Differential microRNA profile underlies the divergent healing responses in skin and oral mucosal wounds

Alyne Simões,Lin Chen,Zujian Chen,Shang Gao,Luisa A Dipietro,Yan Zhao,Yang Dai,Phillip T Marucha,Xiaofeng Zhou

doi:10.1038/s41598-019-43682-w

Alyne Simões, Lin Chen + Show 7 more

Open Access

https://doi.org/10.1038/s41598-019-43682-w

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Abstract

Oral mucosal wounds heal faster than skin wounds, yet the role of microRNAs in this differential healing has never been examined. To delineate the role of microRNAs in this site-specific injury response, we first compared the microRNAome of uninjured skin and oral mucosa in mice. A total of 53 tissue-specific microRNAs for skin and oral mucosa epithelium were identified. The most striking difference was the high abundance of miR-10a/b in skin (accounting for 21.10% of the skin microRNAome) as compared to their low expression in oral mucosa (2.87%). We further examined the dynamic changes of microRNAome throughout the time course of skin and oral mucosal wound healing. More differentially expressed microRNAs were identified in skin wounds than oral wounds (200 and 33, respectively). More specifically, miR-10a/b was significantly down-regulated in skin but not oral wounds. In contrast, up-regulation of miR-21 was observed in both skin and oral wounds. The therapeutic potential of miR-10b and miR-21 in accelerating wound closure was demonstrated in in vitro assays and in a murine skin wound model. Thus, we provided the first site-specific microRNA profile of skin and oral mucosal wound healing, and demonstrate the feasibility of a microRNA-based therapy for promoting wound closure.

Highlights

Impaired wound healing is a significant clinical problem, and affects approximately 6.5 million people in the United States
Intrinsic differences in growth factor production and stem cell levels have all been suggested to support oral mucosal wound repair. These results suggest that the site-specific wound healing phenotype is stable and heritable, and involves intrinsic differences in epithelial cells and their response to a wound
We demonstrated the therapeutic potential of accelerating skin wound closure by manipulating the expression of selected microRNAs that are differentially expressed in mucosa and skin wounds

Summary

Introduction

Impaired wound healing is a significant clinical problem, and affects approximately 6.5 million people in the United States. Comparative studies on paired skin and oral mucosal wounds represent a unique opportunity to reveal intrinsic regulators that orchestrate the differential healing process in adult tissues. Intrinsic differences in growth factor production and stem cell levels have all been suggested to support oral mucosal wound repair These results suggest that the site-specific wound healing phenotype is stable and heritable, and involves intrinsic differences in epithelial cells and their response to a wound. Our prior study provided the first dynamic transcriptome profiles of a paired oral mucosa and skin wound healing model, and showed that site-specific injury responses exist at each site[11]. More recent studies in humans demonstrate that skin and oral mucosa differ both at baseline and throughout the time course of healing[12] While these studies advance our understanding of wound healing, most prior efforts are focused on protein coding genes. Our results provide a foundation for developing novel microRNA-based therapeutic approaches to promote skin wound closure and/or prevent chronic wounds

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