The roles of microRNAs in skin wound healing

Abstract

Skin is an essential biological barrier of the human body, and wound healing is the fundamental physiological process to keep its integrity. Chronic non-healing wounds are growing socioeconomic and health concerns, which longs for more understanding of their pathophysiology to discover effective treatments. In this thesis, we focused on how microRNAs (miR) work together with their target protein-coding genes to regulate the complex wound healing process, and by exploring the roles they play in chronic wounds we aimed to discover potential therapeutic targets.

In paper I, a distinct up-regulation of miR-31 in human acute wounds was identified from profiling analysis. We discovered miR-31 as a pivotal regulator in promoting keratinocyte proliferation and migration by targeting EMP1 during wound healing, emphasizing its importance in re-epithelialization. In paper II, miR-34 family, as a famous tumour suppressor, popped out amidst the top upregulated microRNAs in venous ulcer. In vitro, miR-34a and miR-34c enhanced inflammatory response of epidermal keratinocytes via targeting LGR4 and positively regulating NF-κB signalling pathway. In vivo, mouse model of either miR-34 local overexpression or Lgr4 knockout displayed impaired wound healing with excessive inflammation and suppressed cell growth. These suggest that miR-34 play a pathological role in chronic wounds by contributing to the excessive inflammation. In paper III, in continuity with our previous report that miR-132 displays anti-inflammatory and pro-proliferative roles in keratinocytes, we studied the function of miR-132 in another major skin resident cell type fibroblasts. By both overexpression and inhibition, miR-132 was proved to facilitate migration of primary human dermal fibroblasts, through targeting RASA1 and regulating Ras signalling. Since fibroblasts derived from chronic wounds are nonmigratory, our study suggests the miR-132-RASA1-Ras axis with potential therapeutic impact. In paper IV, we tested the therapeutic potential of microRNAs, taken miR-132 as an example. A significant downregulation of miR-132 was revealed in diabetic foot ulcer. Intradermal injection of liposome-encapsulated miR-132 mimics effectively accelerated wound healing. Moreover, ex vivo human model exhibited ameliorated re-epithelialization upon miR132 topical application, denoting that local treatment of miR-132 deserves further evaluation in a clinical trial as a potential target for treating chronic wounds.

Conclusively, this thesis investigated the crucial functions of miR-31, miR-34 and miR-132 in different phases of normal skin wound healing process and in chronic wounds, and pointed out a promising potential of microRNA-based therapy in treating chronic wounds.