A vasculature niche orchestrates stromal cell phenotype through PDGF signaling: Importance in human fibrotic disease

Fibrosis is characterized by excessive matrix protein accumulation and contributes to significant morbidity and mortality in the Western world. The relative lack of effective antifibrotic therapeutics for the majority of these conditions reflects the difficulty in identifying targets for human fibrosis. Animal models fail to recapitulate all of the facets of human disease, and the limited clinical samples from patients with fibrosis of visceral organs are usually of late-stage disease [J. Nanchahal, B. Hinz, Proc. Natl. Acad. Sci. U.S.A. 113, 7291-7293 (2016)]. Here, we use Dupuytren's disease (DD), a localized fibrotic condition of the hand, as a model to profile the vasculature niche of human fibrosis at single-cell resolution. Our spatially resolved molecular taxonomy of fibrotic blood vessels identifies distinct endothelial and pericyte populations and demonstrates a complex topological organization in the fibrotic microenvironment. In developing fibrosis, we show that the endothelium acts to promote immune regulatory fibroblast phenotype through platelet-derived growth factor (PDGF) signaling, thereby sustaining an immune cell-enriched perivascular niche. Moreover, we highlight pericytes as housing a putative myofibroblast precursor in DD. Overall, our results elucidate a tightly coupled vasculature niche in fibrosis that instructs the differentiation of func-tionally distinct stromal cells. These findings provide an important translational resource and highlight the therapeutic potential of targeting blood vessel signaling in human fibrosis.

Automated summary

Fibrosis, characterized by excessive accumulation of matrix protein, has significant impact on health in the Western world. However, there is a lack of effective antifibrotic treatments due to the difficulty in identifying targets for human fibrosis. In this study, researchers used Dupuytren's disease as a model to analyze the vasculature niche of human fibrosis at a single-cell resolution. The results showed distinct populations of endothelial and pericyte cells, and revealed a complex topological organization in the fibrotic microenvironment. It was found that endothelium promotes immune regulatory fibroblast phenotype through platelet-derived growth factor signaling, leading to an immune cell-enriched perivascular niche. Additionally, pericytes were found to house a putative myofibroblast precursor. These findings provide valuable insights for fibrosis research and highlight the therapeutic potential of targeting blood vessel signaling in human fibrosis.