Ionizing Radiation Mediates Dose Dependent Effects Affecting the Healing Kinetics of Wounds Created on Acute and Late Irradiated Skin

Diaz, Candice; Hayward, Cindy Jean; Safoine, Meryem; Paquette, Caroline; Langevin, Josée; Galarneau, Josée; Théberge, Valérie; Ruel, Jean; Archambault, Louis; Fradette, Julie

doi:10.3390/surgeries2010004

Cited by 6 publications

(11 citation statements)

References 73 publications

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“…DFO treated irradiated wounds were demonstrably thicker than their untreated counterparts, indicative of both increased granulation tissue and a thicker neoepidermis which more closely mimicked that of the nonirradiated wounds. This is in contrast to the untreated irradiated wounds which were much thinner and are known to suffer from reduced granulation tissue formation and a thinner neoepidermis in other studies as well [11]. Both of these factors likely contribute to the clinically well-documented fragility and unpredictability of irradiated wounds [11,36].…”

Section: Deferoxamine Alters Collagen Deposition In Irradiated Woundsmentioning

confidence: 80%

“…This is in contrast to the untreated irradiated wounds which were much thinner and are known to suffer from reduced granulation tissue formation and a thinner neoepidermis in other studies as well [11]. Both of these factors likely contribute to the clinically well-documented fragility and unpredictability of irradiated wounds [11,36].…”

Section: Deferoxamine Alters Collagen Deposition In Irradiated Woundsmentioning

confidence: 80%

“…Over time, this progresses to RIF and leads to the many hurdles impairing tissue healing [3,8,9]. In the skin, irradiated fibroblasts and myofibroblasts exhibit altered collagen deposition and reduced wound contraction, respectively [11,29,30]. The initial microvascular damage and the subsequent chronic hypovascularity impair nutrient delivery to the healing wound, further delaying the healing process.…”

Section: Discussionmentioning

confidence: 99%

“…An unsupervised machine learning algorithm determined that DFO-treated irradiated wounds more closely resembled nonirradiated wounds based on 294 learned parameters that were examined within the collagen ultrastructure. Prior studies have also asserted DFO's ability to improve fibril organization in irradiated skin; irradiated wounds typically exhibit thin, disorganized collagen fiber deposition [11,19]. These differences resulted in improved scar elasticity in the DFO treated irradiated wounds that again aligned more closely to nonirradiated wounds.…”

Section: Deferoxamine Alters Collagen Deposition In Irradiated Woundsmentioning

confidence: 95%

“…Reduced keratinocyte proliferation results in delayed epithelial migration and hyperplasia [10]. Granulation tissue formation is also delayed due to impaired collagen deposition resulting in significantly reduced collagen density and weaker breaking strength in the healing wound bed [11]. The slow healing rates and poor quality of healing are further amplified by microvascular insufficiency and decreased angiogenesis causing poor nutrient supply to the wound bed.…”

Section: Introductionmentioning

confidence: 99%

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Transdermal deferoxamine administration improves excisional wound healing in chronically irradiated murine skin

et al. 2022

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Background Radiation-induced skin injury is a well-known risk factor for impaired wound healing. Over time, the deleterious effects of radiation on skin produce a fibrotic, hypovascular dermis poorly suited to wound healing. Despite increasing understanding of the underlying pathophysiology, therapeutic options remain elusive. Deferoxamine (DFO), an iron-chelating drug, has been shown in prior murine studies to ameliorate radiation-induced skin injury as well as improve wound healing outcomes in various pathologic conditions when administered transdermally. In this preclinical study, we evaluated the effects of deferoxamine on wound healing outcomes in chronically irradiated murine skin. Methods Wild-type mice received 30 Gy of irradiation to their dorsal skin and were left to develop chronic fibrosis. Stented excisional wounds were created on their dorsal skin. Wound healing outcomes were compared across 4 experimental conditions: DFO patch treatment, vehicle-only patch treatment, untreated irradiated wound, and untreated nonirradiated wounds. Gross closure rate, wound perfusion, scar elasticity, histology, and nitric oxide assays were compared across the conditions. Results Relative to vehicle and untreated irradiated wounds, DFO accelerated wound closure and reduced the frequency of healing failure in irradiated wounds. DFO augmented wound perfusion throughout healing and upregulated angiogenesis to levels observed in nonirradiated wounds. Histology revealed DFO increased wound thickness, collagen density, and improved collagen fiber organization to more closely resemble nonirradiated wounds, likely contributing to the observed improved scar elasticity. Lastly, DFO upregulated inducible nitric oxide synthase and increased nitric oxide production in early healing wounds. Conclusion Deferoxamine treatment presents a potential therapeutic avenue through which to target impaired wound healing in patients following radiotherapy.

