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Journal of Wound Management and Research > Volume 20(2); 2024 > Article
Shojaeian: Deciphering the Role of Non-Coding RNAs as Regulators in the Wound Healing Process

Abstract

Various factors can influence the complex process of wound healing. Non-coding RNAs (ncRNAs), which include long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), as well as microRNAs (miRNAs), contribute critically to the regulation of wound healing mechanisms. Specific miRNAs regulate fibroblast proliferation, migration, and extracellular matrix production, while others influence keratinocyte migration and re-epithelialization. Some miRNAs also modulate the inflammatory response and regulate angiogenesis during wound healing. The emerging significance of circRNAs in regulating fibroblast and keratinocyte functions during wound healing are also to be noted, as are the significant roles lncRNAs play in influencing various aspects of wound healing. This review underscores the pivotal roles played by ncRNAs in orchestrating the intricate processes involved in wound healing, providing insights into potential therapeutic targets and strategies for enhancing wound healing outcomes.

Introduction

The skin, our largest and most exposed organ, constantly faces the challenges of trauma and complex pathophysiological conditions. Clinicians encounter severe medical situations. Skin wound healing is a meticulously orchestrated process aimed at restoring the skin’s barrier function. In general, skin wound healing is often categorized into four sequential but overlapping phases. The phases are known as the hemostasis (several hours after injury), inflammation (1–3 days), proliferation (4–21 days), and tissue remodeling (21 days-1 year) phase [1,2]. Various factors such as the size of the wound, the person’s age, vascular diseases, diabetes, infections, and numerous other conditions can slow down the healing process, leading to long-term complications. This delay in wound healing imposes a significant health and economic strain on both patients and society [3]. At present, a variety of treatments are available for wound healing, including tissue-engineered substitutes, skin autografts, as well as numerous types of wound dressings. However, their effectiveness can be limited according to the circumstances surrounding the wound. As a result, there is an urgent need to comprehend the biological mechanisms involved in the wound healing process to develop more effective wound healing treatments for more satisfactory results [4].
Epigenetics has been defined as the research on inheritable alterations/changes in gene-related functions without involvement of changes in the underlying DNA sequence. Recent applications of epigenetics include studies on multiple complex morbidities and diseases such as fibrosis, diabetes as well as cancer. The primary mechanisms employed in epigenetics include regulating non-coding RNAs (ncRNAs) and modifying DNA(s) and histone [5].
Despite making up less than 2% of the human genome, protein-coding genes have been the subject of research for decades. The vast majority of the human genome is transcribed to RNAs that lack protein-coding capacity. Nonetheless, the ENCODE (ENCyclopedia Of DNA Elements) study reported in 2012 that transcription accounts for about 80% of the genome. Consequently, the majority of the RNAs that are not able to code for proteins make up the transcriptional output of the human genome [6]. Over the last 20 years, extensive research has shown that these ncRNAs, a heterogeneous group of RNA molecules (transcripts) that are not translated into proteins, play crucial roles in regulating cellular physiology and disease, making them potential therapeutic and diagnostic entities [7]. These ncRNAs include microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) [8].
Investigating the role of ncRNAs reveals emerging concepts and is a promising prospect for pharmacological intervention. The study of Ghatak et al. [9] showed that the expression of Dicer, an essential enzyme for miRNA biogenesis, increased during wound healing. Xie et al. [10] demonstrated that miR-1908 plays a crucial role in wound healing by promoting the proliferation and production of growth factors such as transforming growth factor β (TGF-β), interleukin (IL)-1, tumor necrosis factor α (TNF-α), and collagen type I. According to Dangwal et al. [11], by specifically targeting zonula occludens-1 (ZO-1), miR-191 suppresses angiogenesis and fibroblast migration, ultimately leading to a delay in skin repair. The approximate number of known miRNAs, lncRNAs and circRNAs are 28,866, 6,066 and 10,732, respectively (Fig. 1).
This review concentrates on the regulatory role of ncRNAs like miRNAs, lncRNAs, as well as circRNAs in wound healing (Fig. 2) [12]. I have chosen not to delve into other epigenetic processes involved in wound healing to ensure the article remains concise and engaging for the readers.

Mechanisms of ncRNAs in wound healing

Wound healing and miRNAs

The first and most crucial ncRNAs, known as miRNAs, are small, single-stranded RNA molecules containing 21 to 23 nucleotides. These highly conserved ncRNA molecules mainly contribute to the regulation of gene expression at the posttranscriptional level. Moreover, miRNAs’ control is linked to delayed wound healing by affecting fibroblast behavior, angiogenesis, keratinocyte (KC) behavior, and regulation of inflammation.

