Cellular Mechanisms in Wound Healing

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Gene and Cell Therapy".

Deadline for manuscript submissions: closed (31 October 2020) | Viewed by 23297

Special Issue Editor

Research Unit of Histology and Embryology, Department of Biology, University of Florence, Florence, Italy
Interests: photobiology; photoimmunology; phototherapy; targeted therapies; photobiomodulation; wound healing; basic sciences
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Special Issue Information

Dear Colleagues,

A wound determines a cascade of chemical and morphological events, directed at hemostasis, prevention or arrest of infection, removal of damaged tissue, and eventually tissue repair. Deep knowledge of the cells and molecules involved in the tissue response to trauma is important to actively control the response to surgical operations and therapies other than help healing chronic ulceration. It may also be relevant to assess the survival time upon a lethal trauma, which is of importance in forensic medicine. Therefore, the purpose of this Special Issue is to stimulate research and clinical interest in this exciting field and to serve as a point of reference for those who are involved in dealing with the problems posed by wounds and their recovery.

Dr. Stefano Bacci
Guest Editor

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Keywords

  • acute wounds
  • blue light emission diode
  • cellular infiltrate
  • chronic wounds
  • forensic medicine
  • healing
  • pharmacological therapies
  • photobiomodulation
  • photodynamic therapy

Published Papers (7 papers)

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Editorial

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4 pages, 193 KiB  
Editorial
Cellular Mechanisms and Therapies in Wound Healing: Looking toward the Future
by Stefano Bacci
Biomedicines 2021, 9(11), 1611; https://doi.org/10.3390/biomedicines9111611 - 04 Nov 2021
Cited by 8 | Viewed by 1865
Abstract
The high professionalism of these publications consists, on the one hand, of revealing some of the mechanisms underlying wound healing and, on the other hand, of proposing alternative therapies for the fine control of inflammation following injury to avoid fibrotic scars or impaired [...] Read more.
The high professionalism of these publications consists, on the one hand, of revealing some of the mechanisms underlying wound healing and, on the other hand, of proposing alternative therapies for the fine control of inflammation following injury to avoid fibrotic scars or impaired wounds [...] Full article
(This article belongs to the Special Issue Cellular Mechanisms in Wound Healing)

