The Centre of Experimental Rheumatology specializes in the investigation of rheumatic and skeletal disorders, including systemic sclerosis (SSc). SSc is a paradigm fibrotic disease characterized by multi-organ fibrosis, including the skin. Currently, tools to investigate SSc pathogenesis include traditional two-dimensional (2D) cell culture and animal models, both of which are established at our institute. Both models can be useful in various scenarios but have significant limitations. 2D cell culture models incorporate the culture of cells on stiff, plastic surfaces. This environment differs greatly from the physiological milieu, leading to the unsuccessful recapitulation of cell-matrix interactions, cell-type specific interactions, and spatial organization of cells in the tissue. Several animal models are used to study SSc, but as a stand-alone, animal models are often inadequate to mimic complex diseases such as SSc due to species-specific alterations in immune and inflammatory response, as well as in extracellular matrix production and skin architecture.
University Hospital Zurich -> University of Düsseldorf
With this initiative, we aim to establish a humanized 3D (fibrosis) model using precision cut tissue-slices (PCTS). This model utilizes tissue explants, which retain the native 3D cellular and microvascular architecture, including the tissue-matrix configuration, along with various organ-specific functions, including metabolic activity and tissue homeostasis, as well as some immunological functions. PCTS have been used extensively as a model for specific organs, such as the heart, lungs, and liver, offering organ-specific insights across different species and pathologies. PCTS can be used for various applications, ranging from toxicity assessments to disease modelling.
Currently, our institute has established processing and experimental protocols involving PCTS for murine hearts, lungs, and kidneys. However, to further extend the physiological relevance of the model and minimize animal sacrifice, we intend to establish this model for human tissues. We will start by establishing the PCTS model for skin (PCSS) in healthy controls and SSc patients due to i) its biosampling ease, ii) availability via pre-existing agreements, and iii) relevance in SSc pathophysiology. For this project, we will use 4mm punch biopsies obtained from SSc patients fulfilling the ACR/EULAR 2013 classification of systemic sclerosis, and age- and sex-matched healthy controls. To establish drug-response signatures, we will use various treatments, both novel and those routinely used in clinical practice, and perform bulk RNA sequencing (and eventually single-cell RNA sequencing) to establish the molecular changes occurring due to the treatment conditions.
PCTS therefore provide a humanized platform to study the pro-fibrotic milieu in physiologically relevant conditions, in contrast to both 2D cell models and animal models.
Ms. Astrid Hofman
Department of Rheumatology
University Hospital Zurich