Comparative transcriptomic profiling of hydrogen peroxide signaling networks in zebrafish and human keratinocytes: Implications toward conservation, migration and wound healing.

Thomas S Lisse,Sandra Rieger,Benjamin L King

doi:10.1038/srep20328

Thomas S Lisse, Sandra Rieger + Show 1 more

Open Access

https://doi.org/10.1038/srep20328

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Abstract

Skin wounds need to be repaired rapidly after injury to restore proper skin barrier function. Hydrogen peroxide (H2O2) is a conserved signaling factor that has been shown to promote a variety of skin wound repair processes, including immune cell migration, angiogenesis and sensory axon repair. Despite growing research on H2O2 functions in wound repair, the downstream signaling pathways activated by this reactive oxygen species in the context of injury remain largely unknown. The goal of this study was to provide a comprehensive analysis of gene expression changes in the epidermis upon exposure to H2O2 concentrations known to promote wound repair. Comparative transcriptome analysis using RNA-seq data from larval zebrafish and previously reported microarray data from a human epidermal keratinocyte line shows that H2O2 activates conserved cell migration, adhesion, cytoprotective and anti-apoptotic programs in both zebrafish and human keratinocytes. Further assessment of expression characteristics and signaling pathways revealed the activation of three major H2O2–dependent pathways, EGF, FOXO1, and IKKα. This study expands on our current understanding of the clinical potential of low-level H2O2 for the promotion of epidermal wound repair and provides potential candidates in the treatment of wound healing deficits.

Highlights

We previously demonstrated that incubation of larval zebrafish for up to 12 hours in 3 mM H2O2 promotes intra-epidermal sensory axon regeneration[23], suggesting that this concentration of H2O2 is highly beneficial for tissue restoration in zebrafish larvae
While larvae treated with the sensor but not H2O2 exhibited no fluorescence, treatment with H2O2 led to selective fluorescence in the skin epithelium and gut, presumably due to ingestion (Fig. 1b)
Likewise within non-mammalian vertebrate systems, such as zebrafish, findings suggest that H2O2 is a crucial second messenger for growth factors and cytokines in the regeneration of axons and the recruitment of leukocytes to the wound during repair[20,21,23]

Summary

Introduction

Across non-vertebrate species, plants have evolved the multifunctional use of lower concentrations of ROS to regulate growth and developmental processes, such as cell elongation[17] and adaptations in response to environmental conditions[18], and the hypersensitive response to wounds[19] that involves activation cascades of multiple kinases and transcription factors. Hepatocyte growth factor or EGF-stimulated human epidermal keratinocytes require extracellular signal-regulated kinase (ERK), but not JNK-AP-1, activation to stimulate cell molitlity[29]. These signaling processes which promote motility are highly dependent on specialized extracellular matrix (ECM)-driven factors[30]. Our findings elaborate on the complexity of the transcriptional response to H2O2 within the cutaneous environment among vertebrate species

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