Interstitial Lung Disease in Patients With Systemic Sclerosis: Toward Personalized-Medicine-Based Prediction and Drug Screening Models of Systemic Sclerosis-Related Interstitial Lung Disease (SSc-ILD)

Abstract

Systemic sclerosis (SSc) is an autoimmune connective tissue disease, characterized by immune dysregulation and progressive fibrosis. Interstitial lung disease (ILD) is the most common cause of death among SSc patients and there are currently very limited approved disease-modifying treatment options for systemic sclerosis-related interstitial lung disease (SSc-ILD). The mechanisms underlying pulmonary fibrosis in SSc-ILD are not completely unraveled, and knowledge on fibrotic processes has been acquired mostly from studies in idiopathic pulmonary fibrosis (IPF). The incomplete knowledge of SSc-ILD pathogenesis partly explains the limited options for disease-modifying therapy for SSc-ILD. Fibrosis in IPF appears to be related to aberrant repair following injury, but whether this also holds for SSc-ILD is less evident. Furthermore, immune dysregulation appears to contribute to pro-fibrotic responses in SSc-ILD, perhaps more than in IPF. In addition, SSc-ILD patient heterogeneity complicates the understanding of the underlying mechanisms of disease development, and more importantly, limits correct clinical diagnosis and treatment effectivity. Therefore, there is an unmet need for patient-relevant (in vitro) models to examine patient-specific disease pathogenesis, predict disease progression, screen appropriate treatment regimens and identify new targets for treatment. Technological advances in in vitro patient-relevant disease modeling, including (human induced pluripotent stem cell (hiPSC)-derived) lung epithelial cells, organoids and organ-on-chip technology offer a platform that has the potential to contribute to unravel the underlying mechanisms of SSc-ILD development. Combining these models with state-of-the-art analysis platforms, including (single cell) RNA sequencing and (imaging) mass cytometry, may help to delineate pathogenic mechanisms and define new treatment targets of SSc-ILD.

Keywords: human disease models; idiopathic pulmonary fibrosis; interstitial lung disease; organoids; pathogenesis; systemic sclerosis.

FIGURE 1

Toward personalized-medicine-based prediction, target identification and drug screening models of SSc-ILD. In SSc-ILD, the interactions and cross-talk between various cell types, including in type 2 alveolar cells (AEC2), AEC1, endothelial cells, fibroblasts and immune cells is disturbed. This may be partly explained by excessive TGF-β signaling activation, leading to AEC1/2 and endothelial cell (EC) transition into a mesenchymal phenotype, (myo)fibroblast activation and proliferation and excessive interstitial extracellular matrix (ECM) deposition. Recruited leukocytes further contribute to the profibrotic environment, leading to lung tissue remodeling and fibrosis. Patient-derived pulmonary cells, either isolated from lung tissue or derived from human induced pluripotent stem cells (hiPSC), can be used to study patient-specific responses in vitro using organoid SSc-ILD disease models. Lung-chip models may add another layer of complexity containing physiological ques, including breathing motions, air-blood flow and stretch, which are often lacking in current available in vitro lung models. Disease-specific features can be measured using cutting-edge techniques such as single-cell-RNA-sequencing and (imaging) mass cytometry. Integrating information derived from SSc-ILD disease models using cells derived from SSc-ILD patients and triggers implicated in disease pathogenesis may lead to novel mechanistic insight and offer a platform for identification of pathogenic processes and drug screening for SSc-ILD.

FIGURE 2

Recent advances in human lung organoid models may help to unravel pathogenic mechanisms and new treatment targets of SSc-ILD. Patient-derived pulmonary cells, either isolated from lung tissue or derived from human induced pluripotent stem cells (hiPSC), can be expanded in vitro using 3D organoid culture models. In these models, a variety of (disease-)relevant characteristics including progenitor cell function, profibrotic features, interactions with other cells (endothelial cells, fibroblasts etc.) and inflammatory cell recruitment can be studied. In addition, in such models the contribution of genetic factors to SSc-ILD can be studied using either patient-derived cells with specific genetic features, or by genetic editing of primary AEC (2) or hiPSC-derived AEC. These 3D lung organoid cultures can be applied to study various aspects of SSc-ILD pathogenic mechanisms and may therefore provide patient-relevant models which may contribute to biomarker and target discovery and aid in personalized drug screening for SSc-ILD.