Research

Jump to: Editorial

23 pages, 6104 KiB  
Article
Effect of NIR Laser Therapy by MLS-MiS Source on Fibroblast Activation by Inflammatory Cytokines in Relation to Wound Healing
by Shirley Genah, Francesca Cialdai, Valerio Ciccone, Elettra Sereni, Lucia Morbidelli and Monica Monici
Biomedicines 2021, 9(3), 307; https://doi.org/10.3390/biomedicines9030307 - 16 Mar 2021
Cited by 9 | Viewed by 2989
Abstract
The fine control of inflammation following injury avoids fibrotic scars or impaired wounds. Due to side effects by anti-inflammatory drugs, the research is continuously active to define alternative therapies. Among them, physical countermeasures such as photobiomodulation therapy (PBMT) are considered effective and safe. [...] Read more.
The fine control of inflammation following injury avoids fibrotic scars or impaired wounds. Due to side effects by anti-inflammatory drugs, the research is continuously active to define alternative therapies. Among them, physical countermeasures such as photobiomodulation therapy (PBMT) are considered effective and safe. To study the cellular and molecular events associated with the anti-inflammatory activity of PBMT by a dual-wavelength NIR laser source, human dermal fibroblasts were exposed to a mix of inflammatory cytokines (IL-1β and TNF-α) followed by laser treatment once a day for three days. Inducible inflammatory key enzymatic pathways, as iNOS and COX-2/mPGES-1/PGE2, were upregulated by the cytokine mix while PBMT reverted their levels and activities. The same behavior was observed with the proangiogenic factor vascular endothelial growth factor (VEGF), involved in neovascularization of granulation tissue. From a molecular point of view, PBMT retained NF-kB cytoplasmatic localization. According to a change in cell morphology, differences in expression and distribution of fundamental cytoskeletal proteins were observed following treatments. Tubulin, F-actin, and α-SMA changed their organization upon cytokine stimulation, while PBMT reestablished the basal localization. Cytoskeletal rearrangements occurring after inflammatory stimuli were correlated with reorganization of membrane α5β1 and fibronectin network as well as with their upregulation, while PBMT induced significant downregulation. Similar changes were observed for collagen I and the gelatinolytic enzyme MMP-1. In conclusion, the present study demonstrates that the proposed NIR laser therapy is effective in controlling fibroblast activation induced by IL-1β and TNF-α, likely responsible for a deleterious effect of persistent inflammation. Full article
(This article belongs to the Special Issue Cellular Mechanisms in Wound Healing)
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14 pages, 2065 KiB  
Article
Photobiomodulation of Human Fibroblasts and Keratinocytes with Blue Light: Implications in Wound Healing
by Francesca Rossi, Giada Magni, Francesca Tatini, Martina Banchelli, Federica Cherchi, Michele Rossi, Elisabetta Coppi, Anna Maria Pugliese, Duccio Rossi degl’Innocenti, Domenico Alfieri, Francesco S. Pavone, Roberto Pini and Paolo Matteini
Biomedicines 2021, 9(1), 41; https://doi.org/10.3390/biomedicines9010041 - 05 Jan 2021
Cited by 22 | Viewed by 3973
Abstract
In recent years, photobiomodulation (PBM) has been recognized as a physical therapy in wound management. Despite several published research papers, the mechanism underlying photobiomodulation is still not completely understood. The investigation about application of blue light to improve wound healing is a relatively [...] Read more.
In recent years, photobiomodulation (PBM) has been recognized as a physical therapy in wound management. Despite several published research papers, the mechanism underlying photobiomodulation is still not completely understood. The investigation about application of blue light to improve wound healing is a relatively new research area. Tests in selected patients evidenced a stimulation of the healing process in superficial and chronic wounds treated with a blue LED light emitting at 420 nm; a study in animal model pointed out a faster healing process in superficial wound, with an important role of fibroblasts and myofibroblasts. Here, we present a study aiming at evidencing the effects of blue light on the proliferation and metabolism in fibroblasts from healthy skin and keratinocytes. Different light doses (3.43, 6.87, 13.7, 20.6, 30.9 and 41.2 J/cm2) were used to treat the cells, evidencing inhibitory and stimulatory effects following a biphasic dose behavior. Electrophysiology was used to investigate the effects on membrane currents: healthy fibroblasts and keratinocytes showed no significant differences between treated and not treated cells. Raman spectroscopy revealed the mitochondrial Cytochrome C (Cyt C) oxidase dependence on blue light irradiation: a significant decrease in peak intensity of healthy fibroblast was evidenced, while it is less pronounced in keratinocytes. In conclusion, we observed that the blue LED light can be used to modulate metabolism and proliferation of human fibroblasts, and the effects in wound healing are particularly evident when studying the fibroblasts and keratinocytes co-cultures. Full article
(This article belongs to the Special Issue Cellular Mechanisms in Wound Healing)
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19 pages, 3805 KiB  
Article
Experimental Study on Blue Light Interaction with Human Keloid-Derived Fibroblasts