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Section: Deferoxamine Alters Collagen Deposition In Irradiated Woundsmentioning

confidence: 80%

Section: Deferoxamine Alters Collagen Deposition In Irradiated Woundsmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Deferoxamine Alters Collagen Deposition In Irradiated Woundsmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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Transdermal deferoxamine administration improves excisional wound healing in chronically irradiated murine skin

et al. 2022

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Epigenetic memory of radiotherapy in dermal fibroblasts impairs wound repair capacity in cancer survivors

Bian,

Piipponen,

Liu

et al. 2024

Nat Commun

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Radiotherapy (RT), a common cancer treatment, unintentionally harms surrounding tissues, including the skin, and hinders wound healing years after treatment. This study aims to understand the mechanisms behind these late-onset adverse effects. We compare skin biopsies from previously irradiated (RT+) and non-irradiated (RT−) sites in breast cancer survivors who underwent RT years ago. Here we show that the RT+ skin has compromised healing capacity and fibroblast functions. Using ATAC-seq, we discover altered chromatin landscapes in RT+ fibroblasts, with THBS1 identified as a crucial epigenetically primed wound repair-related gene. This is further confirmed by single-cell RNA-sequencing and spatial transcriptomic analysis of human wounds. Notably, fibroblasts in both murine and human post-radiation wound models show heightened and sustained THBS1 expression, impairing fibroblast motility and contractility. Treatment with anti-THBS1 antibodies promotes ex vivo wound closure in RT+ skin from breast cancer survivors. Our findings suggest that fibroblasts retain a long-term radiation memory in the form of epigenetic changes. Targeting this maladaptive epigenetic memory could mitigate RT’s late-onset adverse effects, improving the quality of life for cancer survivors.

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Improving Cutaneous Wound Healing in Diabetic Mice Using Naturally Derived Tissue‐Engineered Biological Dressings Produced under Serum‐Free Conditions

Safoine,

Paquette,

Gingras

et al. 2024

Stem Cells International

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Long-term diabetes often leads to chronic wounds refractory to treatment. Cell-based therapies are actively investigated to enhance cutaneous healing. Various cell types are available to produce biological dressings, such as adipose-derived stem/stromal cells (ASCs), an attractive cell source considering their abundancy, accessibility, and therapeutic secretome. In this study, we produced human ASC-based dressings under a serum-free culture system using the self-assembly approach of tissue engineering. The dressings were applied every 4 days to full-thickness 8-mm splinted skin wounds created on the back of polygenic diabetic NONcNZO10/LtJ mice and streptozotocin-induced diabetic K14-H2B-GFP mice. Global wound closure kinetics evaluated macroscopically showed accelerated wound closure in both murine models, especially for NONcNZO10/LtJ; the treated group reaching 98.7% ± 2.3% global closure compared to 76.4% ± 11.8% for the untreated group on day 20 (p=0.0002). Histological analyses revealed that treated wounds exhibited healed skin of better quality with a well-differentiated epidermis and a more organized, homogeneous, and 1.6-fold thicker granulation tissue. Neovascularization, assessed by CD31 labeling, was 2.5-fold higher for the NONcNZO10/LtJ treated wounds. We thus describe the beneficial impact on wound healing of biologically active ASC-based dressings produced under an entirely serum-free production system facilitating clinical translation.

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Ionizing Radiation Mediates Dose Dependent Effects Affecting the Healing Kinetics of Wounds Created on Acute and Late Irradiated Skin

Cited by 6 publications

References 73 publications

Transdermal deferoxamine administration improves excisional wound healing in chronically irradiated murine skin

Transdermal deferoxamine administration improves excisional wound healing in chronically irradiated murine skin

Epigenetic memory of radiotherapy in dermal fibroblasts impairs wound repair capacity in cancer survivors

Improving Cutaneous Wound Healing in Diabetic Mice Using Naturally Derived Tissue‐Engineered Biological Dressings Produced under Serum‐Free Conditions

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