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Wound Healing Protects Against Chemotherapy-induced Alopecia in Young Rats via Up-regulating Interleukin-1β-mediated Signaling

ABSTRACT: 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).

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE98105 | GEO | 2017/06/29

SECONDARY ACCESSION(S): PRJNA384003

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:Proteases control complex tissue responses by modulating inflammation, cell proliferation and migration, and matrix remodeling. All these processes are orchestrated in cutaneous wound healing to restore the skinâ€™s barrier function upon injury. Altered protease activity has been implicated in the pathogenesis of healing impairments, and proteases are important targets in diagnosis and therapy of this pathology. Global assessment of proteolysis at critical turning points after injury will define crucial events in acute healing that might be disturbed in healing disorders. As optimal biospecimens, wound exudates contain an ideal proteome to detect extracellular proteolytic events, are non-invasively accessible, and can be collected at multiple time points along the healing process from the same wound in the clinics. In this study, we applied multiplexed Terminal Amine Isotopic Labeling of Substrates (TAILS) to globally assess proteolysis in early phases of cutaneous wound healing. By quantitative analysis of proteins and protein N termini in wound fluids from a clinically relevant pig wound model, we identified more than 650 proteins and discerned major healing phases through distinctive abundance clustering of markers of inflammation, granulation tissue formation, and re-epithelialization. TAILS revealed a high degree of proteolysis at all time points after injury by detecting almost 1300 N-terminal peptides in ~450 proteins, most of which could not be assigned to known mature protein N termini. Quantitative positional proteomics mapped pivotal interdependent processing events in the blood coagulation cascade, detailed activating thrombin cleavages in vivo, and temporally discerned clotting and fibrinolysis during the healing process. Similarly, we found virtually all major cleavages in complement activation and inactivation and demonstrated time-dependent changes in the proteolytic potential of the wound milieu by detecting processing of complement C3 at distinct time points after wounding and by different proteases.

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Wound Healing Protects Against Chemotherapy-induced Alopecia in Young Rats via Up-regulating Interleukin-1β-mediated Signaling

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