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18 pages, 4326 KiB

Open AccessArticle

Accelerated Wound Healing and Keratinocyte Proliferation through PI3K/Akt/pS6 and VEGFR2 Signaling by Topical Use of Pleural Fluid

by Chen-Liang Tsai, Chih-Ying Changchien, Ying Chen, Hsin-Han Chang, Wen-Chiuan Tsai, Yi-Wen Wang, Kai-Chieh Chou, Ming-Hsien Chiang, Yu-Ling Tsai, Hao-Chung Tsai, Chieh-Yung Wang, Ming-Sheng Shen, Li-Ting Cheng, Hung-Yi Lin, Tse-Bin Yang and Chih-Feng Chian

Cells 2022, 11(5), 817; https://doi.org/10.3390/cells11050817 - 26 Feb 2022

Cited by 7 | Viewed by 3626

Abstract

Impaired wound healing is an ongoing issue that cancer patients undergoing chemotherapy or radiotherapy face. Our previous study regarding lung-cancer-associated pleural fluid (LCPF) demonstrated its propensity to promote endothelial proliferation, migration, and angiogenesis, which are crucial features during cutaneous wound healing. Therefore, the [...] Read more.

Impaired wound healing is an ongoing issue that cancer patients undergoing chemotherapy or radiotherapy face. Our previous study regarding lung-cancer-associated pleural fluid (LCPF) demonstrated its propensity to promote endothelial proliferation, migration, and angiogenesis, which are crucial features during cutaneous wound healing. Therefore, the current study aimed to investigate the effect of pleural fluid on cutaneous wound closure in vitro and in vivo using HaCaT keratinocytes and a full-thickness skin wound model, respectively. Both heart-failure-associated pleural fluid (HFPF) and LCPF were sequentially centrifuged and filtered to obtain a cell-free status. Treatment with HFPF and LCPF homogeneously induced HaCaT proliferation with cell cycle progression, migration, and MMP2 upregulation. Western blotting revealed increased PI3K/Akt phosphorylation and VEGFR2/VEGFA expression in HaCaT cells. When treated with the PI3K inhibitor, LCPF-induced keratinocyte proliferation was attenuated with decreased pS6 levels. By applying the VEGFR2 inhibitor, LCPF-induced keratinocyte proliferation was ameliorated by pS6 and MMP2 downregulation. The effect of LCPF-induced cell junction rearrangement was disrupted by co-treatment with a VEGFR2 inhibitor. Compared with a 0.9% saline dressing, LCPF significantly accelerated wound closure and re-epithelization when used as a dressing material in a full-thickness wound model. Histological analysis revealed increased neo-epidermis thickness and dermis collagen synthesis in the LCPF-treated group. Furthermore, LCPF treatment activated basal keratinocytes at the wound edge with the upregulation of Ki-67, VEGFA, and MMP2. Our preliminaries provided the benefit of wet dressing with pleural fluid to improve cutaneous wound closure through enhanced re-epithelization and disclosed future autologous application in cancer wound treatment. Full article

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

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15 pages, 20661 KiB

Open AccessArticle

The Candidate IBD Risk Gene CCNY Is Dispensable for Intestinal Epithelial Homeostasis

by Andrea Molinas, Stéphanie Heil and Stefan Koch

Cells 2021, 10(9), 2330; https://doi.org/10.3390/cells10092330 - 6 Sep 2021

Cited by 2 | Viewed by 3422

Abstract

The CCNY gene, which encodes cyclin Y, has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Cyclin Y promotes Wnt/β-catenin signaling and autophagy, which are critical for intestinal epithelial cell (IEC) homeostasis, and may thereby contribute to wound repair in colitis. [...] Read more.

