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Single cell RNA-seq analyses of dermis from wound day 18 large skin wounds that healed in a fibrotic or regenerative fashion.

ABSTRACT: Human and murine skin wounding commonly result in fibrotic scarring but the murine wounding model Wound Induced Hair Neogenesis (WIHN) can frequently result in a regenerative repair response. Here we show in single cell RNA-seq comparisons of semi-regenerative and fibrotic WIHN wounds, increased expression of phagocytic/lysosomal genes in macrophages associated with predominance of fibrotic myofibroblasts in fibrotic wounds. Investigation revealed that macrophages in the late wound drive fibrosis by phagocytizing dermal Wnt inhibitor SFRP4 to establish persistent Wnt activity. In accordance, phagocytosis abrogation resulted in transient Wnt activity and a more regenerative healing. Phagocytosis of SFRP4 was integrin-mediated and dependent on the interaction of SFRP4 with the EDA splice variant of fibronectin. In the human skin condition Hidradenitis suppurativa, phagocytosis of SFRP4 by macrophages correlated with fibrotic wound repair. These results reveal that macrophages can modulate a key signaling pathway via phagocytosis to alter the skin wound healing fate.

ORGANISM(S): Mus musculus

PROVIDER: GSE141814 | GEO | 2019/12/12

REPOSITORIES: GEO

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Project description:Adult mammalian skin wound healing is typically accompanied by fibrotic scar that impairs normal skin function and regeneration of skin appendages. Interestingly, however, in adult mice, large severe skin injuries exhibit de novo formation of HFs following severe skin injuries (a phenomenon termed wound-induced HF neogenesis, WIHN). Understanding the competent cell types and molecular mechanisms that enable regenerative wound healing will be critical for developing treatments that restore skin function after injury. We described the existence of an adult bipotent hair follicle dermal stem cell (hfDSC) that functions to regenerate the connective tissue sheath and to populate the DP with new cells (Rahmani et al., 2014). Based on this, we hypothesized that the mesenchymal cells comprised within the neogenic HFs might originate from hfDSCs. To test this, we employed αSMACreERT2:ROSAYFP and Hic1CreERT2:TDTmt mice to examine the contribution of hfDSCs or hfDSCs and reticular/hypodermal progenitors, respectively, to the formation of neodermis and regeneration of de novo HFs. Mice received full-thickness excision wounds (>1 cm2) and then harvested at 18-140 days post-wounding (dpw). αSMA+ve and Hic1-lineage cells were activated upon wounding, migrated into the wound, and contributed to both DP and DS in almost all de novo-formed HFs. Surprisingly, hfDSCs contributed only a minority of cells (20%) to nascent DP cells, whereas Hic1-lineage cells generated >90% of the neogenic DP cells. In both cases, cells integrating into neogenic HF mesenchyme appeared to restore the hfDSC pool, since they repopulated the neogenic mesenchyme over successive regenerative hair cycles. Finally, using an ex vivo HF formation assay, we found that prospectively isolated extrafollicular Hic-lineage cells could participate in HF formation when exposed to a permissive environment. Our data reveal that despite their origin in the reticular/hypodermis, Hic1-lineage dermal progenitors are able to adopt a regenerative response during wound healing if provided with a permissive local environment.

Project description:While considerable progress has been made towards understanding the complex processes and pathways that regulate human wound healing, regenerative medicine has been unable to develop therapies that coax the natural wound environment to heal scar-free. The inability to induce perfect skin regeneration stems partly from our limited understanding of how scar-free healing occurs in a natural setting. Here we have investigated the wound repair process in adult axolotls and demonstrate that they are capable of perfectly repairing full thickness excisional wounds made on the flank. In the context of mammalian wound repair, our findings reveal a substantial reduction in hemostasis, reduced neutrophil infiltration and a relatively long delay in production of new extracellular matrix (ECM) during scar-free healing. Additionally, we test the hypothesis that metamorphosis leads to scarring and instead show that terrestrial axolotls also heal scar-free, albeit at a slower rate. Analysis of newly forming dermal ECM suggests that low levels of fibronectin and high levels of tenascin-C promote regeneration in lieu of scarring. Lastly, a genetic analysis during wound healing comparing epidermis between aquatic and terrestrial axolotls suggests that matrix metalloproteinases may regulate the fibrotic response. Our findings outline a blueprint to understand the cellular and molecular mechanisms coordinating scar-free healing that will be useful towards elucidating new regenerative therapies targeting fibrosis and wound repair. We used microarray analysis to determine the gene expression changes that take place during scar free wound healing in aquatic and terrestrial axolotl salamanders. Epidermal tissue was harvested using a 4mm biopsy punch. Two wounds were made along the flank and posterior to the forelimbs. Harvested epidermis was pooled for each animal. Four biological replicates were collected from uninjured epidermis (D0) and at 1, 3, and 7 days post injury.

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Single cell RNA-seq analyses of dermis from wound day 18 large skin wounds that healed in a fibrotic or regenerative fashion.

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