The behavior of fibroblasts and KCs during wound healing is influenced by miRNAs

Fibroblasts, which are highly diverse cells, have a critical contribution to wound healing. In addition, their lineage, phenotype, and adaptability are closely tied to the outcomes of wound repair [13]. Specifically, dermal fibroblasts have been identified as central participants in the process of healing, transitioning from a pro-inflammatory state to an anti-inflammatory one during wound repair. These cells are both involved in synthesizing and remodeling extracellular matrix (ECM) proteins, but they also regulate immune cells, KCs, endothelial cells (ECs), and mast cells by releasing various signaling molecules [14].
Research by Zhou et al. [15] demonstrated that miR-200b, a type of miRNA, reduces fibroblast proliferation, migration, and collagen production by down-regulating the expression of Zeb1. This disruption negatively impacts wound healing. Additionally, miR-21, another miRNA, appears to be a key player in non-healing diabetic wounds, as it is involved in fibroblast migration in vitro [16]. Furthermore, miR-378a knockdown accelerates fibroblast migration, differentiation, and angiogenesis, ultimately speeding up the healing of wounds through integrin β3 and vimentin up-regulation [17]. miR-132 had been demonstrated to enhance the migration of human dermal fibroblasts through down-regulation of the expression of RAS P21 protein activator 1 (RASA1) in the course of wound healing [18]. Lastly, stimulating D-glucose suppresses expression of miR-21-3p in fibroblasts, whereas an miR-21-3p agonist promotes the release of growth factors, proliferation of fibroblasts, and collagen synthesis, thus accelerating diabetic wound healing [19].
miR-145 enhances the expression of α-smooth muscle actin (α-SMA), a critical factor for generating contractile force in myofibroblasts. It achieves this by directly targeting Kruppel-like factor 4 (KLF4), a known inhibitor of α-SMA. When myofibroblasts were treated with miR-145 inhibitors, there was a significant reduction in collagen I expression, TGF-β1 secretion, contractile force generation, and migration [20].
KCs do more than just offer structural support; they also interact with other cells and play a significant role in immunomodulation during wound healing. Being the most prevalent cell in human skin, KCs have a variety of roles influenced by miRNAs during key stages of wound healing [21]. Gaining insight into the complex contribution of KCs to the pathology of chronic wounds could potentially open up new pathways to speed up wound healing.
Sundaram and colleagues suggested that miR-198 hinders the migration of KCs and the re-epithelialization process during wound healing by suppressing urokinase-type plasminogen activator (PLAU), diaphanous related formin 1 (DIAPH1), as well as laminin subunit gamma 2 (LAMC2) [22].
Hu et al. [23] demonstrated that TGF-β1 has the potential to down-regulate KH-type splicing regulatory protein (KSRP), thereby controlling one of the single primary transcripts of miR-198 and follistatin-like 1 (FSTL1). This leads to the promotion of FSTL1 expression and the suppression of miR-198 expression. TGF-β1 can also elevate the expression of miR-23b in HaCaT cells, which in turn promotes the migration of KCs via down-regulating tissue inhibitor metalloproteinase (TIMP) metallopeptidase inhibitor 3 (TIMP3) [23].
Aunin et al. [24] conducted a comprehensive miRNA analysis on wound skin obtained from both old and young mice. They discovered elevated miR-200c expression in the older group, and determined that miR-200c may potentially hinder wound healing in aged skin via disrupting KC differentiation and obstructing KC migration.
In a separate study, Tang and Ran [25] proposed that hypoxia in KCs led to increased miR-219-5p as well as a decrease in transmembrane protein 98 (TMEM98). miR-219-5p has the ability to target TMEM98, thereby suppressing the positive impact of TMEM98 on wound healing. These impacts of TMEM98 include promotion of cell proliferation and migration, and also reduction of the inflammatory response. On the other hand, miR-126 enhances KC proliferation and migration through reducing the levels of polo-like kinase 2 (PLK2) as well as activating the signaling pathway of phosphoinositide-3 kinase/protein kinase B (PI3K/AKT) [26].
Overexpression of miR-96-5p reduced the proliferation and migration of human primary KCs in in vitro experiments by suppressing the BCL2 interacting protein 3/focal adhesion kinase (BNIP3/FAK) pathway. This suggests the ability of miR-96-5p to modulate KCs, potentially delaying wound healing [27].
Moreover, Jin et al. [28] discovered down-regulation of miR-99 family members in wounded skin. The miR-99 family enhanced KC proliferation and migration and expedited the healing process of wounds through the mammalian target of rapamycin (mTOR) and PI3K/AKT pathways. Additionally, in their study, Yang et al. [29] observed that TGF-β1 could up-regulate miR-21 expression in KCs, and that miR-21 overexpression facilitated migration as well as re-epithelialization of KCs by reducing TIMP3 and T-lymphoma invasion and metastasis (TIAM) Rac1-associated levels of guanine nucleotide exchange factor (GEF) 1 (TIAM1) in the process of wound healing.
Dallas et al. [30] stated that miR-210 was linked to reduced KC proliferation and migration, which negatively impacted wound healing. In contrast, the expression of miR-132 in KCs showed dynamic increases during the inflammatory phase and reached its peak during the subsequent proliferative phase. Li et al. [31] demonstrated that miR-132 enhances KC growth by activating signal transducer and activator of transcription 3 (STAT3) as well as mitogen-activated protein kinase 1 (also known as ERK) pathways, while also mitigating inflammation through inhibition of the nuclear factor kappa B subunit 1 (NF-κB) pathway.
Furthermore, Shi et al.’s findings [32] revealed that miR-31 expression in KCs was up-regulated during the inflammatory phase, and it reached its peak during the proliferative phase. Additionally, miR-34c and miR-34a overexpression was observed in KCs obtained from venous ulcers. Interestingly, miR-34 enhanced the production of pro-inflammatory chemokines and cytokines by KCs via inhibition of LGR4 during the inflammation-related phase, which ultimately impaired the wound healing process [33]. Table 1 provides a summary of some of these miRNAs [16,23,32-39].