The CCNY gene, which encodes cyclin Y, has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Cyclin Y promotes Wnt/β-catenin signaling and autophagy, which are critical for intestinal epithelial cell (IEC) homeostasis, and may thereby contribute to wound repair in colitis. However, whether cyclin Y has an essential function in IECs is unknown. We, therefore, investigated the epithelial injury response and mucosal regeneration in mice with conditional knock-out of Ccny in the intestinal epithelium. We observed that Ccny-deficient mice did not exhibit any differences in cell proliferation and disease activity compared to wild-type littermates in the dextran sulfate sodium (DSS) colitis model. Complementary in vitro experiments showed that loss of CCNY in model IECs did not affect Wnt signaling, cell proliferation, or autophagy. Additionally, we observed that expression of the cyclin-Y-associated cyclin-dependent kinase (CDK) 14 is exceedingly low specifically in IEC. Collectively, these results suggest that cyclin Y does not contribute to intestinal epithelial homeostasis, possibly due to low levels of specific CDKs in these cells. Thus, it is unlikely that CCNY mutations are causatively involved in IBD pathogenesis. Full article

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

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14 pages, 3416 KiB

Open AccessArticle

Endothelial and Vascular Health: A Tale of Honey, H₂O₂ and Calcium

by Elia Ranzato, Gregorio Bonsignore, Mauro Patrone and Simona Martinotti

Cells 2021, 10(5), 1071; https://doi.org/10.3390/cells10051071 - 30 Apr 2021

Cited by 6 | Viewed by 2528

Abstract

Intracellular Ca²⁺ regulation plays a pivotal role in endothelial biology as well as during endothelial restoration processes. Interest in honey utilization in wound approaches is rising in recent years. In order to evaluate the positive effects of buckwheat honey on endothelial responses, [...] Read more.

Intracellular Ca²⁺ regulation plays a pivotal role in endothelial biology as well as during endothelial restoration processes. Interest in honey utilization in wound approaches is rising in recent years. In order to evaluate the positive effects of buckwheat honey on endothelial responses, we utilized an immortalized endothelial cell line to evaluate cellular responses upon honey exposure, with particular interest in Ca²⁺ signaling involvement. The results highlight the positive effects of buckwheat honey on endothelial cells’ responses and the central role played by Ca²⁺ signaling as an encouraging target for more efficacious clinical treatments. Full article

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

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8 pages, 922 KiB

Open AccessArticle

Analysis of Rinsing Fluid during Negative Pressure Wound Therapy with Instillation: A Potential Monitoring Tool in Acute and Chronic Wound Treatment. A Pilot Study

by Christian D. Taeger, Stefan Wallner, Teresa Martini, Daniel Schiltz, Andreas Kehrer, Lukas Prantl and Niklas Biermann

Cells 2021, 10(4), 732; https://doi.org/10.3390/cells10040732 - 26 Mar 2021

Cited by 4 | Viewed by 2220

Abstract

Background: During negative pressure wound therapy (NPWT), open wounds are draped with a nontransparent sponge, making daily wound evaluation impossible. Sometimes, late or undetected bacterial infections and postoperative bleeding result in repetitive surgery, thus prolonging inpatient time. With the introduction of additional fluid [...] Read more.

Background: During negative pressure wound therapy (NPWT), open wounds are draped with a nontransparent sponge, making daily wound evaluation impossible. Sometimes, late or undetected bacterial infections and postoperative bleeding result in repetitive surgery, thus prolonging inpatient time. With the introduction of additional fluid instillation (NPWTi), the wound surface is rinsed, and bacteria, proteins and biomarkers are flushed into a collecting canister, which is later discarded. Methods: The aim of this pilot study was to analyze rinsing fluid samples (0.9% sodium chloride) from the NPWTi device in patients with acute and chronic wounds. In 31 consecutive patients a standardized laboratory analysis was performed to evaluate cellular composition and potassium, phosphate, lactate dehydrooxygenase, pH and total protein levels. Results: While there was an increase in the total cellular amount and the number of polymorphonuclear cells, the number of red blood cells (RBC) decreased after surgery. Potassium and pH showed no significant changes in the first three postoperative days, whereas total protein showed an undulant and partially significant course. Conclusion: We were able to quantify cellular metabolites by analyzing the rinsing fluid of NPWTi. We propose the analysis of this material as a novel and potentially promising tool to monitor wound status without removal of the dressing. The establishment of reference values might help to improve the NPWTi therapy. Full article

