Gene Expression Profiling of the Extracellular Matrix Signature in Macrophages of Different Activation Status: Relevance for Skin Wound Healing

The extracellular matrix (ECM) provides structural support for tissue architecture and is a major effector of cell behavior during skin repair and inflammation. Macrophages are involved in all stages of skin repair but only limited knowledge exists about macrophage-specific expression and regulation of ECM components. In this study, we used transcriptome profiling and bioinformatic analysis to define the unique expression of ECM-associated genes in cultured macrophages. Characterization of the matrisome revealed that most genes were constitutively expressed and that several genes were uniquely regulated upon interferon gamma (IFNγ) and dexamethasone stimulation. Among those core matrisome and matrisome-associated components transforming growth factor beta (TGFβ)-induced, matrix metalloproteinase 9 (MMP9), elastin microfibril interfacer (EMILIN)-1, netrin-1 and gliomedin were also present within the wound bed at time points that are characterized by profound macrophage infiltration. Hence, macrophages are a source of ECM components in vitro as well as during skin wound healing, and identification of these matrisome components is a first step to understand the role and therapeutic value of ECM components in macrophages and during wound healing.

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Overexpression of the Oral Mucosa-Specific microRNA-31 Promotes Skin Wound Closure

International Journal of Molecular Sciences ◽

10.3390/ijms20153679 ◽

2019 ◽

Vol 20 (15) ◽

pp. 3679 ◽

Cited By ~ 3

Author(s):

Lin Chen ◽

Alyne Simões ◽

Zujian Chen ◽

Yan Zhao ◽

Xinming Wu ◽

...

Keyword(s):

Wound Healing ◽

Oral Mucosa ◽

Wound Closure ◽

Expression Patterns ◽

Skin Wound ◽

Skin Wound Healing ◽

Specific Expression ◽

Keratinocyte Proliferation

Wounds within the oral mucosa are known to heal more rapidly than skin wounds. Recent studies suggest that differences in the microRNAome profiles may underlie the exceptional healing that occurs in oral mucosa. Here, we test whether skin wound-healing can be accelerating by increasing the levels of oral mucosa-specific microRNAs. A panel of 57 differentially expressed high expresser microRNAs were identified based on our previously published miR-seq dataset of paired skin and oral mucosal wound-healing [Sci. Rep. (2019) 9:7160]. These microRNAs were further grouped into 5 clusters based on their expression patterns, and their differential expression was confirmed by TaqMan-based quantification of LCM-captured epithelial cells from the wound edges. Of these 5 clusters, Cluster IV (consisting of 8 microRNAs, including miR-31) is most intriguing due to its tissue-specific expression pattern and temporal changes during wound-healing. The in vitro functional assays show that ectopic transfection of miR-31 consistently enhanced keratinocyte proliferation and migration. In vivo, miR-31 mimic treatment led to a statistically significant acceleration of wound closure. Our results demonstrate that wound-healing can be enhanced in skin through the overexpression of microRNAs that are highly expressed in the privileged healing response of the oral mucosa.

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Impairment of the Hif-1α regulatory pathway in Foxn1-deficient (Foxn1−/−) mice affects the skin wound healing process

10.1101/2020.08.04.237388 ◽

2020 ◽

Author(s):

Sylwia Machcinska ◽

Marta Kopcewicz ◽

Joanna Bukowska ◽

Katarzyna Walendzik ◽

Barbara Gawronska-Kozak

Keyword(s):

Wound Healing ◽

Transforming Growth Factor ◽

Healing Process ◽

Transforming Growth Factor Β ◽

Skin Wound ◽

Wound Healing Process ◽

Limiting Factor ◽

Skin Wound Healing ◽

Collagen Iii

ABSTRACTHypoxia and hypoxia-regulated factors [e. g., hypoxia-inducible factor-1α (Hif-1α), factor inhibiting Hif-1α (Fih-1), thioredoxin-1 (Trx-1), aryl hydrocarbon receptor nuclear translocator 2 (Arnt-2)] have essential roles in skin wound healing. Using Foxn1−/− mice that can heal skin injuries in a unique scarless manner, we investigated the interaction between Foxn1 and hypoxia-regulated factors. The Foxn1−/− mice displayed impairments in the regulation of Hif-1α, Trx-1 and Fih-1 but not Arnt-2 during the healing process. An analysis of wounded skin showed that the skin of the Foxn1−/− mice healed in a scarless manner, displaying rapid re-epithelialization and an increase in transforming growth factor β (Tgfβ-3) and collagen III expression. An in vitro analysis revealed that Foxn1 overexpression in keratinocytes isolated from the skin of the Foxn1−/− mice led to reduced Hif-1α expression in normoxic but not hypoxic cultures and inhibited Fih-1 expression exclusively under hypoxic conditions. These data indicate that in the skin, Foxn1 affects hypoxia-regulated factors that control the wound healing process and suggest that under normoxic conditions, Foxn1 is a limiting factor for Hif-1α.