The impact of miRNAs on inflammation in wound healing

As mentioned earlier, miRNA has a crucial contribution to the healing process of wounds, especially in the challenging management of the inflammatory process during wound recovery. In the context of diabetic wounds, elevated TGF-β levels suppress DNA methyltransferase 3 beta (DNMT3b)-mediated hypermethylation by boosting miR-29b expression, which in turn enhances cyclooxygenase-2/prostaglandin E2 (COX-2/PGE2) production [36].
miR-497 expression was found to be decreased in skin wounds of diabetic mice. However, when miR-497 was injected intradermally, it speeded up the wound healing process by reducing proinflammatory cytokines such as TNF-α, IL-1β, and IL-6 [40]. In their study, Xu et al. [35] found that expression of miR-146a was reduced in wounds of diabetic mice, while pro-inflammatory target gene expression increased. However, treatment with mesenchymal stromal/stem cells (MSCs) made a positive impact, reducing inflammation and enhancing the healing process of wounds in diabetic mice by up-regulating the expression of miR-146a.
miR-155 is a versatile miRNA that plays a crucial role in the development and functioning of immune cells. Ye et al. [37] demonstrated that inhibiting miR-155 can decrease wound site inflammation. This also enhances the granulation tissue formation, angiogenesis, and collagen synthesis, all of which are crucial for wound healing. Yang et al. [41] presented findings of miR-155 up-regulation during the inflammatory phase in skin wounds of mice. When specific miR-155 inhibitors were used to treat wounds in mice, they observed reduced recruitment of inflammatory cells to the wound site and improved tissue architecture during regeneration. Interestingly, miR-155 mutant mice exhibited faster wound closure and increased deposition of type-1 collagen compared to wild-type mice [42].
The shift from M1 to M2 macrophages plays a crucial role in wound healing. Disruption of this transition has been linked to the development of chronic wounds. Interestingly, miRNAs are also involved in regulating macrophage polarization. For example, miR-9, miR-127, miR-155, and miR-125b promote M1 polarization, while miR-124, miR-223, miR-34a, let-7c, miR-132, miR-146a, and miR-125a-5p induce M2 polarization [43,44]. When miR-155 was knocked out, there was an enhancement in the total number of M2 macrophages in mice, improving wound healing [42].
Moura et al. [45] found that miR-155 boosts the infiltration of inflammatory cells into wounds and suppresses proliferation and migration of KCs or fibroblasts via targeting fibroblast growth factor 7 (FGF7). This suggests that inhibiting miR-155 could potentially speed up the healing process of wounds in diabetic people. In addition, the elimination of miR-155 led to a reduced IL-17/IL-9 response during wound healing, which in turn decreased inflammation mediated by T cells by targeting c-Maf in these cells [46]. The results from these studies imply that miR-155 might be a promising target for mitigating inflammation in wound tissues.

