Primed to resolve: A single cell atlas of the shoulder capsule reveals a cellular basis for resolving inflammatory fibrosis

Abstract

Fibrotic conditions are a significant global disease burden. While some therapies delay disease progression, none reverse fibrosis. To gain insights into how fibrosis might resolve, we developed a comparative single cell atlas of frozen shoulder capsule tissue; a chronic inflammatory fibrotic human disease that resolves spontaneously. We identified both a population of pro-inflammatory MERTKlowCD48+ macrophages (Mφ) and a population of MERTK+LYVE1+MRC1+Mφ enriched for negative regulators of inflammation. Micro-cultures of patient-derived cells identified cell-matrix interactions between MERTK+Mφ and DKK3+ and POSTN+ fibroblasts, suggesting that matrix remodelling plays a role in the resolution of frozen shoulder. Cross-tissue analysis revealed a shared gene expression cassette between MERTK+Mφ in the shoulder capsule and a similar cell population enriched in synovial tissues from rheumatoid arthritis patients in disease remi ssion, supporting the concept that MERTK+Mφ provide a cellular basis for the resolution of inflammation and fibrosis. Single-cell transcriptomic profiling and spatial analysis of human foetal shoulder tissues identified MERTK+LYVE1+MRC1+Mφ and DKK3+ and POSTN+ fibroblast populations analogous to those identified in adult shoulder capsule, suggesting that the template to resolve fibrosis is established during development. Therapeutic enhancement of crosstalk between MerTK+Mφ and pro-resolving DKK3+ and POSTN+ fibroblasts could accelerate resolution of frozen shoulder and resolve persistent inflammatory fibrotic disease in other tissues.

Single-Cell Analysis of ADSC Interactions with Fibroblasts and Endothelial Cells in Scleroderma Skin

“…Most significant interactions are based on ECM components such as CCNs, collagens, tenascins, and fibronectin. Rather than directly acting upon fibroblasts via these molecules, ADSCs might change the composition of the ECM and reinstate tissue homeostasis [ 21 , 75 ]. Consequently, the altered ECM can influence the behaviour of fibroblasts through molecular and mechanotransduction processes.…”

Three-dimensional, in-vitro approaches for modelling soft-tissue joint diseases

“…The precise cellular and molecular cues that govern whether inflammatory fibrosis persists or resolves remain to be identified. Knowledge from how fibrosis successfully resolves in the shoulder joint capsule could inform the biological cues to push persistent fibrotic diseases like knee arthrofibrosis towards a resolving trajectory 5 . As an example of a condition without highly developed animal models, the development of 3DMs comprised of patient-derived cells isolated from resolving shoulder fibrosis could uniquely highlight critical cellular and molecular programmes that regulate the persistence or resolution of arthrofibrosis.…”

“…Recent investigations into the cell types comprising tissues of the joint have revealed insights into the functional biology of these tissues. For instance, we now understand the heterogeneity of fibroblasts in joint soft tissues (JSTs) such as synovium and tendon 3,4 and that functionally distinct fibroblast subsets drive joint damage, inflammation and resolution 3,5 . The microanatomical niches in which these cells occupy provide insights into cell behaviour during disease, including RA as a disease of the synovial sub-lining (where proximity of THY1 pos fibroblasts to NOTCH+ endothelial cells drives inflammation), in contrast to THY1 neg fibroblasts in the synovial lining mediating joint destruction 3,6 .…”