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Cellular and Molecular Mechanisms of Wound Healing

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Chemical Biology".

Deadline for manuscript submissions: closed (31 August 2021) | Viewed by 83744

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Dr. Ryan Moseley

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Guest Editor

Regenerative Biology Group, Oral and Biomedical Sciences, School of Dentistry, Cardiff Institute of Tissue Engineering and Repair (CITER), Cardiff University, Heath Park, Cardiff, UK
Interests: wound healing; regenerative medicine; chronic wounds; myofibroblasts; scarring and fibrosis; natural compounds; drug development; oxidative stress; cellular senescence; type II diabetes
Special Issues, Collections and Topics in MDPI journals

Dr. Robert Steadman

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Welsh Kidney Research Unit, Division of Infection and Immunity, Cardiff Institute of Tissue Engineering and Repair (CITER), School of Medicine, Cardiff University, Heath Park, Cardiff, UK
Interests: scarring; fibrosis; myofibroblast cell biology; wound healing; scarless healing; hyaluronan; regenerative medicine; kidney disease

Dr. Adam C. Midgley

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Guest Editor

College of Life Sciences, Nankai University, Tianjin, China
Interests: fibrosis; wound healing; cell biology; molecular signaling; nanomedicine; biomaterials; gene therapy; peptide engineering; alternative splicing; epigenetic regulation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Normal wound healing in postnatal skin is a complex process, involving many different stages and cell types as well as numerous signalling molecules and pathways, which aim to restore skin structure and function. However, abnormalities in these processes can cause significantly impaired or excessive wound healing, culminating in clinical situations such as non-healing chronic wounds and dermal fibrosis, respectively.

Chronic wounds, such as venous and diabetic ulcers, are a major cause of disability and patient morbidity, particularly amongst ever-increasing ageing and type II diabetes patient populations. Excessive dermal scarring (fibrosis) is another largely unmet clinical need, usually occurring as a consequence of surgery, trauma or burn injuries. Consequently, both conditions pose significant challenges to healthcare services worldwide, confounded by current acceptance that existing therapies are largely unsatisfactory in their treatment.

Although much is now known regarding the cell and molecular changes which mediate the pathophysiology of these aberrant healing outcomes, novel roles for particular genes, proteins and signalling pathways in these processes are ever emerging. Furthermore, by understanding the fundamental mechanisms underlying regenerative tissue scenarios associated with rapid healing and minimal scarring, such as those established for early-gestational foetal skin, oral mucosa and unique mammalian models of tissue regeneration, such as Acomys cahirinus, it may be possible to gain insights leading to the development of new therapeutic approaches for the prevention or improved treatment of these conditions.

This Special Issue of Biomolecules seeks manuscripts that provide new insights on 1) the cellular and molecular mechanisms involved in normal dermal wound healing and scarring; 2) the cellular and molecular mechanisms associated with aberrant healing situations in the skin, such as non-healing chronic wounds or dermal fibrosis; 3) the cellular and molecular mechanisms in privileged wound healing scenarios, such as foetal skin and oral mucosa; and 4) the development of novel treatment strategies aiming to enhance wound healing responses or minimise scarring in the skin.

We encourage scientists working in this area of research to submit original research articles or critical reviews that synthesize the current research literature and discuss emerging directions. Thus, these studies will contribute to the development of therapeutic interventions that target the mechanisms of dermal injury and wound repair.

Dr. Ryan Moseley
Dr. Robert Steadman
Dr. Adam C. Midgley
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Normal wound healing
Scarring
Chronic wounds
Inflammation
Angiogenesis
Fibroblasts
Keratinocytes
Scarless healing
Tissue regeneration
Therapy development.

Published Papers (11 papers)

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Research

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15 pages, 5107 KiB

Open AccessArticle

Pinocembrin Ameliorates Skin Fibrosis via Inhibiting TGF-β1 Signaling Pathway

by Xiaohe Li, Yunqian Zhai, Buri Xi, Wei Ma, Jianwei Zhang, Xiaoyang Ma, Yang Miao, Yongjian Zhao, Wen Ning, Honggang Zhou and Cheng Yang

Biomolecules 2021, 11(8), 1240; https://doi.org/10.3390/biom11081240 - 19 Aug 2021