The impact of miRNAs on angiogenesis in wound healing

Reduced blood vessel formation and blood flow to the wound bed are crucial factors in impaired wound healing. In relation to diabetic foot ulcers (DFU) as well as other chronic conditions like pressure ulcers and venous stasis, various types of miRNAs are involved in vascular insufficiency, blood vessel formation, and the transcription of genes related to blood vessel formation [47].
Pizzino et al. [38] demonstrated that the use of antagomirs for miR-15b and miR-200b led to increased angiogenesis in diabetic wounds. This was achieved by enhancing the expression of angiopoietin 1 (Ang-1) together with vascular endothelial growth factor (VEGF) A and its receptor.
Patients suffering from infected DFUs experienced elevated miR-23c expression, while the expression of stromal cell-derived factor (SDF)-1α was notably reduced in individuals with infected DFU and type 2 diabetes mellitus [39]. This suggests that miR-23c may hinder angiogenesis in the wounds of diabetic people via targeting SDF-1α.
Xu et al. [48] utilized the Gene Expression Omnibus database for identifying differential expression of post-traumatic stress disorder in patients with diabetes, with miR-152-3p emerging as a potent upstream regulator of phosphatase and tensin homolog (PTEN). Inhibition of miR-152-3p enhanced the proliferation as well as angiogenesis of human umbilical vein ECs (HUVECs) and sped up the healing process of wounds by upregulating PTEN. Additionally, the miR-92a inhibitor MRG-110 increased expression of the miR-92a target gene integrin subunit alpha 5 (ITGA5), leading to enhanced formation of granulation tissue, wound re-epithelialization, and improved angiogenesis in DB/DB mice [49].
Miscianinov et al. [34] discovered that increased expression of miR-148b boosted EC growth, movement, and blood vessel formation. Additionally, it suppressed cytokine-triggered changes in cell behavior known as epithelial-mesenchymal transition in laboratory settings by specifically targeting TGF-β2 and mothers against decapentaplegic homolog 2 (SMAD2).
Wang et al. [50] discovered that the expression of miR-27b was reduced in angiogenic cells derived from the bone marrow of diabetic mice. However, when they introduced a miR-27b mimic, it enhanced the effectiveness of bone marrow aspirate concentrate (BMAC) therapy for closing diabetic skin wounds and restored impaired BMAC angiogenic function. This improvement was achieved by suppressing the activity of p66shc, semaphorin 6A (Sema6A), and thrombospondin-1 (TSP-1).
According to Liu et al. [51], increased expression of miR-195 after negative-pressure wound therapy led to higher microvessel density and reduced levels of NLR family member X1 (NLRX1) in granulation tissue. Ultimately, this enhancement contributed to the acceleration of wound healing.

