Wound healing defect of Vav3−/− mice due to impaired β2-integrin–dependent macrophage phagocytosis of apoptotic neutrophils

Blood ◽  
2009 ◽  
Vol 113 (21) ◽  
pp. 5266-5276 ◽  
Author(s):  
Anca Sindrilaru ◽  
Thorsten Peters ◽  
Jürgen Schymeinsky ◽  
Tsvetelina Oreshkova ◽  
Honglin Wang ◽  
...  
Keyword(s):  
Wound Healing ◽  
Rho Gtpases ◽  
Transforming Growth Factor ◽  
Local Injection ◽  
Nucleotide Exchange ◽  
Impaired Wound Healing ◽  
Β2 Integrin ◽  
Macrophage Phagocytosis ◽  
Tgf Β1 ◽  
Β2 Integrins

Abstract Vav proteins are guanine-nucleotide exchange factors implicated in leukocyte functions by relaying signals from immune response receptors and integrins to Rho-GTPases. We here provide first evidence for a role of Vav3 for β2-integrins–mediated macrophage functions during wound healing. Vav3−/− and Vav1−/−/Vav3−/− mice revealed significantly delayed healing of full-thickness excisional wounds. Furthermore, Vav3−/− bone marrow chimeras showed an identical healing defect, suggesting that Vav3 deficiency in leukocytes, but not in other cells, is causal for the impaired wound healing. Vav3 was required for the phagocytotic cup formation preceding macrophage phagocytosis of apoptotic neutrophils. Immunoprecipitation and confocal microscopy revealed Vav3 activation and colocalization with β2-integrins at the macrophage membrane upon adhesion to ICAM-1. Moreover, local injection of Vav3−/−or β2-integrin(CD18)−/− macrophages into wound margins failed to restore the healing defect of Vav3−/− mice, suggesting Vav3 to control the β2-integrin–dependent formation of a functional phagocytic synapse. Impaired phagocytosis of apoptotic neutrophils by Vav3−/− macrophages was causal for their reduced release of active transforming growth factor (TGF)-β1, for decreased myofibroblasts differentiation and myofibroblast-driven wound contraction. TGF-β1 deficiency in Vav3−/− macrophages was causally responsible for the healing defect, as local injection of either Vav3-competent macrophages or recombinant TGF-β1 into wounds of Vav3−/− mice fully rescued the delayed wound healing.

scholarly journals LncRNA MALAT1 Modulates TGF-β1-Induced EMT in Keratinocyte

2021 ◽  
Vol 22 (21) ◽  
pp. 11816
Author(s):  
Liping Zhang ◽  
Junyi Hu ◽  
Bahar I. Meshkat ◽  
Kenneth W. Liechty ◽  
Junwang Xu
Keyword(s):  
Wound Healing ◽  
Transforming Growth Factor Beta ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Hacat Cells ◽  
Impaired Wound Healing ◽  
Mesenchymal Transition ◽  
Lncrna Malat1 ◽  
Diabetic Wounds ◽  
Tgf Β1

One of the major complications in diabetes is impaired wound healing. Unfortunately, effective therapies are currently lacking. Epithelial to mesenchymal transition (EMT) is a critical process involved in cutaneous wound healing. In response to injury, EMT is required to activate and mobilize stationary keratinocytes in the skin toward the wound bed, which allows for re-epithelialization. This process is stalled in diabetic wounds. In this study, we investigate the role of long non-coding RNA (lncRNA), MALAT1, in transforming growth factor beta 1(TGF-β1)-induced EMT of human keratinocyte (HaCaT) cells. Initially, we detected MALAT1 and TGF-β1 expression in non-diabetic and diabetic wounds and found that these expression are significantly up-regulated in diabetic wounds. Then, HaCaT cells were cultured and exposed to TGF-β1. The EMT of HaCaT cells were confirmed by the increased expression of CDH2, KRT10, and ACTA2, in addition to the down-regulation of CDH1. Knockdown of MALAT1 was achieved by transfecting a small interfering RNA (SiRNA). MALAT1 silencing attenuates TGFβ1-induced EMT. Mechanistically, MALAT1 is involved in TGF-β1 mediated EMT through significantly induced ZEB1 expression, a critical transcription factor for EMT. In summary, lncRNA MALAT1 is involved in TGFβ1-induced EMT of human HaCaT cells and provides new understanding for the pathogenesis of diabetic wounds.