Cited by 18 | Viewed by 3557

Abstract

Skin fibrotic diseases, such as keloids, are mainly caused by pathologic scarring of wounds during healing and characterized by benign cutaneous overgrowths of dermal fibroblasts. Current surgical and therapeutic modalities of skin fibrosis are unsatisfactory. Pinocembrin, a natural flavonoid, has been shown to possess a vast range of pharmacological activities including antimicrobial, antioxidant, anti-inflammatory, and anti-tumor activities. In this study we explored the potential effect and mechanisms of pinocembrin on skin fibrosis in vitro and in vivo. In vitro studies indicated that pinocembrin dose-dependently suppressed proliferation, migration, and invasion of keloid fibroblasts and mouse primary dermal fibroblasts. The in vivo studies showed that pinocembrin could effectively alleviate bleomycin (BLM)-induced skin fibrosis and reduce the gross weight and fibrosis-related protein expression of keloid tissues in xenograft mice. Further mechanism studies indicated that pinocembrin could suppress TGF-β1/Smad signaling and attenuate TGF-β1-induced activation of skin fibroblasts. In conclusion, our results demonstrate the therapeutic potential of pinocembrin for skin fibrosis. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Wound Healing)

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17 pages, 1891 KiB

Open AccessArticle

Cold Atmospheric Plasma Promotes the Immunoreactivity of Granulocytes In Vitro

by Laura S. Kupke, Stephanie Arndt, Simon Lenzer, Sophia Metz, Petra Unger, Julia L. Zimmermann, Anja-Katrin Bosserhoff, Michael Gruber and Sigrid Karrer

Biomolecules 2021, 11(6), 902; https://doi.org/10.3390/biom11060902 - 17 Jun 2021

Cited by 11 | Viewed by 2471

Abstract

Cold atmospheric plasma (CAP) reduces bacteria and interacts with tissues and cells, thus improving wound healing. The CAP-related induction of neutrophils was recently described in stained sections of wound tissue in mice. Consequently, this study aimed to examine the functionality of human polymorphonuclear cells (PMN)/granulocytes through either a plasma-treated solution (PTS) or the direct CAP treatment with different plasma modes and treatment durations. PTS analysis yielded mode-dependent differences in the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) after CAP treatment. Live-cell imaging did not show any chemo-attractive or NETosis-inducing effect on PMNs treated with PTS. The time to maximum ROS production (T_maxROS) in PMNs was reduced by PTS and direct CAP treatment. PMNs directly treated with CAP showed an altered cell migration dependent on the treatment duration as well as decreased T_maxROS without inducing apoptosis. Additionally, flow cytometry showed enhanced integrin and selectin expression, as a marker of activation, on PMN surfaces. In conclusion, the modification of PMN immunoreactivity may be a main supporting mechanism for CAP-induced improvement in wound healing. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Wound Healing)

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21 pages, 14257 KiB

Open AccessArticle

Cerium-Containing N-Acetyl-6-Aminohexanoic Acid Formulation Accelerates Wound Reparation in Diabetic Animals

by Ekaterina Blinova, Dmitry Pakhomov, Denis Shimanovsky, Marina Kilmyashkina, Yan Mazov, Tatiana Demura, Vladimir Drozdov, Dmitry Blinov, Olga Deryabina, Elena Samishina, Aleksandra Butenko, Sofia Skachilova, Alexey Sokolov, Olga Vasilkina, Bashar A. Alkhatatneh, Olga Vavilova, Andrey Sukhov, Daniil Shmatok, Ilya Sorokvasha, Oxana Tumutolova and Elena Lobanova Show full author list Hide full author list

Biomolecules 2021, 11(6), 834; https://doi.org/10.3390/biom11060834 - 03 Jun 2021