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

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13 pages, 4026 KiB

Open AccessArticle

Influence of Recombinant Codon-Optimized Plasmid DNA Encoding VEGF and FGF2 on Co-Induction of Angiogenesis

by Ilnur I. Salafutdinov, Ilnaz M. Gazizov, Dilara K. Gatina, Ruslan I. Mullin, Alexey A. Bogov, Rustem R. Islamov, Andrey P. Kiassov, Ruslan F. Masgutov and Albert A. Rizvanov

Cells 2021, 10(2), 432; https://doi.org/10.3390/cells10020432 - 18 Feb 2021

Cited by 13 | Viewed by 3145

Abstract

Several methods for the stimulation of skin wound repair have been proposed over the last few decades. The most promising among them are gene and stem cell therapy. Our present experiments combined several approaches via the application of human umbilical cord blood mononuclear [...] Read more.

Several methods for the stimulation of skin wound repair have been proposed over the last few decades. The most promising among them are gene and stem cell therapy. Our present experiments combined several approaches via the application of human umbilical cord blood mononuclear cells (hUCB-MC) that were transfected with pBud-VEGF165-FGF2 plasmid (gene-cell therapy) and direct gene therapy using pBud-VEGF165-FGF2 plasmid to enhance healing of full thickness skin wounds in rats. The dual expression cassette plasmid pBud-VEGF165-FGF2 encodes both VEGF and FGF2 therapeutic genes, expressing pro-angiogenic growth factors. Our results showed that, with two weeks post-transplantation, some transplanted cells still retained expression of the stem cell and hematopoietic markers C-kit and CD34. Other transplanted cells were found among keratinocytes, hair follicle cells, endothelial cells, and in the derma. PCNA expression studies revealed that transplantation of transfected cells terminated proliferative processes in regenerating wounds earlier than transplantation of untransfected cells. In the direct gene therapy group, four days post-operatively, the processes of flap revascularization, while using Easy LDI Microcirculation Camera, was higher than in control wounded skin. We concluded that hUCB-MC can be used for the treatment of skin wounds and transfection these cells with VEGF and FGF2 genes enhances their regenerative abilities. We also concluded that the application of pBud-VEGF165-FGF2 plasmids is efficient for the direct gene therapy of skin wounds by stimulation of wound revascularization. Full article

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

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Review

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46 pages, 5516 KiB

Open AccessReview

Innovative Treatment Strategies to Accelerate Wound Healing: Trajectory and Recent Advancements

by Praveen Kolimi, Sagar Narala, Dinesh Nyavanandi, Ahmed Adel Ali Youssef and Narendar Dudhipala

Cells 2022, 11(15), 2439; https://doi.org/10.3390/cells11152439 - 6 Aug 2022

Cited by 136 | Viewed by 20542

Abstract

Wound healing is highly specialized dynamic multiple phase process for the repair of damaged/injured tissues through an intricate mechanism. Any failure in the normal wound healing process results in abnormal scar formation, and chronic state which is more susceptible to infections. Chronic wounds [...] Read more.

Wound healing is highly specialized dynamic multiple phase process for the repair of damaged/injured tissues through an intricate mechanism. Any failure in the normal wound healing process results in abnormal scar formation, and chronic state which is more susceptible to infections. Chronic wounds affect patients’ quality of life along with increased morbidity and mortality and are huge financial burden to healthcare systems worldwide, and thus requires specialized biomedical intensive treatment for its management. The clinical assessment and management of chronic wounds remains challenging despite the development of various therapeutic regimens owing to its painstakingly long-term treatment requirement and complex wound healing mechanism. Various conventional approaches such as cell therapy, gene therapy, growth factor delivery, wound dressings, and skin grafts etc., are being utilized for promoting wound healing in different types of wounds. However, all these abovementioned therapies are not satisfactory for all wound types, therefore, there is an urgent demand for the development of competitive therapies. Therefore, there is a pertinent requirement to develop newer and innovative treatment modalities for multipart therapeutic regimens for chronic wounds. Recent developments in advanced wound care technology includes nanotherapeutics, stem cells therapy, bioengineered skin grafts, and 3D bioprinting-based strategies for improving therapeutic outcomes with a focus on skin regeneration with minimal side effects. The main objective of this review is to provide an updated overview of progress in therapeutic options in chronic wounds healing and management over the years using next generation innovative approaches. Herein, we have discussed the skin function and anatomy, wounds and wound healing processes, followed by conventional treatment modalities for wound healing and skin regeneration. Furthermore, various emerging and innovative strategies for promoting quality wound healing such as nanotherapeutics, stem cells therapy, 3D bioprinted skin, extracellular matrix-based approaches, platelet-rich plasma-based approaches, and cold plasma treatment therapy have been discussed with their benefits and shortcomings. Finally, challenges of these innovative strategies are reviewed with a note on future prospects. Full article

