scholarly journals Phagocytosis of Wnt inhibitor SFRP4 by late wound macrophages drives chronic Wnt activity for fibrotic skin healing

2020 ◽  
Vol 6 (12) ◽  
pp. eaay3704 ◽  
Author(s):  
Denise Gay ◽  
Giulia Ghinatti ◽  
Christian F. Guerrero-Juarez ◽  
Rubén A. Ferrer ◽  
Federica Ferri ◽  
...  
Keyword(s):  
Hidradenitis Suppurativa ◽  
Wound Repair ◽  
Skin Condition ◽  
Skin Wound ◽  
Skin Wound Healing ◽  
Single Cell Rna Sequencing ◽  
Wnt Inhibitor ◽  
Skin Healing ◽  
Skin Wounding ◽  
Regenerative Repair

Human and murine skin wounding commonly results in fibrotic scarring, but the murine wounding model wound-induced hair neogenesis (WIHN) can frequently result in a regenerative repair response. Here, we show in single-cell RNA sequencing comparisons of semi-regenerative and fibrotic WIHN wounds, increased expression of phagocytic/lysosomal genes in macrophages associated with predominance of fibrotic myofibroblasts in fibrotic wounds. Investigation revealed that macrophages in the late wound drive fibrosis by phagocytizing dermal Wnt inhibitor SFRP4 to establish persistent Wnt activity. In accordance, phagocytosis abrogation resulted in transient Wnt activity and a more regenerative healing. Phagocytosis of SFRP4 was integrin-mediated and dependent on the interaction of SFRP4 with the EDA splice variant of fibronectin. In the human skin condition hidradenitis suppurativa, phagocytosis of SFRP4 by macrophages correlated with fibrotic wound repair. These results reveal that macrophages can modulate a key signaling pathway via phagocytosis to alter the skin wound healing fate.

Abstract 13373: Exercise Improves Angiogenic Function of Circulating Exosomes in Type 2 Diabetes: Role of Extracellular SOD

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Kareem Abdelsaid ◽  
Sudhahar Varadarajan ◽  
Archita Das ◽  
Yutao Liu ◽  
Xuexiu Fang ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Wound Healing ◽  
Endothelial Dysfunction ◽  
Wound Repair ◽  
Cell Communication ◽  
Tube Formation ◽  
Skin Wound ◽  
Skin Wound Healing

Background: Exosomes, key mediators of cell-cell communication, derived from type 2 diabetes mellitus (T2DM) have detrimental effects. Exercise not only improves endothelial dysfunction and angiogenesis in T2DM but also induces secretion of exosomes into circulation. Extracellular superoxide dismutase (ecSOD) is a major secretory Cu containing antioxidant enzyme that catalyzes dismutation of O 2 •- to H 2 O 2 and its full activity requires Cu transporter ATP7A. We reported that ecSOD-derived H 2 O 2 in endothelial cells (ECs) enhances angiogenesis while impaired ATP7A-ecSOD axis in diabetes induces endothelial dysfunction. Here we examined whether exercise-derived exosomes (Exe-Exo) may have pro-angiogenic effects via regulating ATP7A-ecSOD axis in T2DM. Results: Two weeks of voluntary wheel exercise of control C57Bl6 mice increased plasma exosome levels (6.2-fold) characterized by Nanosight, TEM and exosome markers (CD63, CD81, Tsg101). Treatment of HUVECs with equal number of exosomes revealed that angiogenic responses such as EC migration (1.8-fold) and tube formation (1.7-fold) were significantly enhanced by Exe-Exo compared to sedentary-derived exosomes (Sed-Exo). This was associated with increased ATP7A (2.9-fold) and ecSOD (1.4-fold) expression in Exe-Exo. Sed-Exo from high fat-induced T2DM mice significantly decreased EC migration (40%) and tube formation (10%) as well as ATP7A expression (28%) compared to Sed-Exo from control mice, which were restored by T2DM Exe-Exo, but not by T2DM/ecSOD KO Exe-Exo. Furthermore, exosomes overexpressing ecSOD (ecSOD-Exo) which mimic exercise increased angiogenesis and H2O2 levels in ECs, which were inhibited by overexpression of catalase. In vivo, skin wound healing model showed that direct application of T2DM Sed-Exo delayed while T2DM Exe-Exo enhanced wound healing of control mice. Furthermore, defective wound healing in T2DM mice or ecSOD KO mice were rescued by ecSOD-Exo application. Conclusion: Exercise training improves pro-angiogenic function of circulating exosomes in T2DM via increasing ATP7A-ecSOD axis, which may provide an effective therapy for promoting angiogenesis and wound repair in metabolic and cardiovascular diseases.

scholarly journals Systemic and topical administration of spermidine accelerates skin wound healing

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.

