Spatial and Single-Cell Transcriptional Profiling Identifies Functionally Distinct Human Dermal Fibroblast Subpopulations

Abstract

Previous studies have shown that mouse dermis is composed of functionally distinct fibroblast lineages. To explore the extent of fibroblast heterogeneity in human skin, we used a combination of comparative spatial transcriptional profiling of human and mouse dermis and single-cell transcriptional profiling of human dermal fibroblasts. We show that there are at least four distinct fibroblast populations in adult human skin, not all of which are spatially segregated. We define markers permitting their isolation and show that although marker expression is lost in culture, different fibroblast subpopulations retain distinct functionality in terms of Wnt signaling, responsiveness to IFN-γ, and ability to support human epidermal reconstitution when introduced into decellularized dermis. These findings suggest that ex vivo expansion or in vivo ablation of specific fibroblast subpopulations may have therapeutic applications in wound healing and diseases characterized by excessive fibrosis.

STAT3 signalling pathway is implicated in keloid pathogenesis by preliminary transcriptome and open chromatin analyses

“…Fibroblasts are the principal mediator of fibroproliferative disorders . Recent lineage tracing and single‐cell transcriptional profiling studies reveal that skin fibroblasts consist of distinct subpopulations arising from different lineages with different roles in determining dermal architecture in skin development and repair . A report combining site‐specific in situ microdissection and gene expression profiling of keloid tissues found distinct gene signatures of clear keloid regions highlighting morphological heterogeneity within the keloid scar .…”

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

“…When analyzing co‐expression of DPP4 with traditional gene markers for FB of the papillary and reticular dermis, we detected DPP4 + FBs in both subsets, suggesting that a clear assignment of DPP4 + FBs to either of the two dermal compartments in the human skin, as suggested previously in mouse skin, is not possible on the transcriptional level (Figure C‐E). Since data on DPP4 expression in the skin are controversial and to confirm our findings of DPP4 + FBs on protein level, we next investigated DPP4 protein expression in human skin by immunofluorescence staining. Strikingly, all antibodies used showed different expression patterns (Figure S13).…”

“…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.…”

A multiscale hybrid mathematical model of epidermal‐dermal interactions during skin wound healing

“…In terms of its limitations, our model does not consider potential heterogeneity in skin fibroblast populations, and the possibility that different fibroblast subtypes can respond differently to signalling cues and exert distinct effects on wound healing. Indeed, several recent studies have identified distinct populations of mouse skin fibroblasts with distinct roles in ECM deposition during development and wound healing. Rinkevich et al identified two populations of mouse skin fibroblasts: En1 (Engrailed homeobox 1)‐negative and En1 ‐positive cells.…”