Cited by 6 | Viewed by 3261

Abstract

Background: The main goal of our study was to explore the wound-healing property of a novel cerium-containing N-acethyl-6-aminohexanoate acid compound and determine key molecular targets of the compound mode of action in diabetic animals. Methods: Cerium N-acetyl-6-aminohexanoate (laboratory name LHT-8-17) as a 10 mg/mL aquatic spray was used as wound experimental topical therapy. LHT-8-17 toxicity was assessed in human skin epidermal cell culture using (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. A linear wound was reproduced in 18 outbred white rats with streptozotocin-induced (60 mg/kg i.p.) diabetes; planar cutaneous defect was modelled in 60 C57Bl₆ mice with streptozotocin-induced (200 mg/kg i.p.) diabetes and 90 diabetic db/db mice. Firmness of the forming scar was assessed mechanically. Skin defect covering was histologically evaluated on days 5, 10, 15, and 20. Tissue TNF-α, IL-1β and IL-10 levels were determined by quantitative ELISA. Oxidative stress activity was detected by Fe-induced chemiluminescence. Ki-67 expression and CD34 cell positivity were assessed using immunohistochemistry. FGFR3 gene expression was detected by real-time PCR. LHT-8-17 anti-microbial potency was assessed in wound tissues contaminated by MRSA. Results: LHT-8-17 4 mg twice daily accelerated linear and planar wound healing in animals with type 1 and type 2 diabetes. The formulated topical application depressed tissue TNF-α, IL-1β, and oxidative reaction activity along with sustaining both the IL-10 concentration and antioxidant capacity. LHT-8-17 induced Ki-67 positivity of fibroblasts and pro-keratinocytes, upregulated FGFR3 gene expression, and increased tissue vascularization. The formulation possessed anti-microbial properties. Conclusions: The obtained results allow us to consider the formulation as a promising pharmacological agent for diabetic wound topical treatment. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Wound Healing)

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0 pages, 22557 KiB

Open AccessArticle

Multifunctional Injectable Hydrogel Loaded with Cerium-Containing Bioactive Glass Nanoparticles for Diabetic Wound Healing

by Yue-Hua Chen, Zhou-Feng Rao, Yu-Jie Liu, Xiang-Sheng Liu, Yu-Fei Liu, Lan-Ju Xu, Ze-Qi Wang, Jing-Yue Guo, Lin Zhang, Yun-Sheng Dong, Chun-Xiao Qi, Chao Yang and Shu-Fang Wang

Biomolecules 2021, 11(5), 702; https://doi.org/10.3390/biom11050702 - 08 May 2021

Cited by 52 | Viewed by 4393 | Correction

Abstract

Diabetic foot wound healing is a major clinical problem due to impaired angiogenesis and bacterial infection. Therefore, an effective regenerative dressing is desiderated with the function of promoting revascularization and anti-bacteria. Herein, a multifunctional injectable composite hydrogel was prepared by incorporation of the cerium-containing bioactive glass (Ce-BG) into Gelatin methacryloyl (GelMA) hydrogel. The Ce-BG was synthesized by combining sol-gel method with template method, which maintained spherical shape, chemical structure and phase constitution of bioactive glass (BG). The Ce-BG/GelMA hydrogels had good cytocompatibility, promoted endothelial cells migration and tube formation by releasing Si ion. In vitro antibacterial tests showed that 5 mol % CeO₂-containing bioactive glass/GelMA (5/G) composite hydrogel exhibited excellent antibacterial properties. In vivo study demonstrated that the 5/G hydrogel could significantly improve wound healing in diabetic rats by accelerating the formation of granulation tissue, collagen deposition and angiogenesis. All in all, these results indicate that the 5/G hydrogel could enhance diabetic wound healing. Therefore, the development of multifunctional materials with antibacterial and angiogenic functions is of great significance to promote the repair of diabetic wound healing. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Wound Healing)

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Review

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31 pages, 953 KiB

Open AccessEditor’s ChoiceReview

Macrophages in Skin Wounds: Functions and Therapeutic Potential

by Seen Ling Sim, Snehlata Kumari, Simranpreet Kaur and Kiarash Khosrotehrani

Biomolecules 2022, 12(11), 1659; https://doi.org/10.3390/biom12111659 - 08 Nov 2022

Cited by 16 | Viewed by 4839

Abstract

Macrophages regulate cutaneous wound healing by immune surveillance, tissue repair and remodelling. The depletion of dermal macrophages during the early and middle stages of wound healing has a detrimental impact on wound closure, characterised by reduced vessel density, fibroblast and myofibroblast proliferation, delayed re-epithelization and abated post-healing fibrosis and scar formation. However, in some animal species, oral mucosa and foetal life, cutaneous wounds can heal normally and remain scarless without any involvement of macrophages. These paradoxical observations have created much controversy on macrophages’ indispensable role in skin wound healing. Advanced knowledge gained by characterising macrophage subsets, their plasticity in switching phenotypes and molecular drivers provides new insights into their functional importance during cutaneous wound healing. In this review, we highlight the recent findings on skin macrophage subsets, their functional role in adult cutaneous wound healing and the potential benefits of targeting them for therapeutic use. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Wound Healing)

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21 pages, 916 KiB

Open AccessFeature PaperReview

Bioactive Antimicrobial Peptides as Therapeutic Agents for Infected Diabetic Foot Ulcers

by Jessica Da Silva, Ermelindo C. Leal and Eugénia Carvalho

Biomolecules 2021, 11(12), 1894; https://doi.org/10.3390/biom11121894 - 17 Dec 2021

