Mini-review - Indian Academy of Sciences

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Mini-review MicroRNAs as regulators of cutaneous wound healing WING-FU LAI1,* and PARCO M SIU2 1

Division in Anatomy and Developmental Biology, Department of Oral Biology, College of Dentistry, Yonsei University, Seoul, Republic of Korea 2 Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong Special Administrative Region, China *Corresponding author (Email, [email protected]) MicroRNAs (miRNAs) have emerged as key post-transcriptional regulators of gene expression, and have displayed important roles in areas spanning from embryonic development to skin physiology. Despite this, till now little is known about the significance of miRNAs in cutaneous wound healing. In this mini-review, we discuss the existing evidence on the roles of miRNAs in physiological processes relevant to cutaneous wound healing, followed by a highlight of the prospects and challenges of future development of miRNA-based wound therapies. With existing technologies of nucleic acid transfer and miRNA modulation, it is anticipated that once the roles of miRNAs in wound healing have been clarified, there will be a vast new vista of opportunities brought up for development of miRNAtargeted therapies for wound care. [Lai W-F and Siu PM 2014 MicroRNAs as regulators of cutaneous wound healing. J. Biosci. 39 519–524] DOI 10.1007/s12038-014-9421-4

Wound healing is a dynamic process characterized by different cellular events including acute and chronic inflammation, re-epithelialization and restoration of the underlying connective tissue. It is also a crucial biological process for survival of organisms and for all surgical branches. Over the years, much effort has been devoted to deciphering the signalling pathways [such as Wnt-Calcineurin-Flt1 signalling (Stefater et al. 2013; Zhang et al. 2009) and notch signalling (Chigurupati et al. 2007; Lu et al. 2012)] controlling wound repair; however, little is known about how microRNAs (miRNAs) are involved. This mini-review represents a digest of existing evidence on the roles of miRNAs in different physiological processes relevant to cutaneous wound healing. As miRNAs are important regulators of gene expression (Ambros 2004; Kloosterman and Plasterk 2006), it is hoped that this article cannot only unveil the possible significance of miRNAs in wound repair but can also illuminate the therapeutic potential of related research in wound treatment. Wound healing is an innate immune response to tissue injury (Sgonc and Gruber 2013). Upon wounding, the process of hemostasis starts and this leads to vasoconstriction and fibrin clot formation. A variety of pro-inflammatory Keywords.

cytokines, chemokines and growth factors [such as plateletderived growth factor (PDGF), epidermal growth factor, transforming growth factor-β (TGF-β), and vascular endothelial cell growth factor (VEGF)] will be released by the clots, and the surrounding tissues will help to draw inflammatory cells to the site of injury to initiate inflammation (Shaw and Martin 2009). During the inflammatory phase, neutrophils will first be recruited to the site of injury. Neutrophils phagocytose invading microbes and devitalize tissue debris, although they also produce agents such as reactive oxygen species that may cause bystander damage (Guo and Dipietro 2010). Later, monocytes also infiltrate into the site and become macrophages. The macrophages remove tissue debris and apoptotic cells, and help to fight against infection. An earlier study revealed that miR-424 is interlinked with the transcription factors PU.1 and NFI-A in a regulatory circuitry to regulate human monocyte/macrophage differentiation (Rosa et al. 2007), suggesting that changes in expression of miR-424 may impact on the availability of macrophages in the wound site. As macrophages are important mediators of wound healing, depletion of them would reduce the production of growth factors which are essential to tissue repair (Mirza et al. 2009). Further, upon stimulation

