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Single-cell transcriptomics of Hic1 lineage cells recruited during regenerative and scar-forming skin wound healing.

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE108677 | GEO | 2020/08/04

REPOSITORIES: GEO

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Project description:Wound healing is a complex process regulated by various cell types and a plethora of mediators. While interactions between wounded skin and the hair follicles (HFs) could induce HF neogenesis or promote wound healing, it remains unknown whether the wound healing-associated signaling milieu can be manipulated to protect against alopecia, such as chemotherapy-induced alopecia (CIA). Utilizing a well-established neonatal rat model of CIA, we show here that skin wounding protects from alopecia caused by several clinically relevant chemotherapeutic regimens, and that protection is dependent on the time of wounding and hair cycle stage. Gene expression profiling unveiled a significant increase in interleukin-1 beta (IL-1β) mediated signaling by skin wounding. Subsequently, we showed that IL-1β is sufficient and indispensable for mediating the CIA-protective effect. Administration of IL-1β alone to unwounded rats exhibited local CIA protection while IL-1β neutralization abrogated CIA protection by wounding. Mechanistically, IL-1β retarded postnatal HF morphogenesis, making HFs at the wound sites or IL-1β treated areas damage-resistant while the rats developed total alopecia elsewhere. We conclude that wound healing switches the cutaneous cytokine milieu to an IL-1β-dominated state thus retarding HF growth progression and rendering the HFs resistant to chemotherapy agents. In the future, manipulation of HF progression through interfering with the IL-1β signaling milieu may provide therapeutic benefits to a variety of conditions, from prevention of CIA to inhibition of hair growth and treatment of hirsutism. In this experiment, we used the Rat MI-Ready array comprised of over 34,000 transcript probes for gene and alternative splice products in ENSEMBL release 37 to profile gene expression changes during acute wound healing in rat skin. 16,198 Selected rat probes were above threshold in at least one group. 3,239 significant genes were found (FDR < 0.1).

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Single-cell transcriptomics of Hic1 lineage cells recruited during regenerative and scar-forming skin wound healing.

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