Cited by 20 | Viewed by 5488

Abstract

Diabetic foot ulcer (DFU) is a devastating complication, affecting around 15% of diabetic patients and representing a leading cause of non-traumatic amputations. Notably, the risk of mixed bacterial–fungal infection is elevated and highly associated with wound necrosis and poor clinical outcomes. However, it is often underestimated in the literature. Therefore, polymicrobial infection control must be considered for effective management of DFU. It is noteworthy that antimicrobial resistance is constantly rising overtime, therefore increasing the need for new alternatives to antibiotics and antifungals. Antimicrobial peptides (AMPs) are endogenous peptides that are naturally abundant in several organisms, such as bacteria, amphibians and mammals, particularly in the skin. These molecules have shown broad-spectrum antimicrobial activity and some of them even have wound-healing activity, establishing themselves as ideal candidates for treating multi-kingdom infected wounds. Furthermore, the role of AMPs with antifungal activity in wound management is poorly described and deserves further investigation in association with antibacterial agents, such as antibiotics and AMPs with antibacterial activity, or alternatively the application of broad-spectrum antimicrobial agents that target both aerobic and anaerobic bacteria, as well as fungi. Accordingly, the aim of this review is to unravel the molecular mechanisms by which AMPs achieve their dual antimicrobial and wound-healing properties, and to discuss how these are currently being applied as promising therapies against polymicrobial-infected chronic wounds such as DFUs. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Wound Healing)

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10 pages, 704 KiB

Open AccessReview

Immunologic Roles of Hyaluronan in Dermal Wound Healing

by Aditya Kaul, Walker D. Short, Sundeep G. Keswani and Xinyi Wang

Biomolecules 2021, 11(8), 1234; https://doi.org/10.3390/biom11081234 - 18 Aug 2021

Cited by 14 | Viewed by 3703

Abstract

Hyaluronic acid (HA), a glycosaminoglycan ubiquitous in the skin, has come into the limelight in recent years for its role in facilitating dermal wound healing. Specifically, HA’s length of linearly repeating disaccharides—in other words, its molecular weight (MW)—determines its effects. High molecular weight (HMW)-HA serves an immunosuppressive and anti-inflammatory role, whereas low molecular weight (LMW)-HA contributes to immunostimulation and thus inflammation. During the inflammatory stage of tissue repair, direct and indirect interactions between HA and the innate and adaptive immune systems are of particular interest for their long-lasting impact on wound repair. This review seeks to synthesize the literature on wound healing with a focus on HA’s involvement in the immune subsystems. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Wound Healing)

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22 pages, 4261 KiB

Open AccessEditor’s ChoiceReview

The Bigger Picture: Why Oral Mucosa Heals Better Than Skin

by Maaike Waasdorp, Bastiaan P. Krom, Floris J. Bikker, Paul P. M. van Zuijlen, Frank B. Niessen and Susan Gibbs

Biomolecules 2021, 11(8), 1165; https://doi.org/10.3390/biom11081165 - 06 Aug 2021

Cited by 48 | Viewed by 10956

Abstract

Wound healing is an essential process to restore tissue integrity after trauma. Large skin wounds such as burns often heal with hypertrophic scarring and contractures, resulting in disfigurements and reduced joint mobility. Such adverse healing outcomes are less common in the oral mucosa, which generally heals faster compared to skin. Several studies have identified differences between oral and skin wound healing. Most of these studies however focus only on a single stage of wound healing or a single cell type. The aim of this review is to provide an extensive overview of wound healing in skin versus oral mucosa during all stages of wound healing and including all cell types and molecules involved in the process and also taking into account environmental specific factors such as exposure to saliva and the microbiome. Next to intrinsic properties of resident cells and differential expression of cytokines and growth factors, multiple external factors have been identified that contribute to oral wound healing. It can be concluded that faster wound closure, the presence of saliva, a more rapid immune response, and increased extracellular matrix remodeling all contribute to the superior wound healing and reduced scar formation in oral mucosa, compared to skin. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Wound Healing)

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27 pages, 1968 KiB

Open AccessFeature PaperReview

Myofibroblasts: Function, Formation, and Scope of Molecular Therapies for Skin Fibrosis

by Yifan Tai, Emma L. Woods, Jordanna Dally, Deling Kong, Robert Steadman, Ryan Moseley and Adam C. Midgley