Angiogenesis; inflammation; microRNA; re-epithelialization; wound healing

Published online: 20 March 2014

J. Biosci. 39(3), June 2014, 519–524, * Indian Academy of Sciences



Wing-Fu Lai and Parco M Siu

of multiple Toll-like receptors (TLRs) (which allow inflammatory cells to recognize pathogenic agents, and are important components of the human innate immune response) (Liu et al. 2009), miR-147 is induced. MiR-147 was reported to function as a negative regulator of TLR-associated signalling events in murine macrophages (Liu et al. 2009). Although more studies for confirmation are required, miR-147 may play a role in preventing excessive inflammatory responses during wound healing. Concurrent with the inflammatory phase is reepithelialization, which is achieved by the proliferation of keratinocytes and epidermal stem cells that reside in the hair follicle bulge and in the basal layer of epidermis (Sgonc and Gruber 2013; Shaw and Martin 2009). Keratinocyte migration and re-epithelialization have been shown to be regulated by miR-21 (Yang et al. 2011), which is one of the few miRNAs that have been comparatively well studied in wound healing. MiR-21 has been frequently linked with cancer (Kanaan et al. 2012). It regulates cell proliferation and invasion through the PTEN/PI-3 K/Akt signalling pathway in human colorectal cancer cells (Xiong et al. 2013), and was found to be highly expressed in carcinoid tumours with lymph node metastasis (Lee et al. 2012a). Recently, by using microarray analysis and the quantitative polymerase chain reaction (PCR), Wang and coworkers (2012) discovered that during granulation tissue formation in mice, the expression of miR-21 was up-regulated by 3.1-fold. MiR-21 was highly expressed in the skin epidermis around the wound, and in mesenchymal cells in the granulation tissues (Wang et al. 2012). In vivo studies suggested that miR-21 is involved in collagen deposition and TGF-β-mediated wound contraction (Wang et al. 2012). Apart from miR-21, expression of miR-203 was found to be up-regulated by 2.5-fold during wound healing (Wang et al. 2012). MiR-203 was considered as a switch between keratinocyte proliferation and differentiation in the adult epidermis by modulating p63 expression post-transcriptionally (Lena et al. 2008). Indeed, granulation tissue formation is an important process in wound healing. During this process, the provisional fibrin matrix formed is replaced by the granulation tissue. Accompanying this is the proliferation of fibroblasts in response to the signals of growth factors such as PDGF and TGF-β, and the synthesis of a variety of extracellular matrix (ECM) components (including proteoglycans, collagen and glycosaminoglycans). Meanwhile, newly formed blood vessels will invade the neomatrix, so that a network of capillaries can be formed and the cells in the matrix can be supplied with oxygen and nutrients (Sgonc and Gruber 2013). A recent study demonstrated that the cellular redox environment in human microvascular endothelial cells (HMECs) can be regulated by miRNAs via a NADPH oxidase-dependent mechanism (Roy and Sen 2012). It also

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substantiated that hypoxia-sensitive miR-200b involves in induction of angiogenesis by directly targeting Ets-1 in HMECs (Roy and Sen 2012). As angiogenesis is pivotal to successful wound healing, proper functioning of miR-200b may be decisive to the healing process. Besides miR-200b, several other miRNAs have been reported to modulate angiogenesis by targeting VEGF. Examples of these include miR-15a (Sun et al. 2013), miR-16 (Sun et al. 2013), miR20b (Cascio et al. 2010), miR-101 (Zhang et al. 2013), and miR-206 (Zhang et al. 2011). Although their actions have only been investigated in the context of cancer, regarding the fact that VEGF is a potent angiogenic factor in skin repair, their possible roles in wound healing are worth detailed investigation. In addition to the aforementioned, there are other miRNAs that might involve in wound repair. Some of these have been listed in table 1. They might be further exploited as targets for wound treatment in the future. Although at this moment, development of miRNA-targeted wound therapies is in its infancy, the technical feasibility of modulating miRNA expression for therapeutic purposes has already been suggested in various pathological conditions. One example is malignant glioma, in which the effectiveness of HSVtk gene therapy has been enhanced upon overexpression of miR-145 (Lee et al. 2012b). The clinical viability of using miRNAs as therapeutic targets has also been reported by a phase I clinical trial, which employed a locked nucleic acid (LNA)-based anti-miRNA targeting miRNA-122 for treatment of hepatitis C (Fasanaro et al. 2010). Recently, another investigational therapy has been developed to tackle hepatitis C virus (HCV) infection by replacing five endogenous miRNA sequences of a natural miRNA cluster (miR-17-92) with sequences that are complementary to the HCV genome (Yang et al. 2013). In the in vitro context, the miRNA cluster effectively prevented the spread of HCV to uninfected cells, and successfully inhibited bona fide HCV replication by up to 95% within 2 days. All this evidence has validated the therapeutic potential of miRNA inhibitors and mimics as a new class of drugs. Despite this encouraging evidence, before miRNAtargeted wound therapies can become a reality, the molecular mechanism undertaken by each of the miRNAs potentially participating in the wound healing process has first to be elucidated. Potential targets for treatment have also to be identified. But this has been complicated by the differences in miRNA expression patterns between normal wounds and those from patients with diseases such as diabetes. This is supported by a recent in vivo study (Madhyastha et al. 2012), which found that besides miR-146b and miR-21, the expression levels of miR-141, miR-142 miR-126, miR-22, miR138, miR-1, miR-196a, miR-215, miR-24, let-7i and miR101b are different between normal and diabetic wounds. In