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

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27 pages, 2500 KiB

Open AccessReview

Macrophage Phenotypes in Normal and Diabetic Wound Healing and Therapeutic Interventions

by Hadeel Al Sadoun

Cells 2022, 11(15), 2430; https://doi.org/10.3390/cells11152430 - 5 Aug 2022

Cited by 30 | Viewed by 5583

Abstract

Macrophage differentiation and polarization are essential players in the success of the wound-healing process. Acute simple wounds progress from inflammation to proliferation/regeneration and, finally, to remodeling. In injured skin, macrophages either reside in the epithelium or are recruited from monocytes. Their main role [...] Read more.

Macrophage differentiation and polarization are essential players in the success of the wound-healing process. Acute simple wounds progress from inflammation to proliferation/regeneration and, finally, to remodeling. In injured skin, macrophages either reside in the epithelium or are recruited from monocytes. Their main role is supported by their plasticity, which allows them to adopt different phenotypic states, such as the M1-inflammatory state, in which they produce TNF and NO, and the M2-reparative state, in which they resolve inflammation and exhibit a reparative function. Reparative macrophages are an essential source of growth factors such as TGF-β and VEGF and are not found in nonhealing wounds. This review discusses the differences between macrophage phenotypes in vitro and in vivo, how macrophages originate, and how they cross-communicate with other cellular components in a wound. This review also highlights the dysregulation of macrophages that occurs in nonhealing versus overhealing wounds and fibrosis. Then, the therapeutic manipulation of macrophages is presented as an attractive strategy for promoting healing through the secretion of growth factors for angiogenesis, keratinocyte migration, and collagen production. Finally, Hoxa3 overexpression is discussed as an example of the therapeutic repolarization of macrophages to the normal maturation state and phenotype with better healing outcomes. Full article

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

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13 pages, 1659 KiB

Open AccessReview

NETosis in Wound Healing: When Enough Is Enough

by Maurizio Sabbatini, Valeria Magnelli and Filippo Renò

Cells 2021, 10(3), 494; https://doi.org/10.3390/cells10030494 - 25 Feb 2021

Cited by 23 | Viewed by 5204

Abstract

The neutrophils extracellular traps (NETs) are a meshwork of chromatin, histonic and non-histonic proteins, and microbicidal agents spread outside the cell by a series of nuclear and cytoplasmic events, collectively called NETosis. NETosis, initially only considered a defensive/apoptotic mechanism, is now considered an [...] Read more.

The neutrophils extracellular traps (NETs) are a meshwork of chromatin, histonic and non-histonic proteins, and microbicidal agents spread outside the cell by a series of nuclear and cytoplasmic events, collectively called NETosis. NETosis, initially only considered a defensive/apoptotic mechanism, is now considered an extreme defensive solution, which in particular situations induces strong negative effects on tissue physiology, causing or exacerbating pathologies as recently shown in NETs-mediated organ damage in COVID-19 patients. The positive effects of NETs on wound healing have been linked to their antimicrobial activity, while the negative effects appear to be more common in a plethora of pathological conditions (such as diabetes) and linked to a NETosis upregulation. Recent evidence suggests there are other positive physiological NETs effects on wound healing that are worthy of a broader research effort. Full article

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

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