The Safety and Efficacy of Mupirocin Topical Spray for Burn Wound Healing in A Rat Model

2019 ◽  
Vol 10 (01) ◽  
Author(s):  
Sritharadol Rutthapol ◽  
Chunhachaichana Charisopon ◽  
Kumlungmak Sukanjana ◽  
Buatong Wilaiporn ◽  
Dechraksa Janwit ◽  
...  
Keyword(s):  
Wound Healing ◽  
Matrix Metalloproteinase ◽  
Rat Model ◽  
Transforming Growth Factor ◽  
Immunohistochemical Study ◽  
Enzyme Linked Immunosorbent Assay ◽  
Burn Wound ◽  
Safety And Efficacy ◽  
Burn Wound Healing ◽  
Tgf Β1

ABSTRACT This study evaluated the effect of mupirocin topical spray on burn wound healing in a rat model. Fifteen male Sprague Dawley rats were used to create full-thickness burns on the rat dorsum using a cylindrical stainless steel rod. The rats were topically treated with normal saline solution (NSS), mupirocin spray, ointment, and solution. The wound size and morphological evaluation were investigated by photographs and clinical criterions for wound healing. The histology was observed by hematoxylin and eosin (HandE) staining assay. The immunohistochemical study was evaluated by detection of transforming growth factor-beta 1 (TGF-β1), and the ratio of matrix metalloproteinase-9 to the tissue inhibitor of matrix metalloproteinase-1 (MMP-9/TIMP-1) was quantified using the enzyme-linked immunosorbent assay (ELISA) assay. A complete healing was observed at 28 days in all treatments. Mupirocin formulations accelerated the wound healing faster than NSS in size. However, the clinical criteria indicated a desirable skin appearance in the mupirocin spray and ointment treated groups. The histological evaluations showed no differences between the treatments while the immunohistochemical study revealed that all treatments reduced the level of TGF-β1 over time, particularly on day 28 in the mupirocin spray and ointment treated groups. The MMP-9/TIMP-1 ratio was significantly lower in the mupirocin spray and ointment treated groups than in the NSS and mupirocin solution groups. This study shows the safety and efficacy in the use of mupirocin topical spray. The topical mupirocin spray is an alternative suitable for development as a human topical anti-infective and wound protection spray.

Transforming growth factor beta 1 dependent regulation of Tenascin-C in radiation impaired wound healing

2004 ◽  
Vol 72 (3) ◽  
pp. 297-303 ◽  
Author(s):  
Falk Wehrhan ◽  
Franz Rödel ◽  
Gerhard G. Grabenbauer ◽  
Kerstin Amann ◽  
Wolfgang Brückl ◽  
...  
Keyword(s):  
Wound Healing ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Impaired Wound Healing ◽  
Tenascin C ◽  
Growth Factor Beta

scholarly journals FAK Inhibition Attenuates Corneal Fibroblast Differentiation In Vitro

Biomolecules ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1682
Author(s):  
Vincent Yeung ◽  
Sriniwas Sriram ◽  
Jennifer A. Tran ◽  
Xiaoqing Guo ◽  
Audrey E. K. Hutcheon ◽  
...  
Keyword(s):  
Wound Healing ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Myofibroblast Differentiation ◽  
Corneal Scarring ◽  
Corneal Fibroblast ◽  
Corneal Fibroblasts ◽  
Corneal Wound ◽  
Tgf Β1

Corneal fibrosis (or scarring) occurs in response to ocular trauma or infection, and by reducing corneal transparency, it can lead to visual impairment and blindness. Studies highlight important roles for transforming growth factor (TGF)-β1 and -β3 as modulators in corneal wound healing and fibrosis, leading to increased extracellular matrix (ECM) components and expression of α-smooth muscle actin (αSMA), a myofibroblast marker. In this study, human corneal fibroblasts (hCF) were cultured as a monolayer culture (2D) or on poly-transwell membranes to generate corneal stromal constructs (3D) that were treated with TGF-β1, TGF-β3, or TGF-β1 + FAK inhibitor (FAKi). Results show that hCF 3D constructs treated with TGF-β1 or TGF-β3 impart distinct effects on genes involved in wound healing and fibrosis—ITGAV, ITGB1, SRC and ACTA2. Notably, in the 3D construct model, TGF-β1 enhanced αSMA and focal adhesion kinase (FAK) protein expression, whereas TGF-β3 did not. In addition, in both the hCF 2D cell and 3D construct models, we found that TGF-β1 + FAKi attenuated TGF-β1-mediated myofibroblast differentiation, as shown by abrogated αSMA expression. This study concludes that FAK signaling is important for the onset of TGF-β1-mediated myofibroblast differentiation, and FAK inhibition may provide a novel beneficial therapeutic avenue to reduce corneal scarring.

scholarly journals Adipose Stem Cells from Type 2 Diabetic Mice Exhibit Therapeutic Potential in Wound Healing

2020 ◽  
Author(s):  
Yongfa Sun ◽  
Lili Song ◽  
Yong Zhang ◽  
Hongjun Wang ◽  
Xiao Dong
Keyword(s):  
Wound Healing ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Therapeutic Potential ◽  
Diabetic Patients ◽  
Therapeutic Effects ◽  
Skin Damage ◽  
Impaired Wound Healing ◽  
Collagen Iii

