Fibroblast pathology in inflammatory diseases
Kevin Wei, Hung N. Nguyen, Michael B. Brenner
Kevin Wei, Hung N. Nguyen, Michael B. Brenner
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Review

Fibroblast pathology in inflammatory diseases

Abstract

Fibroblasts are important cells for the support of homeostatic tissue function. In inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease, fibroblasts take on different roles (a) as inflammatory cells themselves and (b) in recruiting leukocytes, driving angiogenesis, and enabling chronic inflammation in tissues. Recent advances in single-cell profiling techniques have transformed the ability to examine fibroblast states and populations in inflamed tissues, providing evidence of previously underappreciated heterogeneity and disease-associated fibroblast populations. These studies challenge the preconceived notion that fibroblasts are homogeneous and provide new insights into the role of fibroblasts in inflammatory pathology. In addition, new molecular insights into the mechanisms of fibroblast activation reveal powerful cell-intrinsic amplification loops that synergize with primary fibroblast stimuli to result in striking responses. In this Review, we focus on recent developments in our understanding of fibroblast heterogeneity and fibroblast pathology across tissues and diseases in rheumatoid arthritis and inflammatory bowel diseases. We highlight new approaches to, and applications of, single-cell profiling techniques and what they teach us about fibroblast biology. Finally, we address how these insights could lead to the development of novel therapeutic approaches to targeting fibroblasts in disease.

Authors

Kevin Wei, Hung N. Nguyen, Michael B. Brenner

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Figure 1

Approaches to examining fibroblast heterogeneity.

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Approaches to examining fibroblast heterogeneity. Schematics for studies...
Schematics for studies using cytometry (left), transcriptomic (middle), and imaging (right) techniques, illustrating fibroblast heterogeneity in patient-derived tissues. Left: cytometric analysis of fibroblasts starts with staining of cells from dissociated tissues, followed by antibody staining against surface proteins expressed by fibroblasts. Whereas traditional flow cytometry discerns fibroblasts based on several surface markers — typically three to seven surface protein markers — mass cytometry studies can leverage 30 to 50 surface protein markers. In both approaches, putative fibroblast subsets can be nominated by differential expression of surface markers. Middle: transcriptomic analysis. Bulk transcriptomic analysis by microarray or RNA-Seq measures RNA from whole tissue, but does not discern cellular sources of gene expression. Purification of fibroblast or fibroblast subsets from the tissue by FACS or other cell-purification techniques followed by RNA-Seq enables deep expression profiling of selected fibroblast subsets. Single-cell RNA-Seq obviates the need to identify tissue fibroblasts by specific markers through gene expression profiling across diverse cell populations. Fibroblast subsets and states are determined through unbiased analysis of differentially expressed genes at a single-cell level. Imaging analysis: traditional imaging techniques, such as immunohistochemistry and RNA in situ hybridization, when applied to tissues, are limited to examining a few proteins or genes of interest. Spatial transcriptomic techniques capture gene expression profiles from intact tissue sections, enabling simultaneous gene expression profiling in the context of tissue architecture.