Cellular census of human fibrosis defines functionally distinct stromal cell types and states

Thomas B Layton,Lynn Williams,Stephen N Sansom,Fiona Mccann,Dominic Furniss,Michael T H Ng,Marc Feldmann,Marco Fritzsche,Huw Colin-York,Weilin Xie,Marisa Cabrita,Jagdeep Nanchahal,Mingjun Zhang

doi:10.1038/s41467-020-16264-y

Abstract

Fibrotic disorders are some of the most devastating and poorly treated conditions in developed nations, yet effective therapeutics are not identified for many of them. A major barrier for the identification of targets and successful clinical translation is a limited understanding of the human fibrotic microenvironment. Here, we construct a stromal cell atlas of human fibrosis at single cell resolution from patients with Dupuytren’s disease, a localized fibrotic condition of the hand. A molecular taxonomy of the fibrotic milieu characterises functionally distinct stromal cell types and states, including a subset of immune regulatory ICAM1+ fibroblasts. In developing fibrosis, myofibroblasts exist along an activation continuum of phenotypically distinct populations. We also show that the tetraspanin CD82 regulates cell cycle progression and can be used as a cell surface marker of myofibroblasts. These findings have important implications for targeting core pathogenic drivers of human fibrosis.

Highlights

Fibrotic disorders are some of the most devastating and poorly treated conditions in developed nations, yet effective therapeutics are not identified for many of them
We examined Dupuytren’s nodules using mass cytometry (CyTOF) and single-cell RNA-seq, constructing a single-cell atlas of an active and cellular fibrotic microenvironment (Fig. 1a–e, Supplementary Fig. 1a–f)
Myofibroblasts are central mediators of the dysregulated woundhealing programme that defines fibrosis[3,4], we studied this population in detail

Summary

Introduction

Fibrotic disorders are some of the most devastating and poorly treated conditions in developed nations, yet effective therapeutics are not identified for many of them. We construct a stromal cell atlas of human fibrosis at single cell resolution from patients with Dupuytren’s disease, a localized fibrotic condition of the hand. A molecular taxonomy of the fibrotic milieu characterises functionally distinct stromal cell types and states, including a subset of immune regulatory ICAM1+ fibroblasts. We show that the tetraspanin CD82 regulates cell cycle progression and can be used as a cell surface marker of myofibroblasts These findings have important implications for targeting core pathogenic drivers of human fibrosis. Our single cell atlas of the fibrotic milieu elucidates functionally distinct stromal cell types and states, including ICAM1+ fibroblasts and CD82high myofibroblasts that contribute discrete pro-fibrotic functions. We demonstrate that the tetraspanin CD82 is expressed on human myofibroblasts and functions to regulate cell cycle progression in this population

Methods

Results

Conclusion