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Keratin Scaffolds Containing Casomorphin Stimulate Macrophage Infiltration and Accelerate Full-Thickness Cutaneous Wound Healing in Diabetic Mice

Molecules ◽

10.3390/molecules26092554 ◽

2021 ◽

Vol 26 (9) ◽

pp. 2554

Author(s):

Marek Konop ◽

Anna K. Laskowska ◽

Mateusz Rybka ◽

Ewa Kłodzińska ◽

Dorota Sulejczak ◽

...

Keyword(s):

Wound Healing ◽

Wound Dressing ◽

Healing Process ◽

Skin Wound ◽

Wound Healing Process ◽

Diabetic Mice ◽

Full Thickness ◽

Skin Wound Healing ◽

Impaired Wound Healing

Impaired wound healing is a major medical challenge, especially in diabetics. Over the centuries, the main goal of tissue engineering and regenerative medicine has been to invent biomaterials that accelerate the wound healing process. In this context, keratin-derived biomaterial is a promising candidate due to its biocompatibility and biodegradability. In this study, we evaluated an insoluble fraction of keratin containing casomorphin as a wound dressing in a full-thickness surgical skin wound model in mice (n = 20) with iatrogenically induced diabetes. Casomorphin, an opioid peptide with analgesic properties, was incorporated into keratin and shown to be slowly released from the dressing. An in vitro study showed that keratin-casomorphin dressing is biocompatible, non-toxic, and supports cell growth. In vivo experiments demonstrated that keratin-casomorphin dressing significantly (p < 0.05) accelerates the whole process of skin wound healing to the its final stage. Wounds covered with keratin-casomorphin dressing underwent reepithelization faster, ending up with a thicker epidermis than control wounds, as confirmed by histopathological and immunohistochemical examinations. This investigated dressing stimulated macrophages infiltration, which favors tissue remodeling and regeneration, unlike in the control wounds in which neutrophils predominated. Additionally, in dressed wounds, the number of microhemorrhages was significantly decreased (p < 0.05) as compared with control wounds. The dressing was naturally incorporated into regenerating tissue during the wound healing process. Applied keratin dressing favored reconstruction of more regular skin structure and assured better cosmetic outcome in terms of scar formation and appearance. Our results have shown that insoluble keratin wound dressing containing casomorphin supports skin wound healing in diabetic mice.

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Systemic and topical administration of spermidine accelerates skin wound healing

10.21203/rs.3.rs-111107/v1 ◽

2020 ◽

Author(s):

Daisuke Ito ◽

Hiroyasu Ito ◽

Takayasu Ideta ◽

Ayumu Kanbe ◽

Soranobu Ninomiya ◽

...

Keyword(s):

Cell Proliferation ◽

Wound Healing ◽

Wound Repair ◽

Healing Process ◽

Topical Administration ◽

Skin Wound ◽

Wound Healing Process ◽

Skin Wound Healing

Abstract Background The skin wound healing process is regulated by various cytokines, chemokines, and growth factors. Recent reports have demonstrated that spermine/spermidine (SPD) promote wound healing through urokinase-type plasminogen activator (uPA)/uPA receptor (uPAR) signaling in vitro. Here, we investigated whether the systemic and topical administration of SPD would accelerate the skin wound-repair process in vivo.Methods A skin wound repair model was established using C57BL/6 J mice. SPD was mixed with white petrolatum for topical administration. For systemic administration, SPD mixed with drinking water was orally administered. Changes in wound size over time were calculated using digital photography.Results Systemic and topical SPD treatment significantly accelerated skin wound healing. The administration of SPD promoted the uPA/uPAR pathway in wound sites. Moreover, topical treatment with SPD enhanced the expression of IL-6 and TNF-α in wound sites. Scratch and cell proliferation assays revealed that SPD administration accelerated scratch wound closure and cell proliferation in vitro.Conclusion These results indicate that treatment with SPD promotes skin wound healing through activation of the uPA/uPAR pathway and induction of the inflammatory response in wound sites. The administration of SPD might contribute to new effective treatments to accelerate skin wound healing.

