Skin Fibrosis and Cutaneous Wound Healing

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: 31 August 2024 | Viewed by 5336

Special Issue Editor


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Guest Editor
Department of Plastic and Reconstructive Surgery, Keio University Hospital, Tokyo 160-8582, Japan
Interests: fibroblasts; inflammation; fibrosis; cutaneous wound healing

Special Issue Information

Dear Colleagues,

During the wound healing process, epithelialization is completed and remodeling of the extracellular matrix that makes up the granulation tissue occurs. Fibroblasts and leukocytes disappear from the granulation tissue formed during the proliferative phase, and collagen fibers are altered to form scar tissue. Granulation tissue contains large amounts of type III collagen, which diminishes during maturation and is replaced by type I collagen. Collagen polymerizes through cross-linking, increasing the support and tensile strength of the scar. If inflammation is prolonged during this period, fibroblasts do not decrease and collagen production continues, causing hypertrophic scars and keloids. The purpose of this Special Issue is to focus on inflammation and fibrosis and to explore their mechanisms.

Dr. Noriko Aramaki-Hattori
Guest Editor

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Published Papers (5 papers)

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Research

23 pages, 11305 KiB  
Article
AT2R Activation Improves Wound Healing in a Preclinical Mouse Model
by Julia M. Harrison, Edwin K. Leong, Natasha D. Osborne, Jean S. Marshall and Michael Bezuhly
Biomedicines 2024, 12(6), 1238; https://doi.org/10.3390/biomedicines12061238 - 3 Jun 2024
Viewed by 264
Abstract
Abnormal skin healing resulting in chronic wounds or hypertrophic scarring remains a major healthcare burden. Here, the antifibrotic angiotensin II type 2 receptor (AT2R) signaling pathway was modulated to determine its impact on cutaneous wound healing. Balb/c mice received two splinted full-thickness wounds. [...] Read more.
Abnormal skin healing resulting in chronic wounds or hypertrophic scarring remains a major healthcare burden. Here, the antifibrotic angiotensin II type 2 receptor (AT2R) signaling pathway was modulated to determine its impact on cutaneous wound healing. Balb/c mice received two splinted full-thickness wounds. Topical treatments with the selective AT2R agonist compound 21 (C21) and/or selective antagonist PD123319 or saline vehicle were administered until sacrifice on post-wounding days 7 or 10. The rate of wound re-epithelialization was accelerated by PD123319 and combination treatments. In vitro, C21 significantly reduced human fibroblast migration. C21 increased both collagen and vascular densities at days 7 and 10 post-wounding and collagen I:III ratio at day 10, while PD123319 and combination treatments decreased them. Genes associated with regeneration and repair were upregulated by C21, while PD123319 treatment increased the expression of genes associated with inflammation and immune cell chemotaxis. C21 treatment reduced wound total leukocyte and neutrophil staining densities, while PD123319 increased these and macrophage densities. Overall, AT2R activation with C21 yields wounds that mature more quickly with structural, cellular, and gene expression profiles more closely approximating unwounded skin. These findings support AT2R signal modulation as a potential therapeutic target to improve skin quality during wound healing. Full article
(This article belongs to the Special Issue Skin Fibrosis and Cutaneous Wound Healing)
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11 pages, 722 KiB  
Article
The Relationship between Time, Race, and Estrogen Receptor Alpha in Estradiol-Induced Dermal Fibrosis
by DeAnna Baker Frost, Alisa Savchenko, Carol Feghali-Bostwick and Bethany Wolf
Biomedicines 2024, 12(1), 182; https://doi.org/10.3390/biomedicines12010182 - 15 Jan 2024
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Abstract
In the skin, estradiol (E2) promotes profibrotic and proinflammatory cytokines, contributing to extracellular matrix (ECM) deposition. However, the magnitude of the response differs. Using the human skin organ culture model, we evaluated donor characteristics and correlations that contribute to E2-induced interleukin-6 (IL-6 [...] Read more.
In the skin, estradiol (E2) promotes profibrotic and proinflammatory cytokines, contributing to extracellular matrix (ECM) deposition. However, the magnitude of the response differs. Using the human skin organ culture model, we evaluated donor characteristics and correlations that contribute to E2-induced interleukin-6 (IL-6), transforming growth factor beta 1 and 2 (TGFB1 and TGFB2), collagen IA2 (Col IA2), collagen IIIA1 (Col IIIA1), and fibronectin (FN) expressions. In vehicle- and E2-treated dermal skin tissue transcripts, we confirm differences in the magnitude; however, there were positive correlations between profibrotic mediators and ECM components 48 h after E2 treatment. Also, positive correlations exist between baseline and E2-induced TGFB1, IL-6, Col IIIA1, and FN transcripts. Since estrogen receptor alpha (ERA) can propagate E2′s signal, we measured and detected differences in its baseline and fold change transcript levels, with a significant decline in baseline levels 48 h after incubation and an increase 48 h after E2 treatment. There was a trend to higher transcript levels in African American donors 24 h earlier. Finally, E2-induced ERA transcript levels negatively correlated with its own baseline levels and positively correlated with FN, TGFB1, and Col IA2 transcript levels. Therefore, our data suggest ERA, E2 exposure time, and race/ethnicity contribute to E2-induced dermal fibrosis. Full article
(This article belongs to the Special Issue Skin Fibrosis and Cutaneous Wound Healing)
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16 pages, 5441 KiB  
Article
Phenotypic Modulation of Adipose-Derived Stem Cells and Fibroblasts Treated with Povidone–Iodine and Chlorhexidine in Mono and Coculture Models
by Alina Chelmuș-Burlacu, Eric Tang and Dragoș Pieptu
Biomedicines 2023, 11(7), 1855; https://doi.org/10.3390/biomedicines11071855 - 29 Jun 2023
Viewed by 1089
