Cross-tissue, single-cell stromal atlas identifies shared pathological fibroblast phenotypes in four chronic inflammatory diseases

Korsunsky, Ilya; Wei, Kevin; Pohin, Mathilde; Kim, Edy Y.; Barone, Francesca; Major, Triin; Taylor, Emily; Ravindran, Rahul; Kemble, Samuel; Watts, Gerald F. M.; Jonsson, Helena; Jeong, Yunju; Athar, Humra; Windell, Dylan; Kang, Je-Won; Friedrich, Matthias; Turner, Jason D.; Nayar, Saba; Fisher, Benjamin A; Raza, Karim; Marshall, Jennifer L.; Croft, Adam P.; Tamura, Tomoyoshi; Sholl, Lynette M.; Vivero, Marina; Rosas, Iván O.; Bowman, Simon; Coles, Mark; Frei, Andreas P.; Filer, Andrew; Powrie, Fiona; Buckley, Christopher D.; Brenner, Michael B.; Raychaudhuri, Soumya

doi:10.1016/j.medj.2022.05.002

Cited by 96 publications

(102 citation statements)

References 93 publications

(132 reference statements)

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“…In the present study, we demonstrated for the first time that LPS has a regulatory effect on the relative XYLT1 mRNA expression of NHDF that is independent of the cell culture density and type of FCS used. The XYLT1 mRNA expression decrease observed in both low- and high-cell-density-culture models is consistent with previous cross-tissue examinations of fibroblasts that highlighted shared fibroblast phenotypes across a spectrum of inflammatory and fibrotic diseases [ 50 , 51 ]. The activated NF-kB in fibroblasts stimulated with LPS was shown to induce Smad7 gene expression [ 27 ].…”

Section: Discussionsupporting

confidence: 89%

The Impact of Inflammatory Stimuli on Xylosyltransferase-I Regulation in Primary Human Dermal Fibroblasts

Lindenkamp

Kara

et al. 2022

Biomedicines

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Inflammation plays a vital role in regulating fibrotic processes. Beside their classical role in extracellular matrix synthesis and remodeling, fibroblasts act as immune sentinel cells participating in regulating immune responses. The human xylosyltransferase-I (XT-I) catalyzes the initial step in proteoglycan biosynthesis and was shown to be upregulated in normal human dermal fibroblasts (NHDF) under fibrotic conditions. Regarding inflammation, the regulation of XT-I remains elusive. This study aims to investigate the effect of lipopolysaccharide (LPS), a prototypical pathogen-associated molecular pattern, and the damage-associated molecular pattern adenosine triphosphate (ATP) on the expression of XYLT1 and XT‑I activity of NHDF. We used an in vitro cell culture model and mimicked the inflammatory tissue environment by exogenous LPS and ATP supplementation. Combining gene expression analyses, enzyme activity assays, and targeted gene silencing, we found a hitherto unknown mechanism involving the inflammasome pathway components cathepsin B (CTSB) and caspase-1 in XT-I regulation. The suppressive role of CTSB on the expression of XYLT1 was further validated by the quantification of CTSB expression in fibroblasts from patients with the inflammation-associated disease Pseudoxanthoma elasticum. Altogether, this study further improves the mechanistic understanding of inflammatory XT-I regulation and provides evidence for fibroblast-targeted therapies in inflammatory diseases.

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Section: Discussionsupporting

confidence: 89%

The Impact of Inflammatory Stimuli on Xylosyltransferase-I Regulation in Primary Human Dermal Fibroblasts

Lindenkamp

Kara

et al. 2022

Biomedicines

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“…In addition to fibrosis, fibroblasts also contribute to chronic inflammation. Studies across multiple inflammatory diseases show that disease-related fibroblasts share common properties and communicate with both immune and vascular compartments, which then contribute to persistent inflammation [ 41 ]. In RA, synovial fibroblasts undergo metabolic reprogramming and mediate tissue priming by enhancing inflammasome activity, which means that sensitized synovial tissues are more prone to reinflammation, a concept that has been termed “stromal memory” [ 42 ].…”