lncRNA and wound healing

lncRNAs are RNA molecules exceeding 200 nucleotides in length that do not encode protein [52]. These fascinating molecules play a crucial role in cellular processes by interacting with miRNAs. By binding to miRNAs, lncRNAs fine-tune gene expression, impacting cellular homeostasis, overall functional performance, as well as genomic stability. Moreover, lncRNAs with aberrant expression are also implicated in cancer and skin regeneration, as well as inflammation. In the context of wound healing, researchers have identified more than 10 lncRNAs with significant roles [53]. In wound healing, the lncRNA growth arrest specific 5 (GAS5) exhibits both positive and negative stimulatory effects. Hu et al. [54] demonstrated that the up-regulated lncRNA GAS5 in the wounds of diabetic people facilitated macrophage polarization towards an M1 phenotype by enhancing STAT1 expression. Meanwhile, reducing the expression of GAS5 facilitated the M1-M2 transition of macrophages, rescuing impaired healing of the wounds caused by diabetes. However, according to Sawaya et al.’s study in this regard [55], topical mevastatin is capable of inhibiting expression of the transcription factor c-Myc, a biomarker of non-healing wounds, via up-regulating lncRNA GAS5. This in turn can accelerate DFU healing through declining the synthesis of cortisol, as was verified in biopsies including KCs from DFU patients. He et al. [56] also reported that lncRNA GAS5 is downregulated in the context of diabetes. Furthermore, the overexpression of lncRNA GAS5 has been shown to facilitate lymphangiogenesis and simplify the healing process of wounds in diabetic conditions, primarily through the miR-217/Prox1 axis.
Another study demonstrated the reduced level of expression of lncRNA antisense ncRNA in the INK4 Locus (ANRIL) in diabetes. It functions as one of the sponges for miR-181a, leading to Prox1 up-regulation. Additionally, inhibited levels of miR-181a suppress hyperglycemia-induced apoptosis in lymphatic ECs (LECs) across the caspase pathway. This process promotes formation of lymphatic vessels and accelerates the healing process of wounds in diabetic individuals [57].
In individuals with diabetes, abnormal expression levels of lncRNA H19 imprinted maternally expressed transcript (H19) is linked to complications. Guo et al. [58] found that after modified preservative fluid-preserved autologous blood transfusion treatment, expression of lncRNA H19 increased in fibroblasts from mice diabetic wounds. Furthermore, the upregulated H19 recruited enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), enhancing hypoxia inducible factor 1 subunit α (HIF-1α) histone H3K4me3 methylation. This process ultimately activated fibroblasts and accelerated the healing process of the diabetic wounds. The lncRNA H19 also functions as a sponge for miR-29b, leading to an increase in fibrillin 1 (FBN1) expression. This, in turn, enhances the migration and proliferation of fibroblasts [59].
In addition, research of Herter et al. [60] revealed downregulation of ANRIL induced through signaling TGF-β in the edges of chronic wounds in humans. WAKMAR2 also played a role in inhibiting the KC production of inflammatory chemokines and enhancing KC migration, thereby accelerating the healing process.
Overexpressed linc00174 plays a crucial role in stimulating EC-mediated angiogenesis, thereby accelerating the healing process of burn wounds through the regulatory axis of linc00174-EZH2-ZNF24/Runx1-VEGFA [61]. Another well-known lncRNA is HOX transcript antisense RNA (HOTAIR). Expression of HOTAIR increased in healing burn wounds. Moreover, up-regulation of HOTAIR was related to enhanced proliferation and stemness of embryonic stem cells (ESCs); HOTAIR-overexpressing ESCs have been shown to facilitate re-epithelialization and promote wound healing in burn injuries [62].
In turn, HOTAIR up-regulates the expression of sciellin (SCEL) via working as the sponge for miR-126. This interaction leads to promotion of HUVEC proliferation, invasion, migration, apoptosis, and also tube formation. Consequently, the axis HOTAIR/miR-126/SCEL may play a crucial role in modulating the burn wound healing via angiogenesis regulation [62]. Fig. 3 provides a concise overview of interactions involving ncRNAs and their roles in wound healing [62].
Zhou et al. [63] observed up-regulation of 10/11 translocation 2 (TET2) interacting long ncRNA (TETILA) in diabetic skin which induced demethylation of the matrix metalloproteinase 9 (MMP-9) promoter. This process negatively impacted diabetic wound healing through the modification of activities of, as well as localization of the demethylation enzymes, specifically TET2.
Liang et al. [64] found that metastasis associated lung adenocarcinoma transcript 1 (MALAT1) enhances the signaling pathway of TGFβ2/SMAD2, thereby regulating fibroblast migration and proliferation. Additionally, MALAT1 promotes the wound healing process via targeting miR-141-3p and upregulating ZNF217 expression. Table 2 provides a summary of some of these lncRNAs [54,58,60-65].