by Giada Magni, Martina Banchelli, Federica Cherchi, Elisabetta Coppi, Marco Fraccalvieri, Michele Rossi, Francesca Tatini, Anna Maria Pugliese, Duccio Rossi Degl’Innocenti, Domenico Alfieri, Paolo Matteini, Roberto Pini, Francesco S. Pavone and Francesca Rossi
Biomedicines 2020, 8(12), 573; https://doi.org/10.3390/biomedicines8120573 - 06 Dec 2020
Cited by 19 | Viewed by 4300
Abstract
Keloids are an exuberant response to wound healing, characterized by an exaggerated synthesis of collagen, probably due to the increase of fibroblasts activity and to the reduction of their apoptosis rate: currently no standard treatments or pharmacological therapies are able to prevent keloid [...] Read more.
Keloids are an exuberant response to wound healing, characterized by an exaggerated synthesis of collagen, probably due to the increase of fibroblasts activity and to the reduction of their apoptosis rate: currently no standard treatments or pharmacological therapies are able to prevent keloid recurrence. To reach this goal, in recent years some physical treatments have been proposed, and among them the PhotoBioModulation therapy (PBM). This work analyses the effects of a blue LED light irradiation (410–430 nm, 0.69 W/cm2 power density) on human fibroblasts, isolated from both keloids and perilesional tissues. Different light doses (3.43–6.87–13.7–20.6–30.9 and 41.2 J/cm2) were tested. Biochemical assays and specific staining were used to assess cell metabolism, proliferation and viability. Micro-Raman spectroscopy was used to explore direct effects of the blue LED light on the Cytochrome C (Cyt C) oxidase. We also investigated the effects of the irradiation on ionic membrane currents by patch-clamp recordings. Our results showed that the blue LED light can modulate cell metabolism and proliferation, with a dose-dependent behavior and that these effects persist at least till 48 h after treatment. Furthermore, we demonstrated that the highest fluence value can reduce cell viability 24 h after irradiation in keloid-derived fibroblasts, while the same effect is observed 48 h after treatment in perilesional fibroblasts. Electrophysiological recordings showed that the medium dose (20.6 J/cm2) of blue LED light induces an enhancement of voltage-dependent outward currents elicited by a depolarizing ramp protocol. Overall, these data demonstrate the potentials that PBM shows as an innovative and minimally-invasive approach in the management of hypertrophic scars and keloids, in association with current treatments. Full article
(This article belongs to the Special Issue Cellular Mechanisms in Wound Healing)
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13 pages, 3754 KiB  
Article
Vivostat Platelet-Rich Fibrin® for Complicated or Chronic Wounds—A Pilot Study
by Andreas Bayer, Gesa Höntsch, Mark Kaschwich, Annika Dell, Markus Siggelkow, Rouven Berndt, Rene Rusch, Jürgen Harder, Regine Gläser and Jochen Cremer
Biomedicines 2020, 8(8), 276; https://doi.org/10.3390/biomedicines8080276 - 06 Aug 2020
Cited by 8 | Viewed by 2909
Abstract
Vivostat Platelet-Rich Fibrin® (PRF) is an autologous platelet concentrate used for the local treatment of chronic or complicated wounds. Still, its application for this indication is not evidence-based. Therefore, we performed this monocentric retrospective pilot study investigating the clinical outcome of a [...] Read more.
Vivostat Platelet-Rich Fibrin® (PRF) is an autologous platelet concentrate used for the local treatment of chronic or complicated wounds. Still, its application for this indication is not evidence-based. Therefore, we performed this monocentric retrospective pilot study investigating the clinical outcome of a local treatment of chronic or complicated wounds in 35 patients (23 male, 12 female, mean age 68.7 years) treated with Vivostat PRF®. This study population is the largest among published studies analyzing the clinical efficacy of Vivostat PRF® on chronic wounds so far. Using the perpendicular method we divided the wounds into three sizes (<10, 10–30, and >30 cm2). The clinical efficacy of the Vivostat PRF treatment was the primary endpoint and was divided into three groups of increasing degrees of wound improvement: (1) no improvement of the wound (wound area was not reduced > 10% under Vivostat PRF® treatment), (2) improvement of the wound (reduced area > 10% under Vivostat PRF® treatment) and (3) complete epithelialization (wounds that were completely re-epithelialized after Vivostat PRF® treatment). We included patients’ diagnosis and concomitant diseases (peripheral arterial occlusive disease (PAOD)), chronic venous insufficiency (CVI)), diabetic foot syndrome (DFS)) in our data analysis in order to investigate their potential impact on the wound healing capacity of Vivostat PRF®. Our results show that in the entire study population, 13 out of 35 (37.1%) patients experienced wound improvement and 14 out of 35 (40%) patients showed complete epithelialization of their wound under Vivostat PRF® treatment. In summary, 77.1% of the treated patients benefited from the Vivostat PRF® therapy. These positive wound healing effects were all observed within the first three to six Vivostat PRF® applications. Subgroup analyses showed that Vivostat PRF® appeared to be more efficient in patients without CVI in comparison to patients with CVI (p = 0.02). Moreover, Vivostat PRF® treatment seems to be particularly efficient in PAOD-related wounds with a reduced crural arterial blood supply (p = 0.01). Additionally, we performed an experimental human in vivo study on ten male students where we artificially generated bilateral gluteal wounds and analyzed the influence of the Vivostat PRF® treatment on the expression of two genes (human beta Defensin-2, ((hBD-2) and human beta-Defensin-3 (hBD-3)) in keratinocytes of resected wound specimens that are induced during wound healing. Interestingly, this analysis revealed that only seven of out ten individuals showed a relevant hBD-2 and hBD-3 gene induction after Vivostat PRF® treatment. This led to the novel “key-lock-hypothesis”. With the goal of an individualized precision medicine approach with optimized wound treatment strategies in the future, this is an important observation that demands further experimental and clinical studies. Full article
