Introduction: Tissue remodeling is a fundamental feature of inflammatory and fibrotic lung disease, in which fibroblast activation plays an crucial role. Fibroblast activation protein (FAP) is widely recognized as a cellular and imaging biomarker of fibroblast activation, yet it is unknown which fibroblasts are associated with FAP expression. Here, we characterize FAP expressing cells in healthy and diseased lungs using scRNAseq.

Methods:

Results: FAP expression was observed in healthy and diseased lungs, predominantly in stromal cells. In pulmonary fibrosis (36%) and COVID-19 (41%)  the proportion of FAP+ fibroblasts of total fibroblasts were increased compared to healthy (25%). Compared to FAP- fibroblasts, FAP+ fibroblasts express fibrotic markers CTHRC1 and COL1A1 indicating involvement in in collagen remodeling. In both diseases, FAP+ fibroblasts interact more strongly than FAP- fibroblasts with immune cells through TGF? and class 3 Semaphorin signaling. SPP1 signaling from myeloid cells was preferentially directed to FAP+ fibroblasts compared to FAP- fibroblasts only in COVID-19 and pulmonary fibrosis.

Conclusion: FAP+ fibroblasts are observed in healthy lung, acute COVID-19 and pulmonary fibrosis and are preferentially involved in stromal-immune cell interactions compared to FAP- fibroblasts. Understanding the role of FAP+ fibroblasts in remodeling in disease may inform future approaches for repairing damaged lung tissues.