MicroRNAs as regulators of cutaneous wound healing


Table 1. List of miRNAs that may involve in different phases of wound healing Phase




Inflammatory phase

miR-105 miR-125b miR-140 miR-146a miR-147 miR-424

TLR2 TNF-α PDGF receptor TNF-α IgG FcγRI (CD64) PU.1 and NFI-A

Benakanakere et al. 2009 Sonkoly et al. 2008 Eberhart et al. 2008 Sonkoly et al. 2008 Xie et al. 2012 Rosa et al. 2007

Granulation phase

miR-15a miR-15b miR-16 miR-17 miR-17-92 miR-20a miR-20b miR-21 miR-92a miR-101 miR-126 miR-130a miR-184 miR-200b miR-203 miR-205 miR-206 miR-210 miR-221 miR-222 miR-296 miR-320 miR-378

VEGF VEGF VEGF Janus Kinase 1 CTGF, TSP-1 VEGF VEGF TIAM1, TIMP3 Integrin-α5 VEGF Spred1, PIK3R2 GAX, HOXA5 Akt Ets1 p63 Rho-ROCK1, SHIP2, VEGF E2F3, EFNA3, ISCU 1/2 c-kit c-kit HGS IGF-1 Fus-1, Sufu

Sun et al. 2013 Hua et al. 2006 Sun et al. 2013 Doebele et al. 2010 Dews et al. 2006; Suarez et al. 2007 Hua et al. 2006 Sun et al. 2013 Yang et al. 2011 Bonauer et al. 2009 Zhang et al. 2013 Fish et al. 2008; Kuhnert et al. 2008; Wang et al. 2008 Chen and Gorski 2008 Yu et al. 2008 Roy and Sen 2012 Lena et al. 2008 Yu et al. 2008 Zhang et al. 2011 Fasanaro et al. 2008; Biswas et al. 2010 Poliseno et al. 2006 Poliseno et al. 2006 Wurdinger et al. 2008 Wang et al. 2009 Lee et al. 2007

Remodelling phase

miR-29a miR-29b miR-29c miR-192

Type I and II collagen β-catenin, Smads β-catenin, Smads SIP1

Maurer et al. 2010 van Rooij et al. 2008; Li et al. 2009 van Rooij et al. 2008; Li et al. 2009 Kato et al. 2007

addition, a subset of miRNAs (miR-20b, miR-10a, miR-10b, miR-96, miR-128, miR-452 and miR-541) have displayed similar basal levels in normal and diabetic skin, but exhibited dysregulation during wound healing under diabetic conditions (Madhyastha et al. 2012). These findings implied that careful evaluation of the medical history of patients may be required before miRNA targets are selected for treatment. No doubt, there are many hurdles to be overcome before miRNA-targeted wound therapies can be practicable clinically. Nevertheless, modulation of miRNAs has already been successfully achieved practically by using anti-sense

oligonucleotides, LNAs and antagomirs (Brock et al. 2012; Lee et al. 2012b; Selvamani et al. 2012). This success, along with recent advances in nucleic acid delivery technologies (Lai 2011a, b, 2013, 2014; Lai and Lin 2009), has already established a platform for future development of therapies targeting miRNAs for treatment of both normal and chronic wounds, including diabetic foot ulcers and pressure ulcers (Siu et al. 2009, 2011; Teng et al. 2011a, b; Sin et al. 2013). Once the roles of miRNAs in wound healing have been clarified, what we are looking forward to soon is to turn miRNA-targeted wound treatment from a conceptual chimera into a reality.

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Wing-Fu Lai and Parco M Siu Acknowledgements

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Wing-Fu Lai and Parco M Siu

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MS received 26 June 2013; accepted 10 February 2014

Corresponding editor: GEETA VEMUGANTI

J. Biosci. 39(3), June 2014