Section: Glossarymentioning

confidence: 99%

Why does understanding the biology of fibroblasts in immunity really matter?

et al. 2023

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Fibroblasts are known for their ability to make and modify the extracellular matrix. However, there is more to them than meets the eye. It is now clear that they help define tissue microenvironments and support immune responses in organs. As technology advances, we have started to uncover the secrets of fibroblasts. In this Essay, we present fibroblasts as not only the builders and renovators of tissue environments but also the rheostat cells for immune circuits. Although they perform location-specific functions, they do not have badges of fixed identity. Instead, they display a spectrum of functional states and can swing between these states depending on the needs of the organ. As fibroblasts participate in a range of activities both in health and disease, finding the key factors that alter their development and functional states will be an important goal to restore homeostasis in maladapted tissues.

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“…These offer a more efficient framework to compare query cell phenotypes with an existing cell reference. A recent study performed joint clustering analysis to reveal two shared pathogenic phenotypes of fibroblasts, a CXCL10+ CCL19+ inflammatory fibroblast phenotype localizing to a T cell enriched niche and a SPARC+ COL3A1+ fibroblast phenotype localizing to a perivascular niche, from four chronic inflammatory diseased tissues including lung, intestine, salivary gland, and synovium ( 63 ). Another study built fibroblast atlases using around 230,000 fibroblasts across 17 mouse tissues and revealed that many fibroblast transcriptional states were conserved between humans and mice ( 64 ).…”

Section: Cross-tissue Single-cell Integrative Analysis Reveals Shared...mentioning

confidence: 99%

Single-cell computational machine learning approaches to immune-mediated inflammatory disease: New tools uncover novel fibroblast and macrophage interactions driving pathogenesis

2023

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Recent advances in single-cell sequencing technologies call for greater computational scalability and sensitivity to analytically decompose diseased tissues and expose meaningful biological relevance in individual cells with high resolution. And while fibroblasts, one of the most abundant cell types in tissues, were long thought to display relative homogeneity, recent analytical and technical advances in single-cell sequencing have exposed wide variation and sub-phenotypes of fibroblasts of potential and apparent clinical significance to inflammatory diseases. Alongside anticipated improvements in single cell spatial sequencing resolution, new computational biology techniques have formed the technical backbone when exploring fibroblast heterogeneity. More robust models are required, however. This review will summarize the key advancements in computational techniques that are being deployed to categorize fibroblast heterogeneity and their interaction with the myeloid compartments in specific biological and clinical contexts. First, typical machine-learning-aided methods such as dimensionality reduction, clustering, and trajectory inference, have exposed the role of fibroblast subpopulations in inflammatory disease pathologies. Second, these techniques, coupled with single-cell predicted computational methods have raised novel interactomes between fibroblasts and macrophages of potential clinical significance to many immune-mediated inflammatory diseases such as rheumatoid arthritis, ulcerative colitis, lupus, systemic sclerosis, and others. Third, recently developed scalable integrative methods have the potential to map cross-cell-type spatial interactions at the single-cell level while cross-tissue analysis with these models reveals shared biological mechanisms between disease contexts. Finally, these advanced computational omics approaches have the potential to be leveraged toward therapeutic strategies that target fibroblast-macrophage interactions in a wide variety of inflammatory diseases.

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Cross-tissue, single-cell stromal atlas identifies shared pathological fibroblast phenotypes in four chronic inflammatory diseases

Cited by 96 publications

References 93 publications

The Impact of Inflammatory Stimuli on Xylosyltransferase-I Regulation in Primary Human Dermal Fibroblasts

The Impact of Inflammatory Stimuli on Xylosyltransferase-I Regulation in Primary Human Dermal Fibroblasts

Why does understanding the biology of fibroblasts in immunity really matter?

Single-cell computational machine learning approaches to immune-mediated inflammatory disease: New tools uncover novel fibroblast and macrophage interactions driving pathogenesis

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