraveling the mechanisms underlying chronic inflammatory processes to mitigate disease-related aging, with a particular emphasis on rheumatic autoimmune diseases. By exploring the molecular changes that occur at key aging milestones, we aim to identify novel therapeutic targets to manage or prevent the chronic inflammation that drives these conditions, and to understand why these diseases also affect younger individuals and whether accelerated aging processes are contributing factors.

Despite extensive research and clinical trials, precise diagnostic tools and effective treatments for systemic rheumatic autoimmune inflammatory diseases (RAIDs) remain elusive. Fcγ receptors (FcγRs), which mediate opsonic phagocytosis, require tight regulation to prevent uncontrolled activation and pro-inflammatory responses. Increased FcγR expression may serve as a biomarker to identify pro-phagocytic macrophages in RAID patients. These macrophages appear capable of triggering inflammatory cascades, with their uncontrolled activation contributing to unresolved inflammation and eventual fibrosis. Our ultimate objective is to establish a comprehensive biomarker panel for early detection of pathogenic changes in RAID patients, enabling the targeted modulation of disease-driving receptors and mediators to prevent severe organ complications.

Funding: Iten-Kohaut Foundation

Living myocardial slices (LMS) are an advanced ex vivo model that preserves the native three-dimensional architecture of myocardial tissue, including its intricate cellular composition and extracellular matrix organization. Unlike traditional in vitro systems, LMS maintains the physiological alignment of cardiomyocytes, fibroblasts, endothelial cells, and other resident cell types, reflecting the structural and functional complexity of the heart. This fidelity makes LMS a powerful platform for studying cardiac function and pathophysiology under conditions that closely mimic the native myocardium.

One of the key advantages of LMS is its ability to support longitudinal investigations. These slices retain viability and functionality over extended periods when cultured under appropriate conditions, allowing to study dynamic processes such as cellular responses to stress, remodeling, and drug treatments. Moreover, LMS enables the simultaneous assessment of contractile function, electrophysiological properties, and molecular signaling pathways, providing a comprehensive understanding of cardiac behavior at multiple levels.

This model is particularly valuable for investigating disease mechanisms, such as cardiac fibrosis, hypertrophy, and arrhythmogenesis, as well as for evaluating therapeutic interventions.

Funding: Swiss Life Jubiläumsstiftung, main applicant.

The mechanisms driving fatal cardiac remodeling remain poorly understood, yet uncovering these processes is crucial for identifying potential therapeutic targets. Advanced 3D in vitro models, which mimic cell-to-cell interactions in the heart, provide a powerful platform for investigating cardiac physiology and pathology.

Conduction system abnormalities are a significant clinical challenge in fibrotic cardiac conditions. However, tools to study the cellular and molecular mechanisms of fibrosis-driven heart failure in humans are limited. Our microtissue models, composed of adult patient primary cardiac cells or induced pluripotent stem cells, replicate the conduction and contraction abnormalities seen in patients. These models offer high-throughput capabilities, reproducibility, pathophysiological relevance, and the ability to examine single-patient cardiac fibroblasts within their native cellular context.

The anticipated results aim to close critical knowledge gaps, shedding light on specific interactions between fibroblasts, cardiomyocytes, endothelial cells, and macrophages during cardiac remodeling. We seek to uncover how healthy versus diseased cardiac cells influence cell-to-cell interactions in failing hearts and identify key factors driving fatal modifications in conduction system function.

Funding: Swiss Heart Foundation, Gebauer Foundation, Vontobel Foundation, Stiftung für wissenschaftliche Forschung an der Universität Zürich.

Cardiovascular and liver diseases are intricately connected, sharing common risk factors and overlapping pathophysiological mechanisms. The liver plays a pivotal role in drug metabolism, and its dysfunction can exacerbate cardiotoxic effects, highlighting the need to explore the dynamic interplay between these organs. Despite the clinical prevalence of heart-liver axis disorders, the underlying mechanisms remain poorly understood. A deeper exploration of this relationship could enhance therapeutic strategies, minimize adverse side effects, and improve patient outcomes.

To address this gap, we employ an innovative multi-organ-on-a-chip (MOoC) model to simulate the physiological and pathological interactions between the organs under controlled conditions. This advanced platform enables the detailed investigation of how liver-derived factors influence cardiac tissue responses, including fibrosis, remodeling, and functional changes. The model also facilitates the study of bidirectional crosstalk, uncovering how cardiac dysfunction might impact hepatic health. Ultimately, this work underscores the potential of MOoC models to advance precision medicine by enabling the development of targeted therapies that address multi-organ complications. By leveraging this platform, we aim to contribute to improved treatment strategies for cardiovascular diseases, particularly those influenced by hepatic dysfunction, and to promote the broader application of organ-on-a-chip systems in biomedical research.

Funding: Gebauer Stiftung, HUMAIN award, Swiss Heart Foundation, Vontobel Stiftung