SFRP2/DPP4 and FMO1/LSP1 Define Major Fibroblast Populations in Human Skin

Abstract

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.

Deciphering the functional heterogeneity of skin fibroblasts using single‐cell RNA sequencing

“…Furthermore, they showed that the location within the dermis affects the expression of various enzymes and likely also their function. A study by Tabib and colleagues suggests a more diverse picture than initially expected . Their work revealed, next to several smaller FB populations, the presence of two major FB populations in human skin, which do not coincide with their location in either the papillary or reticular dermis .…”

“…A study by Tabib and colleagues suggests a more diverse picture than initially expected . Their work revealed, next to several smaller FB populations, the presence of two major FB populations in human skin, which do not coincide with their location in either the papillary or reticular dermis . Together, recent literature on skin FBs suggests FB heterogeneity in the skin, and a sole classification of skin FBs based on the anatomical localization into papillary and reticular FBs might not be sufficient to fully understand their specific roles in skin homeostasis and tissue regeneration after injury.…”

“…15,16 In contrast, Korosec et al have recently demonstrated that DPP4 + FBs in human skin are mainly located in the papillary dermis, but also detectable at lower levels in the reticular dermis. 12 In addition, Tabib et al 13 show DPP4 expression in FBs of both dermal layers in human skin, and suggest a novel major FB population characterized by co-expression of DPP4 and secreted frizzled related protein 2 (SFRP2), a soluble modulator of Wnt signaling. 17,18 However, most of the relevant literature on the role of DPP4-expressing skin fibroblasts still originates from mouse studies.…”

“…19 Interestingly, inhibition of DPP4 activity results in attenuated matrix secretion and reduced transforming growth factor beta 1 (TGFB1)-mediated pro-fibrotic effects, indicating a prominent role of DPP4 in wound healing and scar formation. 20,21 In contrast to mouse studies, reports on the expression and the properties of DPP4 in human skin are scarce and inconsistent, 12,13,[22][23][24][25][26] complicating clinical translation of these findings. Moreover, the existence of a DPP4 + FB subset responsible for the production of the ECM has not been confirmed in human skin so far.…”

Origin and functional heterogeneity of fibroblasts

“…In the skin, distinct enrichment of fibroblast subpopulations is observed in the mouse upper and lower dermis, especially in wound repair . In both murine and human skin, scRNA sequencing identified a DPP4 (dipeptidyl‐peptidase‐4)‐rich fibroblast population that expresses type I collagen and possibly plays a role in scarification . DPP4 transcripts and protein are also recognized as a fibroblast activation marker in systemic sclerosis .…”