Abstract
Topical antiseptics are essential in wound treatment, and adipose-derived stem cells (ADSCs) have recently been proven to facilitate healing. However, the impact of antiseptics on ADSCs has not been fully elucidated, especially in relation to other relevant cell types present in the wound [...] Read more.
Topical antiseptics are essential in wound treatment, and adipose-derived stem cells (ADSCs) have recently been proven to facilitate healing. However, the impact of antiseptics on ADSCs has not been fully elucidated, especially in relation to other relevant cell types present in the wound microenvironment, e.g., fibroblasts. This study evaluated the effects of chlorhexidine and povidone–iodine on four cellular constructs in 2D and 3D in vitro culture systems. Cell constructs were treated with two concentrations of each antiseptic, after which cell migration activity, α-SMA, and Ki67 marker expressions were assessed and compared. Both tested concentrations of povidone–iodine impaired migration and sprouting compared to chlorhexidine, which had minimal effects when used in low concentrations. The gap in the wound healing assay did not close after 24 h of povidone–iodine treatment, although, at the lower concentration, cells started to migrate in a single-cell movement pattern. Similarly, in 3D culture systems, sprouting with reduced spike formation was observed at high povidone–iodine concentrations. Both antiseptics modulated α-SMA and Ki67 marker expressions at 5 days following treatment. Although both antiseptics had cytotoxic effects dependent on drug concentration and cell type, povidone–iodine contributed more substantially to the healing process than chlorhexidine, acting especially on fibroblasts. Full article
(This article belongs to the Special Issue Skin Fibrosis and Cutaneous Wound Healing)
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11 pages, 16695 KiB  
Article
Compound 13 Promotes Epidermal Healing in Mouse Fetuses via Activation of AMPK
by Kento Takaya, Keisuke Okabe, Shigeki Sakai, Noriko Aramaki-Hattori, Toru Asou and Kazuo Kishi
Biomedicines 2023, 11(4), 1013; https://doi.org/10.3390/biomedicines11041013 - 27 Mar 2023
Cited by 1 | Viewed by 1198
Abstract
Unlike adults, early developing fetuses can completely regenerate tissue, and replicating this could lead to the development of treatments to reduce scarring. Mice epidermal structures, including wound healing patterns, are regenerated until embryonic day (E) 13, leaving visible scars thereafter. These patterns require [...] Read more.
Unlike adults, early developing fetuses can completely regenerate tissue, and replicating this could lead to the development of treatments to reduce scarring. Mice epidermal structures, including wound healing patterns, are regenerated until embryonic day (E) 13, leaving visible scars thereafter. These patterns require actin cable formation at the epithelial wound margin through AMP-activated protein kinase (AMPK) activation. We aimed to investigate whether the administration of compound 13 (C13), a recently discovered AMPK activator, to the wound could reproduce this actin remodeling and skin regeneration pattern through its AMPK activating effect. The C13 administration resulted in partial formations of actin cables, which would normally result in scarring, and scar reduction during the healing of full-layer skin defects that occurred in E14 and E15 fetuses. Furthermore, C13 was found to cause AMPK activation in these embryonic mouse epidermal cells. Along with AMPK activation, Rac1 signaling, which is involved in leaflet pseudopodia formation and cell migration, was suppressed in C13-treated wounds, indicating that C13 inhibits epidermal cell migration. This suggests that actin may be mobilized by C13 for cable formation. Administration of C13 to wounds may achieve wound healing similar to regenerative wound healing patterns and may be a potential candidate for new treatments to heal scars. Full article
(This article belongs to the Special Issue Skin Fibrosis and Cutaneous Wound Healing)
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12 pages, 6951 KiB  
Article
Fetal Fibroblast Transplantation via Ablative Fractional Laser Irradiation Reduces Scarring
by Shigeki Sakai, Noriko Aramaki-Hattori and Kazuo Kishi
Biomedicines 2023, 11(2), 347; https://doi.org/10.3390/biomedicines11020347 - 26 Jan 2023
Viewed by 1400
Abstract
Scar treatments include fractional laser treatment, cell transplantation, surgery, skin needling, and dermal fillers. Fractional laser treatments are used to reduce scarring and blurring. Cell transplantation is promising, with mature fibroblasts and adipose-derived stem cells being used clinically, while embryonic fibroblasts are used [...] Read more.
Scar treatments include fractional laser treatment, cell transplantation, surgery, skin needling, and dermal fillers. Fractional laser treatments are used to reduce scarring and blurring. Cell transplantation is promising, with mature fibroblasts and adipose-derived stem cells being used clinically, while embryonic fibroblasts are used experimentally. Herein, we developed a combination of ablative CO2 (carbon dioxide) fractional laser and cell transplantation for the treatment of scars. Eight-week-old male C57Bl/6 mice were used to create a full-layer skin defect in the back skin and create scars. The scar was then irradiated using a CO2 fractional laser. The cells were then transplanted onto the scar surface and sealed with a film agent. The transplanted cells were GFP-positive murine fetal fibroblasts (FB), fetal fibroblasts with a long-term sphere-forming culture (LS), and fetal skin with a short-term sphere-forming culture (SS). After transplantation, green fluorescent protein (GFP)-positive cells were scattered in the dermal papillary layer and subcutis in all the groups. LS significantly reduced the degree of scarring, which was closest to normal skin. In conclusion, the combination of ablative fractional laser irradiation and fetal fibroblast transplantation allowed us to develop new methods for scar treatment. Full article
(This article belongs to the Special Issue Skin Fibrosis and Cutaneous Wound Healing)
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