CD39+ Fibroblasts Enhance Myofibroblast Activation by Promoting IL-11 Secretion in Hypertrophic Scars.

ABSTRACT Fibroblasts (Fbs) are critical to hypertrophic scar (HTS) formation and were recently demonstrated to be highly heterogeneous. However, Fb heterogeneity in HTSs has not been fully elucidated. Here, we observed an increased fraction of CD39+ Fbs in HTS after screening four Fb subtypes (CD26+, CD36+, FAP+, and CD39+). CD39+ Fbs, enriched in the upper dermis, were positively correlated with scar severity. The transcriptional analysis of CD39+ and CD39- Fbs sorted from HTS revealed that IL-11 was more highly expressed in CD39+ Fbs. We then demonstrated that IL-11 was upregulated in HTSs and that its expression was induced by TGF-β1 in vitro. TGF-β1 also stimulated the expression of CD39 at the transcriptional and protein levels, mediating the maintenance of the CD39-positive phenotype. Furthermore, IL-11 facilitated myofibroblast activation and extracellular matrix production in both CD39+ and CD39- Fbs. Interestingly, CD39+ Fbs secreted more IL-11 upon TGF-β1 treatment and were less responsive to IL-11 than CD39- Fbs. Notably, a CD39 inhibitor effectively reduced stretch-induced scar formation and attenuated bleomycin-induced skin fibrosis, suggesting an antiscarring approach by targeting CD39+ Fbs.