Fibroblasts produce matrix, regulate inflammation, mediate reparative processes, and serve as pluripotent mesenchymal cells. Analyzing digested normal human skin by single-cell RNA sequencing, we explored different fibroblast populations. T-distributed stochastic neighbor embedding and clustering of single-cell RNA sequencing data from six biopsy samples showed two major fibroblast populations, defined by distinct genes, including SFRP2 and FMO1, expressed exclusively by these two major fibroblast populations. Further subpopulations were defined within each of the SFRP2 and FMO1 populations and five minor fibroblast populations, each expressing discrete genes: CRABP1, COL11A1, FMO2, PRG4, or C2ORF40. Immunofluorescent staining confirmed that SFRP2 and FMO1 define cell types of dramatically different morphology. SFRP2+ fibroblasts were small, elongated, and distributed between collagen bundles. FMO1+ fibroblasts were larger and distributed in both interstitial and perivascular locations. Differential gene expression by SFRP2+, FMO1+, and COL11A1+ fibroblasts suggests roles in matrix deposition, inflammatory cell retention, and connective tissue cell differentiation, respectively.
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