MicroRNA as Therapeutic Targets for Chronic Wound Healing

Abstract

Wound healing is a highly complex biological process composed of three overlapping phases: inflammation, proliferation, and remodeling. Impairments at any one or more of these stages can lead to compromised healing. MicroRNAs (miRs) are non-coding RNAs that act as post-transcriptional regulators of multiple proteins and associated pathways. Thus, identification of the appropriate miR involved in the different phases of wound healing could reveal an effective third-generation genetic therapy in chronic wound care. Several miRs have been shown to be upregulated or downregulated during the wound healing process. This article examines the biological processes involved in wound healing, the miR involved at each stage, and how expression levels are modulated in the chronic wound environment. Key miRs are highlighted as possible therapeutic targets, either through underexpression or overexpression, and the healing benefits are interrogated. These are prime miR candidates that could be considered as a gene therapy option for patients suffering from chronic wounds. The success of miR as a gene therapy, however, is reliant on the development of an appropriate delivery system that must be designed to overcome both extracellular and intracellular barriers.

Keywords: chronic wounds; gene therapy; microRNA; wound healing.

Graphical abstract

Figure 1

Biogenesis of miR Biogenesis of miR and the resulting post-transcriptional gene silencing mechanisms. Pri-miR is transcribed within the nucleus and then cleaved by the DROSHA complex to form pre-miR. Exportin 5 transports this pre-miR into the cytoplasm of the cell. There it is further sliced to form mature miR. This miR then binds with the RISC to form a RISC-miR complex, which acts as a translational repressor and degrades mRNA.

Figure 2

Therapeutic Wound Healing Targets of miR-21 Schematic diagram of miR-21 targets TIMP3 and PTEN. By inhibiting PTEN, miR-21 promotes the activation of many cell survival pathways. The Akt pathway functionality increases; thus, the mTOR pathway, for example, is heightened, which regulates protein synthesis, mitochondrial function, and glucose homeostasis. Nf-_kB inhibits apoptosis and Akt inhibits BAD, which is a pro-apoptotic pathway.

Figure 3

Therapeutic Wound Healing Targets of miR-424 Schematic diagram of miR-424 targeting CUL2. By targeting CUL2, the levels on HIF-1 increase within the cell and its proteosomal degradation is inhibited. Elevated HIF-1 increases the transcription of VEGF and Glut1.

Figure 4

EMP-1 as a Therapeutic Wound Healing Target of miR-31 Schematic diagram of miR-31 targeting EMP-1. EMP-1 inhibits migration and proliferation of cells; thus, its inhibition will result in an increase of these functions.

Figure 5

FIH-1 as a Therapeutic Wound Healing Target of miR-31 Schematic diagram of miR-31 targeting FIH-1. Thus, increasing the levels of HIF-1 within the cells. This leads to an increase in the levels of VEGF, thus increasing angiogenesis.