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.
Highlights
Cell lineage relationships within the epidermis have been studied in detail (Kretzschmar and Watt, 2012), the functional identity of fibroblasts in the dermis is less well characterized (Driskell and Watt, 2015)
Other fibroblast subpopulations that have been identified in mouse and human dermis include the dermal papilla cells at the base of the hair follicle (Lee and Tumbar, 2012; Sennett and Rendl, 2012), the cells of the arrector pili muscle, and pericytes that are in close association with blood vessels (Paquet-Fifield et al, 2009)
Differential expression of genes associated with Wnt, extracellular matrix (ECM), and immune signaling in neonatal mouse fibroblast subpopulations GFPþ fibroblasts isolated from the back skin of PdgfraH2BeGFP reporter mice at postnatal day 2 can be separated by flow cytometry on the basis of expression of cell surface markers CD26, Sca1, and Dlk1 (Driskell et al, 2013)
Summary
Cell lineage relationships within the epidermis have been studied in detail (Kretzschmar and Watt, 2012), the functional identity of fibroblasts in the dermis is less well characterized (Driskell and Watt, 2015). The dermis has distinct layers that are readily identified histologically: the papillary dermis lies closest to the epidermis, whereas the underlying reticular dermis is thicker and contains the bulk of the fibrillar extracellular matrix (Harper and Grove, 1979). In the case of mouse dermis, we and others have shown, via lineage tracing under homeostatic conditions, during wound healing and in skin reconstitution assays, that the papillary and reticular fibroblasts represent functionally distinct lineages that arise from a multipotent progenitor population during embryonic development (Driskell et al, 2013; Rinkevich et al, 2015). Reticular fibroblasts are the first to enter a wound and express the so-called fibroblast activation marker a-smooth muscle actin
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