circRNA and wound healing

circRNAs fall within a broad class of endogenous ncRNAs. They have been found to have end-to-end structural links, creating single-chain molecules that have a covalently closed loop configuration that is formed through reverse splicing of the pre-mRNAs, involving both exons and introns. Among these, exon-derived circRNAs predominantly occur in cytoplasm, whereas intron-derived circRNAs primarily reside in the nucleus. Interestingly, some circularized exons retain introns, resulting in a subtype known as the exon-intron circRNAs, which is generally detected within the nucleus. Though the exact mechanisms of circRNA formation remains incompletely understood, three models have been proposed: RNA-binding protein (RBP)-mediated circularization, lariat-driven circularization, as well as intron-pairing-driven circularization [66].
circRNAs have been observed in various contexts: in the human E-twenty-six-1 (ETS-1) gene, in yeast mitochondria, in the sex-determining region Y (Sry) of mice, in the human P450 2C18 gene, in the rat cytochrome P450 2C24 gene, as well as in hepatitis delta virus [66]. These circRNAs abound in a variety of cells and tissues, existing in both pathological and physiological cases. The significant contribution of circRNAs in wound healing has increasingly been highlighted in several studies. For instance, circ-Amotl1 enhances fibroblast migration and growth, thereby accelerating the wound healing process. This effect is achieved by reducing the expression of miR-17-5p and promoting STAT3 nuclear translocation [67].
Han et al. [68] discovered that circ_ protein kinase catalytic subunit (PRKDC) expression was down-regulated during the healing process of skin wounds. Furthermore, circ_PRKDC knock-down led to the activation of KC migration, thereby accelerating the wound healing process through the axis miR-31/FBN1.
Finally, hsa_circ_0084443 is one of the circRNAs down-regulated during normal wound healing, as it acts as a negative regulator of KC migration. hsa_circ_0084443 has been found to be elevated in DFU tissue samples, implying its involvement in pathological processes. These findings provide insights into the significant contribution of circRNAs to the healing process of human skin [69,70]. Table 3 provides a summary of some of these circRNAs involved in wound healing [67-69,71,72].
Table 4 provides specific examples of the mechanisms employed by these ncRNAs, including acting as miRNA sponges, recruiting epigenetic modifiers, and regulating signaling pathways and gene expression [54,59,65,68,72-78]. Table 5 presents a summary of the role of lncRNAs and circRNAs in various wound healing mechanisms such as cellular migration, proliferation, inflammation, and angiogenesis. While some lncRNAs and circRNAs promote wound healing by positively influencing these processes, others can impede wound healing by negatively regulating these events.

Conclusion and future direction

The epigenetic regulation of gene expression through ncRNAs including lncRNAs, circRNAs, and miRNAs plays a pivotal role in the complex procedure of wound healing. This review has highlighted the diverse functions of these ncRNAs in modulating key aspects of wound repair, such as the behavior of fibroblasts and KCs, inflammation, and angiogenesis. miRNAs have emerged as critical regulators, with some promoting wound healing by enhancing cell migration, proliferation, and angiogenesis, while others impair the process by increasing inflammation or inhibiting these cellular functions. lncRNAs like GAS5, HOTAIR, and MALAT1 have also been identified as crucial players, acting through various mechanisms like sponging miRNAs, recruiting epigenetic modifiers, and regulating signaling pathways. Moreover, circRNAs have gained attention for their roles in wound healing, with certain circRNAs promoting processes like fibroblast activation, KC migration, and angiogenesis, while others may impede these events.
The intricate interplay between these different classes of ncRNAs adds another layer of complexity to the regulatory networks governing wound repair. While significant progress has been made in elucidating the roles of ncRNAs in wound healing, many questions remain unanswered. Further investigations are needed to fully understand the specific mechanisms by which these ncRNAs exert their effects, and also their potency as treatment targets or biomarkers for wound management. Additionally, concerted efforts should be directed towards developing ncRNA-based therapeutic interventions, integrating ncRNA studies with investigations into other epigenetic mechanisms like DNA methylation and histone modifications, and leveraging cutting-edge bioinformatics and computational approaches to identify key ncRNA regulators, predict their targets, and elucidate their functional roles in orchestrating the complex wound healing cascade.
While this article highlights the pivotal roles played by various ncRNAs in regulating key aspects of the wound healing process, the successful manipulation of these ncRNAs in a clinical setting presents several hurdles. One major challenge lies in developing effective delivery mechanisms that can precisely target and deliver the desired ncRNA molecules to the intended sites of action within the wound microenvironment. Additionally, the inherent instability and susceptibility of RNA molecules to degradation by cellular enzymes pose significant obstacles for maintaining their bioavailability and functional integrity. Furthermore, given the multifaceted roles of ncRNAs in various cellular processes, the potential for off-target effects and unintended consequences upon their manipulation cannot be overlooked. Addressing these challenges will require interdisciplinary collaborations involving experts in fields such as biomaterials, nanotechnology, and pharmacokinetics, to develop innovative delivery systems, stabilization strategies, and methods for minimizing off-target effects.
The potential for integrating ncRNA-based therapies with existing treatments, such as tissue-engineered scaffolds, growth factor delivery, or cell-based therapies, presents an exciting opportunity to create more comprehensive and effective approaches for promoting tissue repair and regeneration. For instance, ncRNA-modulating agents could be incorporated into biomaterial scaffolds or combined with stem cell therapies to enhance their therapeutic efficacy. Furthermore, the development of targeted delivery systems for ncRNAs could enable site-specific modulation of the wound healing microenvironment, minimizing off-target effects. Interdisciplinary collaborations between researchers in the fields of ncRNA biology, biomaterials science, and tissue engineering could pave the way for innovative regenerative strategies that harness the regulatory potential of ncRNAs for improving wound healing outcomes and addressing various tissue repair challenges.

Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Fig. 1.
Distribution of non-coding RNAs.
jwmr-2024-02999f1.jpg
Fig. 2.
Structures of various types of non-coding RNAs. MicroRNAs (miRNAs) are a category of small non-coding RNAs, with a length of 19–25 nucleotides. They inhibit gene expression by directly binding to the 3’-untranslated region (UTR), 5’-UTR, and coding sequence regions of their target messenger RNAs, which results in translational repression and/or cleavage. On the other hand, long non-coding RNAs (lncRNAs) are the largest non-coding RNAs, exceeding 200 nucleotides in length, and they lack an open reading frame. They perform physiological functions by modulating gene expressions at various levels, including DNA methylation, recruitment of transcriptional factors, acting as miRNA sponges, and facilitating protein-protein interactions. Lastly, circular RNAs (circRNAs) are distinguished by their covalently closed single-stranded loop structures, devoid of free 3’ and 5’ ends. The most commonly reported function of circRNAs is their ability to bind miRNAs, thereby preventing them from binding to their canonical messenger RNA target genes, a phenomenon known as the “sponge effect.” Reprinted from Jiang et al. Exp Ther Med 2021;21:555 [12].
jwmr-2024-02999f2.jpg
Fig. 3.
Comparison of epigenetic regulation via non-coding RNAs. Macrophages, keratinocytes, fibroblasts, and vascular endothelial cells play crucial roles in wound repair. Epigenetic modifications can control the release of inflammatory factors, the transition between M1 and M2 macrophage states, and the migration of macrophages. In addition, epigenetic modifications also impact the proliferation and migration abilities of keratinocytes, fibroblasts, and vascular endothelial cells, either promoting or impairing the processes of re-epithelialization, collagen deposition, and angiogenesis during wound healing. Reprinted from Yu et al. Front Physiol 2022;13:949498 [62].
jwmr-2024-02999f3.jpg
Table 1.
Some of the miRNAs involved in wound healing
miRNA Function Reference
miR-23b Accelerate wound healing [23]
miR-21 Accelerate wound healing [16]
miR-148b Accelerate wound healing [34]
miR-31 Accelerate wound healing [32]
miR-146a Accelerate wound healing [35]
miR-29b Impair wound healing [36]
miR-155 Impair wound healing [37]
miR-15b Impair wound healing [38]
miR-23c Impair wound healing [39]
miR-34 Impair wound healing [33]

miRNA, microRNA.

Table 2.
Some of the lncRNAs involved in wound healing
lncRNA Function Reference
MALAT1 Accelerate wound healing [64]
H19 Accelerate wound healing [58]
ANRIL Accelerate wound healing [60]
WAKMAR2 Accelerate wound healing [60]
HOTAIR Accelerate wound healing [62]
Linc00174 Accelerate wound healing [61]
GAS5 Impair wound healing [54]
lnc-URIDS Impair wound healing [65]
TETILA Impair wound healing [63]

lncRNA, long non-coding RNA.

Table 3.
Some of the circRNAs involved in wound healing
circRNA Function Reference
mmu_circ_0000250 Accelerate wound healing [71]
circ-Amotl1 Accelerate wound healing [67]
hsa_circ_0084443 Impair wound healing [69]
circ_PRKDC Impair wound healing [68]
hsa_circ_0075932 Impair wound healing [72]
hsa_circ_0084443 Impair wound healing [69]
circ_0000250 Impair wound healing [71]

circRNA, circular RNA.