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

2020 ◽  
Vol 8 ◽  
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.

scholarly journals Enzyme-Crosslinked Gelatin Hydrogel with Adipose-Derived Stem Cell Spheroid Facilitating Wound Repair in the Murine Burn Model

Polymers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 2997
Author(s):  
Ting-Yu Lu ◽  
Kai-Fu Yu ◽  
Shuo-Hsiu Kuo ◽  
Nai-Chen Cheng ◽  
Er-Yuan Chuang ◽  
...  
Keyword(s):  
Wound Healing ◽  
Wound Repair ◽  
Three Dimensional ◽  
Stromal Vascular Fraction ◽  
Skin Wound ◽  
3D Scaffold ◽  
Skin Wound Healing ◽  
Cell Spheroid ◽  
Cell Spheroids ◽  
Adipose Derived Stem Cell

Engineered skin that can facilitate tissue repair has been a great advance in the field of wound healing. A well-designed dressing material together with active biological cues such as cells or growth factors can overcome the limitation of using auto-grafts from patients. Recently, many studies showed that human adipose-derived stem cells (hASCs) can be used to promote wound healing and skin tissue engineering. hASCs have already been widely applied for clinical trials. hASCs can be harvested abundantly because they can be easily isolated from fat tissue known as the stromal vascular fraction (SVF). On the other hand, increasing studies have proven that cells from spheroids can better simulate the biological microenvironment and can enhance the expression of stemness markers. However, a three-dimensional (3D) scaffold that can harbor implanted cells and can serve as a skin-repaired substitute still suffers from deficiency. In this study, we applied a gelatin/microbial transglutaminase (mTG) hydrogel to encapsulate hASC spheroids to evaluate the performance of 3D cells on skin wound healing. The results showed that the hydrogel is not toxic to the wound and that cell spheroids have significantly improved wound healing compared to cell suspension encapsulated in the hydrogel. Additionally, a hydrogel with cell spheroids was much more effective than other groups in angiogenesis since the cell spheroid has the possibility of cell–cell signaling to promote vascular generation.

scholarly journals 4-aminopyridine promotes accelerated skin wound healing

2021 ◽  
Author(s):  
Jagadeeshaprasad Mashanipalya ◽  
Prem Kumar Govindappa ◽  
Amanda Nelson ◽  
Mark Noble ◽  
John Elfar
Keyword(s):  
Wound Healing ◽  
Growth Factor ◽  
Wound Closure ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β ◽  
Skin Wound ◽  
Skin Wound Healing ◽  
S 100 ◽  
Skin Healing

Abstract The discovery of ways to enhance skin healing is of great importance due to the frequency and severity of skin wounds. We discovered that 4-aminopyridine (4-AP), a potassium channel blocker, greatly enhances skin wound healing. Benefits include faster wound closure, restoration of normal-appearing skin architecture and epidermal thickness, increased vascularization and increases in K14+ keratinocytes. Hair follicle number was increased, both histologically and by analysis of K15 and K17 expression. Levels of vimentin (which marks fibroblasts) and α-smooth muscle actin (α-SMA, which marks collagen-producing myofibroblasts) increased, as did α-SMA+ cell numbers. 4-AP also increased numbers of axons and S-100+ Schwann cells, and increased expression of p75-NTR and SOX10. Treatment also increased levels of nerve growth factor, transforming growth factor-β, Substance P and PGP9.5, important modulators of wound healing. As 4-AP is already used for treatment of multiple sclerosis and other chronic neurological syndromes, it has strong potential for rapid translational development.