Abstract BACKGROUND: Diabetic patients suffer from impaired wound healing. Mesenchymal stem cell (MSC) therapy represents a promising approach toward improving skin wound healing through release of soluble growth factors and cytokines that stimulate new vessel formation and modulate inflammation. Whether adipose-derived MSCs (ASCs) from type 2 diabetes donors are suitable for skin damage repair remains largely unknown. METHODS: In this study, we compared the phenotype and functionality of ASCs harvested from high fat diet (HFD) and streptozotocin (STZ)-induced T2D or control mice, and assessed their abilities to promote wound healing in an excisional wound splinting mouse model with T2D. RESULTS: T2D ASCs expressed similar cellular markers as control ASCs, but secreted less hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and transforming growth factor β (TGF-β). T2D ASCs were somewhat less effective in promoting healing of the wound, as manifested by slightly reduced re-epithelialization, cutaneous appendage regeneration, and collagen III deposition in wound tissues. In vitro, T2D ASCs promoted proliferation and migration of skin fibroblasts to a comparable extent as control ASCs via suppression of inflammation and macrophage infiltration. CONCLUSIONS: From these findings, we conclude that, although ASCs from T2D mice are marginally inferior to control ASCs, they possess comparable therapeutic effects in wound healing.

Acceleration of Palatal Wound Healing in Smad3-deficient Mice

2009 ◽  
Vol 88 (8) ◽  
pp. 757-761 ◽  
Author(s):  
K. Jinno ◽  
T. Takahashi ◽  
K. Tsuchida ◽  
E. Tanaka ◽  
K. Moriyama
Keyword(s):  
Wound Healing ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Monocyte Chemoattractant Protein 1 ◽  
Inflammatory Protein ◽  
Complex Process ◽  
Dermal Cells ◽  
Macrophage Inflammatory Protein ◽  
Tgf Β1

Wound healing is a well-orchestrated complex process leading to the repair of injured tissues. It is suggested that transforming growth factor (TGF)-β/Smad3 signaling is involved in wound healing. The purpose of this study was to investigate the role of TGF-β/Smad3 signaling in palatal wound healing in Smad3-deficient (Smad3−/−) mice. Histological examination showed that wound closure was accelerated by the proliferation of epithelium and dermal cells in Smad3−/− mice compared with wild-type (WT) mice. Macrophage/monocyte infiltration at wounded regions in Smad3−/− mice was decreased in parallel with the diminished production of TGF-β1, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1α compared with WT mice. Fibrocytes, expressing hematopoietic surface marker and fibroblast products, were recruited and produced α-smooth-muscle actin in WT mice, but were not observed in Smad3−/− mice. These results suggest that TGF-β/Smad3 signaling may play an important role in the regulation of palatal wound healing.

Curcumin differentially regulates TGF-β1, its receptors and nitric oxide synthase during impaired wound healing

BioFactors ◽  
2002 ◽  
Vol 16 (1-2) ◽  
pp. 29-43 ◽  
Author(s):  
Haresh Mani ◽  
Gurmel S. Sidhu ◽  
Ranjana Kumari ◽  
Jaya P. Gaddipati ◽  
Pankaj Seth ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Wound Healing ◽  
Nitric Oxide Synthase ◽  
Impaired Wound Healing ◽  
Oxide Synthase ◽  
Tgf Β1

scholarly journals FOXO1 promotes wound healing through the up-regulation of TGF-β1 and prevention of oxidative stress

2013 ◽  
Vol 203 (2) ◽  
pp. 327-343 ◽  
Author(s):  
Bhaskar Ponugoti ◽  
Fanxing Xu ◽  
Chenying Zhang ◽  
Chen Tian ◽  
Sandra Pacios ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Wound Healing ◽  
Cell Death ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Critical Aspect ◽  
Independent Manner ◽  
Forkhead Box ◽  
Negative Effect ◽  
Tgf Β1

Keratinocyte mobilization is a critical aspect of wound re-epithelialization, but the mechanisms that control its precise regulation remain poorly understood. We set out to test the hypothesis that forkhead box O1 (FOXO1) has a negative effect on healing because of its capacity to inhibit proliferation and promote apoptosis. Contrary to expectations, FOXO1 is required for keratinocyte transition to a wound-healing phenotype that involves increased migration and up-regulation of transforming growth factor β1 (TGF-β1) and its downstream targets, integrin-α3 and -β6 and MMP-3 and -9. Furthermore, we show that FOXO1 functions in keratinocytes to reduce oxidative stress, which is necessary to maintain cell migration and prevent cell death in a TGF-β1–independent manner. Thus, our studies identify a novel function for FOXO1 in coordinating the response of keratinocytes to wounding through up-regulation of TGF-β1 and other factors needed for keratinocyte migration and protection against oxidative stress, which together promote migration and decrease apoptosis.

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