Biomolecules 2021, 11(8), 1095; https://doi.org/10.3390/biom11081095 - 23 Jul 2021

Cited by 76 | Viewed by 13483

Abstract

Myofibroblasts are contractile, α-smooth muscle actin-positive cells with multiple roles in pathophysiological processes. Myofibroblasts mediate wound contractions, but their persistent presence in tissues is central to driving fibrosis, making them attractive cell targets for the development of therapeutic treatments. However, due to shared cellular markers with several other phenotypes, the specific targeting of myofibroblasts has long presented a scientific and clinical challenge. In recent years, myofibroblasts have drawn much attention among scientific research communities from multiple disciplines and specialisations. As further research uncovers the characterisations of myofibroblast formation, function, and regulation, the realisation of novel interventional routes for myofibroblasts within pathologies has emerged. The research community is approaching the means to finally target these cells, to prevent fibrosis, accelerate scarless wound healing, and attenuate associated disease-processes in clinical settings. This comprehensive review article describes the myofibroblast cell phenotype, their origins, and their diverse physiological and pathological functionality. Special attention has been given to mechanisms and molecular pathways governing myofibroblast differentiation, and updates in molecular interventions. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Wound Healing)

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15 pages, 1955 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Immunomodulatory Properties of Host Defence Peptides in Skin Wound Healing

by Marija Petkovic, Michelle Vang Mouritzen, Biljana Mojsoska and Håvard Jenssen

Biomolecules 2021, 11(7), 952; https://doi.org/10.3390/biom11070952 - 28 Jun 2021

Cited by 23 | Viewed by 5746

Abstract

Cutaneous wound healing is a vital biological process that aids skin regeneration upon injury. Wound healing failure results from persistent inflammatory conditions observed in diabetes, or autoimmune diseases like psoriasis. Chronic wounds are incurable due to factors like poor oxygenation, aberrant function of peripheral sensory nervature, inadequate nutrients and blood tissue supply. The most significant hallmark of chronic wounds is heavily aberrant immune skin function. The immune response in humans relies on a large network of signalling molecules and their interactions. Research studies have reported on the dual role of host defence peptides (HDPs), which are also often called antimicrobial peptides (AMPs). Their duality reflects their potential for acting as antibacterial peptides, and as immunodulators that assist in modulating several biological signalling pathways related to processes such as wound healing, autoimmune disease, and others. HDPs may differentially control gene regulation and alter the behaviour of epithelial and immune cells, resulting in modulation of immune responses. In this review, we shed light on the understanding and most recent advances related to molecular mechanisms and immune modulatory features of host defence peptides in human skin wound healing. Understanding their functional role in skin immunity may further inspire topical treatments for chronic wounds. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Wound Healing)

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25 pages, 1744 KiB

Open AccessReview

Immunology of Acute and Chronic Wound Healing

by Kamila Raziyeva, Yevgeniy Kim, Zharylkasyn Zharkinbekov, Kuat Kassymbek, Shiro Jimi and Arman Saparov

Biomolecules 2021, 11(5), 700; https://doi.org/10.3390/biom11050700 - 08 May 2021

Cited by 276 | Viewed by 23091

Abstract

Skin wounds greatly affect the global healthcare system, creating a substantial burden on the economy and society. Moreover, the situation is exacerbated by low healing rates, which in fact are overestimated in reports. Cutaneous wounds are generally classified into acute and chronic. The immune response plays an important role during acute wound healing. The activation of immune cells and factors initiate the inflammatory process, facilitate wound cleansing and promote subsequent tissue healing. However, dysregulation of the immune system during the wound healing process leads to persistent inflammation and delayed healing, which ultimately result in chronic wounds. The microenvironment of a chronic wound is characterized by high quantities of pro-inflammatory macrophages, overexpression of inflammatory mediators such as TNF-α and IL-1β, increased activity of matrix metalloproteinases and abundance of reactive oxygen species. Moreover, chronic wounds are frequently complicated by bacterial biofilms, which perpetuate the inflammatory phase. Continuous inflammation and microbial biofilms make it very difficult for the chronic wounds to heal. In this review, we discuss the role of innate and adaptive immunity in the pathogenesis of acute and chronic wounds. Furthermore, we review the latest immunomodulatory therapeutic strategies, including modifying macrophage phenotype, regulating miRNA expression and targeting pro- and anti-inflammatory factors to improve wound healing. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Wound Healing)

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