Table 4.
Comparing lncRNAs and circRNAs in wound healing
Name Expression Sponge Type of animal study Target gene Pathway Phase Reference
lncRNAs
 GAS5 Up-regulate, promotes the M1phenotypicpolarization of macrophages through the up-regulation of STAT1 Mouse STAT1 Inflammation, leading to prolonged inflammatory phase and delayed wound closure [54]
 GAS5 Up-regulate, activates the HIF-1α/VEGF pathway Mouse TAF15 HIF-1α/VEGF, GAS5 activates the HIF-1α/VEGF pathway by binding to TATA box Proliferation, leading to accelerated wound healing [72]
 MALAT1 Down-regulate, leading to insufficient HIF-1α/VEGF activation and impeding angiogenesis HIF-1α/Nrf2 Proliferation, leading to impeded wound healing [73]
 lnc01435 Up-regulate, increase HDAC 8 expression Mouse YY1, HDACs Activates Notch Proliferation, leading to accelerated wound healing [74]
 H19 Up-regulate, promotes ECM accumulation miRNA-29b, H19 acts as a sponge for miR-29b and competitively represses miR-29b expression Mouse FBN1 Activates TGF-β/Smad Regeneration, leading to accelerated wound healing [59]
 H19 Up-regulate, activating CTGF and its downstream MAPK signaling pathway to accelerate fibroblast proliferation and wound healing Rat CTGF, SRF Activates MAPK Regeneration, leading to accelerated wound healing [75]
 URIDS Up-regulate, highly expressed in diabetic skin and dermal fibroblasts Plod1 Activates VEGF/TGF-β Regeneration, leads to dysregulated collagen deposition and delayed wound healing [65]
 CASC2 Down-regulate, promote fibroblast migration and proliferation, increased apoptosis miR-155, miR-155 overexpression inhibited the function of CASC2 Mouse HIF-1α Regeneration, leading to impeded wound healing [76]
circRNAs
 circ_0084443 Up-regulate, impeding re-epithelialization and angiogenesis Proliferation, leading to impeded wound healing [77]
 circ_PRKDC Down-regulate, promotes epidermal keratinocyte migration miR-31, circ_PRKDC knockdown promotes epidermal keratinocyte migration via the miR-31/FBN1 axis FBN1 Proliferation, leading to accelerated wound healing [68]
 circ_Klhl8 Up-regulate, increases the therapeutic effect of EPCs to promote diabetic wound healing miR-212-3p, circ-Klhl8 overexpression increases the therapeutic effect of EPCs to promote diabetic wound healing by targeting the miR-212-3p/SIRT5 axis Mouse SIRT5 Proliferation, leading to accelerated wound healing [78]

lncRNAs, long non-coding RNAs; circRNAs, circular RNAs; STAT1, signal transducer and activator of transcription 3; HIF-1α, hypoxia inducible factor 1 subunit α; VEGF, vascular endothelial growth factor; GAS5, growth arrest specific 5; HDAC, histone deacetylase; ECM, extracellular matrix; TGF-β, transforming growth factor β; CTGF, connective tissue growth factor; MAPK, mitogen-activated protein kinase; CASC2, cancer susceptibility candidate 2; EPC, endothelial progenitor cell; SIRT5, sirtuin 5.

Table 5.
Summary of the role of lncRNA and circRNAs in wound healing based on this article
Feature lncRNAs circRNAs
Examples promoting wound healing MALAT1, H19, ANRIL, WAKMAR2, HOTAIR, Linc00174 circ-Amotl1, mmu_circ_0000250
Examples impeding wound healing GAS5, lnc-URIDS, TETILA hsa_circ_0084443, circ_PRKDC, hsa_circ_0075932, circ_0000250
Mechanisms of action Act as miRNA sponges, recruit epigenetic modifiers, regulate signaling pathways (e.g., TGF-β, HIF-1α) Act as miRNA sponges (e.g., circ-Amotl1 sponges miR-17-5p), regulate gene expression (e.g., circ_PRKDC targets miR-31/FBN1 axis)
Effects on cellular processes Influence fibroblast migration, proliferation, and activation; keratinocyte migration and re-epithelialization; inflammation; angiogenesis Modulate fibroblast migration and proliferation; keratinocyte migration and proliferation; angiogenesis
Specific examples GAS5 promotes M1 macrophage polarization, impeding wound healing, H19 recruits EZH2, activating HIF-1α and fibroblasts, ANRIL promotes lymphangiogenesis via miR-217/Prox1 axis circ-Amotl1 promotes STAT3 nuclear translocation, enhancing fibroblast migration, hsa_circ_0084443 inhibits keratinocyte migration and proliferation

lncRNAs, long non-coding RNAs; circRNAs, circular RNAs; miRNA, microRNAs; TGF-β, transforming growth factor β; HIF-1α, hypoxia inducible factor 1 subunit α.

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