(This article belongs to the Special Issue Cellular Mechanisms in Wound Healing)
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14 pages, 6095 KiB  
Article
Secreted Factors from Keloid Keratinocytes Modulate Collagen Deposition by Fibroblasts from Normal and Fibrotic Tissue: A Pilot Study
by Mansour A. Alghamdi, Laith N. AL-Eitan, Andrew Stevenson, Nutan Chaudhari, Nicole Hortin, Hilary J. Wallace, Patricia L. Danielsen, Mitali Manzur, Fiona M. Wood and Mark W. Fear
Biomedicines 2020, 8(7), 200; https://doi.org/10.3390/biomedicines8070200 - 08 Jul 2020
Cited by 7 | Viewed by 2688
Abstract
Interactions between keratinocytes and fibroblasts in the skin layers are crucial in normal tissue development, wound healing, and scarring. This study has investigated the role of keloid keratinocytes in regulating collagen production by primary fibroblasts in vitro. Keloid cells were obtained from removed [...] Read more.
Interactions between keratinocytes and fibroblasts in the skin layers are crucial in normal tissue development, wound healing, and scarring. This study has investigated the role of keloid keratinocytes in regulating collagen production by primary fibroblasts in vitro. Keloid cells were obtained from removed patients’ tissue whereas normal skin cells were discarded tissue obtained from elective surgery procedures. Fibroblasts and keratinocytes were isolated, cultured, and a transwell co-culture system were used to investigate the effect of keratinocytes on collagen production using a ‘scar-in-a-jar’ model. Keloid fibroblasts produced significantly more collagen than normal skin fibroblasts in monoculture at the RNA, secreted protein, and stable fibrillar protein level. When keloid keratinocytes were added to normal skin fibroblasts, expression of collagen was significantly upregulated in most samples, but when added to keloid fibroblasts, collagen I production was significantly reduced. Interestingly, keloid keratinocytes appear to decrease collagen production by keloid fibroblasts. This suggests that signaling in both keratinocytes and fibroblasts is disrupted in keloid pathology. Full article
(This article belongs to the Special Issue Cellular Mechanisms in Wound Healing)
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16 pages, 1847 KiB  
Article
Identification of Differentially Methylated CpG Sites in Fibroblasts from Keloid Scars
by Mansour A. Alghamdi, Hilary J. Wallace, Phillip E. Melton, Eric K. Moses, Andrew Stevenson, Laith N. Al-Eitan, Suzanne Rea, Janine M. Duke, Patricia L. Danielsen, Cecilia M. Prêle, Fiona M. Wood and Mark W. Fear
Biomedicines 2020, 8(7), 181; https://doi.org/10.3390/biomedicines8070181 - 28 Jun 2020
Cited by 12 | Viewed by 3234
Abstract
As a part of an abnormal healing process of dermal injuries and irritation, keloid scars arise on the skin as benign fibroproliferative tumors. Although the etiology of keloid scarring remains unsettled, considerable recent evidence suggested that keloidogenesis may be driven by epigenetic changes, [...] Read more.
As a part of an abnormal healing process of dermal injuries and irritation, keloid scars arise on the skin as benign fibroproliferative tumors. Although the etiology of keloid scarring remains unsettled, considerable recent evidence suggested that keloidogenesis may be driven by epigenetic changes, particularly, DNA methylation. Therefore, genome-wide scanning of methylated cytosine-phosphoguanine (CpG) sites in extracted DNA from 12 keloid scar fibroblasts (KF) and 12 control skin fibroblasts (CF) (six normal skin fibroblasts and six normotrophic fibroblasts) was conducted using the Illumina Human Methylation 450K BeadChip in two replicates for each sample. Comparing KF and CF used a Linear Models for Microarray Data (Limma) model revealed 100,000 differentially methylated (DM) CpG sites, 20,695 of which were found to be hypomethylated and 79,305 were hypermethylated. The top DM CpG sites were associated with TNKS2, FAM45B, LOC723972, GAS7, RHBDD2 and CAMKK1. Subsequently, the most functionally enriched genes with the top 100 DM CpG sites were significantly (p ≤ 0.05) associated with SH2 domain binding, regulation of transcription, DNA-templated, nucleus, positive regulation of protein targeting to mitochondrion, nucleoplasm, Swr1 complex, histone exchange, and cellular response to organic substance. In addition, NLK, CAMKK1, LPAR2, CASP1, and NHS showed to be the most common regulators in the signaling network analysis. Taken together, these findings shed light on the methylation status of keloids that could be implicated in the underlying mechanism of keloid scars formation and remission. Full article
(This article belongs to the Special Issue Cellular Mechanisms in Wound Healing)
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