Scarless wound repair: a human fetal skin model

Development ◽  
1992 ◽  
Vol 114 (1) ◽  
pp. 253-259 ◽  
Author(s):  
H.P. Lorenz ◽  
M.T. Longaker ◽  
L.A. Perkocha ◽  
R.W. Jennings ◽  
M.R. Harrison ◽  
...  
Keyword(s):  
Wound Healing ◽  
Gestational Age ◽  
Animal Studies ◽  
Wound Repair ◽  
Mouse Skin ◽  
Skin Wound ◽  
Scar Formation ◽  
Fetal Skin ◽  
Skin Wound Healing ◽  
Thickness Skin

Animal studies demonstrate that the fetus heals cutaneous wounds by reformation of normal tissue architecture without scar formation. We have developed a new model to study human fetal skin wound healing. Grafts of human fetal skin placed onto athymic mice retain the morphologic features of normal development, although they differentiate at an accelerated rate when placed cutaneously compared to subcutaneously. Full-thickness skin grafts from human fetuses at 15 (n = 12), 17 (n = 11), 18 (n = 25), 19 (n = 20) and 22 (n = 13) weeks gestational age were placed onto athymic (nu/nu) mice in 2 locations: (1) cutaneously onto a fascial bed and thereby exposed to air or (2) subcutaneously in a pocket under the murine panniculus carnosus. Linear incisions were made in each graft 7 days after transplantation. Grafts were harvested at 7, 14 and 21 days postwounding and analyzed histologically for scar formation. By hematoxylin & eosin and Mallory's trichrome stains, complete epidermal and dermal graft wound healing without scar formation was demonstrated in the subcutaneous grafts at each gestational age studied. In contrast, scar was seen at all time points in the cutaneous grafts in both the incisional wound and at the interface of the fetal human skin graft and adult mouse skin, regardless of fetal skin gestational age.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals A New Role for Activin in Endometrial Repair after Menses

Endocrinology ◽  
2008 ◽  
Vol 150 (4) ◽  
pp. 1904-1911 ◽  
Author(s):  
Tu'uhevaha J. Kaitu'u-Lino ◽  
David J. Phillips ◽  
Naomi B. Morison ◽  
Lois A. Salamonsen
Keyword(s):  
Mouse Model ◽  
Wound Repair ◽  
Abnormal Uterine Bleeding ◽  
Transgenic Animals ◽  
Skin Wound ◽  
Uterine Bleeding ◽  
Epithelial Cell Line ◽  
Skin Wound Healing ◽  
Endometrial Epithelial Cell

Abnormal uterine bleeding can severely affect the quality of life for women. After menstruation, the endometrium must adequately repair to limit and stop bleeding. Abnormal uterine bleeding may result from incorrect or inadequate endometrial repair after menstruation. Previous studies have shown an important contribution of activin to skin wound healing, with severely delayed wound repair observed in animals transgenically induced to overexpress activin’s natural inhibitor, follistatin. Activin subunits have also been identified within human endometrium; however, their role in endometrial repair is unknown. We assessed the contribution of activin to endometrial repair after menses using a human in vitro cell wounding method and our well-characterized mouse model of endometrial breakdown and repair applied to mice overexpressing follistatin. Endometrial repair after menses is initiated with reepithelialization of the uterine surface. To mimic this repair, we utilized a human endometrial epithelial cell line (ECC-1) and demonstrated significant stimulation of wound closure after activin A administration, and attenuation of this response by addition of follistatin. Immunolocalization of activin subunits, βA and βB, in control endometrium from the mouse model demonstrated specific epithelial and stromal localization and some leukocyte staining (βA) around sites of endometrial repair, suggestive of a role for activin in this process. Follistatin-overexpressing animals had significantly higher circulating follistatin levels than wild-type littermates. There was a significant delay in endometrial repair after breakdown in follistatin transgenic animals compared with control animals. This study demonstrates for the first time a functional role for activin in endometrial repair after menses.

scholarly journals Electrospun PCL-Surgihoney meshes for skin wound healing applications

2020 ◽  
Vol 318 ◽  
pp. 01029
Author(s):  
Enes Aslan
Keyword(s):  
Wound Dressing ◽  
Cell Attachment ◽  
Positive Impact ◽  
Dermal Fibroblast ◽  
Healing Process ◽  
Human Dermal Fibroblast ◽  
Skin Wound ◽  
Regulatory Function ◽  
Skin Wound Healing ◽  
Skin Healing

Skin is a complex and very important tissue, playing a significant protective and regulatory function. It is also prone to a large number of wounds and defects due to external factors such as temperature, chemical agents, and radiation. Accelerating the skin healing process and minimizing the risk of infection is a relevant research challenge. This paper investigates a novel wound dressing based on polycaprolactone (PCL), a synthetic biocompatible and biodegradable polymer, and honey-Surgihoney® (SH). Solution electrospinning was used to produce the wound dressing meshes. Different polymer solutions were prepared by mixing PCL and SH with acetic acid. Human dermal fibroblast were used to assess the biological characteristics of the electrospun meshes. Results show that the presence of SH1 has a positive impact on cell attachment and proliferation.