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Different Trypanosoma cruzi calreticulin domains mediate migration and proliferation of fibroblasts in vitro and skin wound healing in vivo

Archives of Dermatological Research ◽

10.1007/s00403-018-1851-7 ◽

2018 ◽

Vol 310 (8) ◽

pp. 639-650 ◽

Cited By ~ 4

Author(s):

Jose Ignacio Arias ◽

Natalia Parra ◽

Carolina Beato ◽

Cristian Gabriel Torres ◽

Christopher Hamilton-West ◽

...

Keyword(s):

Wound Healing ◽

Trypanosoma Cruzi ◽

Skin Wound ◽

Skin Wound Healing

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Dioscorea villosa Leaf Extract Enhances in vitro Wound Healing and Expression of Extra Cellular Matrix Factors Transforming Growth Factor-Beta 1 and Collagen-1 in L929 Cell Lines

Pharmacognosy Magazine ◽

10.4103/pm.pm_81_19 ◽

2019 ◽

Vol 15 (66) ◽

pp. 483

Author(s):

SurapaneniKrishna Mohan ◽

Murad Alsawalha ◽

AbeerMohammed Al-Subaie ◽

ReemYousuf Al-Jindan ◽

SrinivasaRao Bolla ◽

...

Keyword(s):

Wound Healing ◽

Growth Factor ◽

Cell Lines ◽

Transforming Growth Factor Beta ◽

Leaf Extract ◽

Transforming Growth Factor ◽

L929 Cell ◽

Growth Factor Beta ◽

Matrix Factors

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Platelet-rich plasma accelerates skin wound healing by promoting re-epithelialization

Burns & Trauma ◽

10.1093/burnst/tkaa028 ◽

2020 ◽

Vol 8 ◽

Cited By ~ 1

Author(s):

Pengcheng Xu ◽

Yaguang Wu ◽

Lina Zhou ◽

Zengjun Yang ◽

Xiaorong Zhang ◽

...

Keyword(s):

Wound Healing ◽

Growth Factor ◽

Wound Repair ◽

Chronic Wounds ◽

Platelet Rich Plasma ◽

Skin Wound ◽

Local Inflammation ◽

Skin Wound Healing

Abstract Background Autologous platelet-rich plasma (PRP) has been suggested to be effective for wound healing. However, evidence for its use in patients with acute and chronic wounds remains insufficient. The aims of this study were to comprehensively examine the effectiveness, synergy and possible mechanism of PRP-mediated improvement of acute skin wound repair. Methods Full-thickness wounds were made on the back of C57/BL6 mice. PRP or saline solution as a control was administered to the wound area. Wound healing rate, local inflammation, angiogenesis, re-epithelialization and collagen deposition were measured at days 3, 5, 7 and 14 after skin injury. The biological character of epidermal stem cells (ESCs), which reflect the potential for re-epithelialization, was further evaluated in vitro and in vivo. Results PRP strongly improved skin wound healing, which was associated with regulation of local inflammation, enhancement of angiogenesis and re-epithelialization. PRP treatment significantly reduced the production of inflammatory cytokines interleukin-17A and interleukin-1β. An increase in the local vessel intensity and enhancement of re-epithelialization were also observed in animals with PRP administration and were associated with enhanced secretion of growth factors such as vascular endothelial growth factor and insulin-like growth factor-1. Moreover, PRP treatment ameliorated the survival and activated the migration and proliferation of primary cultured ESCs, and these effects were accompanied by the differentiation of ESCs into adult cells following the changes of CD49f and keratin 10 and keratin 14. Conclusion PRP improved skin wound healing by modulating inflammation and increasing angiogenesis and re-epithelialization. However, the underlying regulatory mechanism needs to be investigated in the future. Our data provide a preliminary theoretical foundation for the clinical administration of PRP in wound healing and skin regeneration.

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Resveratrol-loaded peptide-hydrogels inhibit scar formation in wound healing through suppressing inflammation

Regenerative Biomaterials ◽

10.1093/rb/rbz041 ◽

2019 ◽

Cited By ~ 2

Author(s):

Chen-Chen Zhao ◽

Lian Zhu ◽

Zheng Wu ◽

Rui Yang ◽

Na Xu ◽

...

