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 shown to be highly heterogeneous. However, Fb heterogeneity in HTSs has not been fully elucidated. In this study, 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 showed that IL-11 was upregulated in HTSs and that its expression was induced by TGFβ1 in vitro. TGFβ1 also stimulated the expression of CD39 at the transcriptional and protein levels, mediating the maintenance of the CD39⁺ phenotype. Furthermore, IL-11 facilitated myofibroblast activation and extracellular matrix production in both CD39⁺ and CD39^- Fbs. Interestingly, CD39⁺ Fbs secreted more IL-11 on TGFβ1 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.