Myostatin-null mice exhibit delayed skin wound healing through the blockade of transforming growth factor-β signaling by decorin

2012 ◽  
Vol 302 (8) ◽  
pp. C1213-C1225 ◽  
Author(s):  
Chen Zhang ◽  
Chek Kun Tan ◽  
Craig McFarlane ◽  
Mridula Sharma ◽  
Nguan Soon Tan ◽  
...  
Keyword(s):  
Wound Healing ◽  
Growth Factor ◽  
Wound Repair ◽  
Transforming Growth Factor ◽  
Healing Process ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
Skin Wound ◽  
Wound Healing Process ◽  
Skin Wound Healing

Myostatin (Mstn) is a secreted growth and differentiation factor that belongs to the transforming growth factor-β (TGF-β) superfamily. Mstn has been well characterized as a regulator of myogenesis and has been shown to play a critical role in postnatal muscle regeneration. Herein, we report for the first time that Mstn is expressed in both epidermis and dermis of murine and human skin and that Mstn-null mice exhibited delayed skin wound healing attributable to a combination of effects resulting from delayed epidermal reepithelialization and dermal contraction. In epidermis, reduced keratinocyte migration and protracted keratinocyte proliferation were observed, which subsequently led to delayed recovery of epidermal thickness and slower reepithelialization. Furthermore, primary keratinocytes derived from Mstn-null mice displayed reduced migration capacity and increased proliferation rate as assessed through in vitro migration and adhesion assays, as well as bromodeoxyuridine incorporation and Western blot analysis. Moreover, in dermis, both fibroblast-to-myofibroblast transformation and collagen deposition were concomitantly reduced, resulting in a delayed dermal wound contraction. These decreases are due to the inhibition of TGF-β signaling. In agreement, the expression of decorin, a naturally occurring TGF-β suppressor, was elevated in Mstn-null mice; moreover, topical treatment with TGF-β1 protein rescued the impaired skin wound healing observed in Mstn-null mice. These observations highlight the interplay between TGF-β and Mstn signaling pathways, specifically through Mstn regulation of decorin levels during the skin wound healing process. Thus we propose that Mstn agonists might be beneficial for skin wound repair.

scholarly journals Increased glucocorticoid activation during mouse skin wound healing

2014 ◽  
Vol 221 (1) ◽  
pp. 51-61 ◽  
Author(s):  
Ana Tiganescu ◽  
Melanie Hupe ◽  
Yoshikazu Uchida ◽  
Theodora Mauro ◽  
Peter M Elias ◽  
...  
Keyword(s):  
Wound Healing ◽  
Wound Repair ◽  
De Novo ◽  
Mouse Skin ◽  
Inflammatory Cells ◽  
Skin Wound ◽  
Skin Wound Healing ◽  
Variable Expression ◽  
Before And After

Glucocorticoid (GC) excess inhibits wound healing causing increased patient discomfort and infection risk. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activates GCs (converting 11-dehydrocorticosterone to corticosterone in rodents) in many tissues including skin, wherede novosteroidogenesis from cholesterol has also been reported. To examine the regulation of 11β-HSD1 and steroidogenic enzyme expression during wound healing, 5 mm wounds were generated in female SKH1 mice and compared at days 0, 2, 4, 8, 14, and 21 relative to unwounded skin. 11β-HSD1 expression (mRNA and protein) and enzyme activity were elevated at 2 and 4 days post-wounding, with 11β-HSD1 localizing to infiltrating inflammatory cells. 11β-HSD2 (GC-deactivating) mRNA expression and activity were undetectable. Although several steroidogenic enzymes displayed variable expression during healing, expression of the final enzyme required for the conversion of 11-deoxycorticosterone to corticosterone, 11β-hydroxylase (CYP11B1), was lacking in unwounded skin and post-wounding. Consequently, 11-deoxycorticosterone was the principal progesterone metabolite in mouse skin before and after wounding. Our findings demonstrate that 11β-HSD1 activates considerably more corticosterone than is generatedde novofrom progesterone in mouse skin and drives GC exposure during healing, demonstrating the basis for 11β-HSD1 inhibitors to accelerate wound repair.

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