Keyword(s):

Wound Healing ◽

Damage Model ◽

Skin Wound ◽

Scar Formation ◽

Wound Dressings ◽

Skin Damage ◽

Skin Wound Healing ◽

Accelerate Wound Healing ◽

Peptide Hydrogels

Abstract Scar formation seriously affects the repair of damaged skin especially in adults and the excessive inflammation has been considered as the reason. The self-assembled peptide-hydrogels are ideal biomaterials for skin wound healing due to their similar nanostructure to natural extracellular matrix, hydration environment and serving as drug delivery systems. In our study, resveratrol, a polyphenol compound with anti-inflammatory effect, is loaded into peptide-hydrogel (Fmoc-FFGGRGD) to form a wound dressing (Pep/RES). Resveratrol is slowly released from the hydrogel in situ, and the release amount is controlled by the loading amount. The in vitro cell experiments demonstrate that the Pep/RES has no cytotoxicity and can inhibit the production of pro-inflammatory cytokines of macrophages. The Pep/RES hydrogels are used as wound dressings in rat skin damage model. The results suggest that the Pep/RES dressing can accelerate wound healing rate, exhibit well-organized collagen deposition, reduce inflammation and eventually prevent scar formation. The Pep/RES hydrogels supply a potential product to develop new skin wound dressings for the therapy of skin damage.

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Film Dressings Based on Hydrogels: Simultaneous and Sustained-Release of Bioactive Compounds with Wound Healing Properties

Pharmaceutics ◽

10.3390/pharmaceutics11090447 ◽

2019 ◽

Vol 11 (9) ◽

pp. 447 ◽

Cited By ~ 7

Author(s):

Fabian Ávila-Salas ◽

Adolfo Marican ◽

Soledad Pinochet ◽

Gustavo Carreño ◽

Oscar Valdés ◽

...

Keyword(s):

Wound Healing ◽

Sustained Release ◽

Bioactive Compounds ◽

Target Therapy ◽

Dicarboxylic Acids ◽

Skin Wound ◽

Dynamics Simulation ◽

Skin Wound Healing

This research proposes the rational modeling, synthesis and evaluation of film dressing hydrogels based on polyvinyl alcohol crosslinked with 20 different kinds of dicarboxylic acids. These formulations would allow the sustained release of simultaneous bioactive compounds including allantoin, resveratrol, dexpanthenol and caffeic acid as a multi-target therapy in wound healing. Interaction energy calculations and molecular dynamics simulation studies allowed evaluating the intermolecular affinity of the above bioactive compounds by hydrogels crosslinked with the different dicarboxylic acids. According to the computational results, the hydrogels crosslinked with succinic, aspartic, maleic and malic acids were selected as the best candidates to be synthesized and evaluated experimentally. These four crosslinked hydrogels were prepared and characterized by FTIR, mechanical properties, SEM and equilibrium swelling ratio. The sustained release of the bioactive compounds from the film dressing was investigated in vitro and in vivo. The in vitro results indicate a good release profile for all four analyzed bioactive compounds. More importantly, in vivo experiments suggest that prepared formulations could considerably accelerate the healing rate of artificial wounds in rats. The histological studies show that these formulations help to successfully reconstruct and thicken epidermis during 14 days of wound healing. Moreover, the four film dressings developed and exhibited excellent biocompatibility. In conclusion, the novel film dressings based on hydrogels rationally designed with combinatorial and sustained release therapy could have significant promise as dressing materials for skin wound healing.

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The effect of earthworm extract on promoting skin wound healing

Bioscience Reports ◽

10.1042/bsr20171366 ◽

2018 ◽

Vol 38 (2) ◽

Cited By ~ 4

Author(s):

Zhen-han Deng ◽

Jian-jian Yin ◽

Wei Luo ◽

Ronak Naveenchandra Kotian ◽

Shan-shan Gao ◽

...

Keyword(s):

Wound Healing ◽

Healthcare System ◽

Transforming Growth Factor ◽

Healing Process ◽

White Blood Cells ◽

Skin Wound ◽

Wound Healing Process ◽

Blood Capillary ◽

Skin Wound Healing

Chronic nonhealing wounds pose a significant challenge to healthcare system because of its tremendous utilization of resources and time to heal. It has a well-deserved reputation for reducing the quality of life for those affected and represent a substantial economic burden to the healthcare system overall. Earthworms are used as a traditional Chinese medicine, and have been applied pharmacologically and clinically since a long time in China. However, there is paucity in data regarding its wound healing effects. Therefore, we investigated the effect of earthworm extract (EE) on skin wound healing process. The obtained data showed that EE has healing effects on local wound of mice. It decreased the wound healing time and reduced the ill-effects of inflammation as determined by macroscopic, histopathologic, hematologic, and immunohistochemistry parameters. The potential mechanism could be accelerated hydroxyproline and transforming growth factor-β secretion—thus increasing the synthesis of collagen, promoting blood capillary, and fibroblast proliferation. It could accelerate the removal of necrotic tissue and foreign bodies by speeding up the generation of interleukin-6, white blood cells, and platelets. It thus enhances immunity, reduces the risk of infection, and promotes wound healing. All in all, the obtained data demonstrated that EE improves quality of healing and could be used as a propitious wound healing agent.

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