Integrins in Wound Healing

Koivisto, Leeni; Heino, Jyrki; Häkkinen, Lari; Larjava, Hannu

doi:10.1089/wound.2013.0436

Cited by 178 publications

(172 citation statements)

References 153 publications

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“…Indeed, they can drive wide-ranging cellular responses including cell spreading, migration, proliferation, and apoptosis, contributing to diverse aspects of organismal physiology, from embryogenesis and wound healing, to immunity and hemostasis. 11,12 In contrast, their aberrant function can lead to pathological events such as inflammatory disease, bleeding, and thrombosis.…”

Section: Introductionmentioning

confidence: 99%

Integrin αIIbβ3 outside-in signaling

Durrant

Bosch

Hers

2017

Blood

189

175

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Integrin αIIbβ3 is a highly abundant heterodimeric platelet receptor that can transmit information bidirectionally across the plasma membrane, and plays a critical role in hemostasis and thrombosis. Upon platelet activation, inside-out signaling pathways increase the affinity of αIIbβ3 for fibrinogen and other ligands. Ligand binding and integrin clustering subsequently stimulate outside-in signaling, which initiates and amplifies a range of cellular events driving essential platelet processes such as spreading, thrombus consolidation, and clot retraction. Integrin αIIbβ3 has served as an excellent model for the study of integrin biology, and it has become clear that integrin outside-in signaling is highly complex and involves a vast array of enzymes, signaling adaptors, and cytoskeletal components. In this review, we provide a concise but comprehensive overview of αIIbβ3 outside-in signaling, focusing on the key players involved, and how they cooperate to orchestrate this critical aspect of platelet biology. We also discuss gaps in the current understanding of αIIbβ3 outside-in signaling and highlight avenues for future investigation.

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Section: Introductionmentioning

confidence: 99%

Integrin αIIbβ3 outside-in signaling

Durrant

Bosch

Hers

2017

Blood

189

175

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“…5 Integrins consist of two subunits, an a and a b subunit, each of which have many subtypes. These two subunits associate together and bind to a variety of ECM proteins, including collagen, fibronectin, and others.…”

Section: Introductionmentioning

confidence: 99%

The impact of quercetin on wound healing relates to changes in αV and β1 integrin expression

Doersch

Newell‐Rogers

2017

Exp Biol Med (Maywood)

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Impact statementScar formation during wound healing can be problematic for patients but there are limited therapies available to treat or prevent excess fibrosis at wound sites. This work examines the impact of quercetin, a flavonoid that decreases fibrosis, on wound healing, and relates quercetin's effects to changes in integrin expression on the surface of fibroblast cells. To our knowledge, this is the first report that quercetin alters integrin expression or that this impact may be part of the mechanism by which quercetin prevents fibrosis. This work demonstrates that quercetin can be used to modulate integrin expression and that this effect may in turn reduce fibrosis during wound healing. Furthermore, this paper identifies the modulation of integrin expression as a possible therapeutic target in preventing scars. This information could be used to improve therapeutics to aid in the cosmetic and functional results following wound healing. AbstractOverly fibrotic wound healing can lead to excess scar formation, causing functional impairment and undesirable cosmetic results. However, there are few successful treatments available to prevent or remediate scars. This study sought to explore the molecular mechanisms by which quercetin, a naturally-occurring antifibrotic agent, diminishes scar formation. Using both mice and fibroblast cells, we examined quercetin's impact on fibrosis and the wound healing rate, and potential molecular mechanisms underlying the quercetinmediated reduction of fibrosis. While cultured fibroblasts demonstrated normal growth in response to quercetin, quercetin increased surface aV integrin and decreased b1 integrin. These changes in surface integrin expression may impact factors that contribute to fibrosis including cell migration, proliferation, and extracellular matrix production. In both quercetintreated and control mice, wounds healed in about 14 days. Masson's trichrome stain revealed diminished fibrosis at the wound site in quercetin-treated animals despite the normal healing rate, indicating the potential for better cosmetic results without delaying healing. An in vitro scratch wound model using cells plated on an artificial extracellular matrix demonstrated delayed closure following quercetin treatment. The extracellular matrix also ameliorated quercetin's effect on aV integrin. Thus, aV integrin recruitment in response to quercetin treatment may promote the quercetin-mediated decrease extracellular matrix because cells require less extracellular matrix to migrate into a wound. With added extracellular matrix, b1 integrin remained diminished in response to quercetin, indicating that quercetin's effect on b1 integrin expression is independent of extracellular matrix -mediated signaling and is likely driven by inhibition of the intracellular mechanisms driving b1 expression. These findings suggest that quercetin could alter the cells' interactions with the extracellular matrix through the regulation of integrin expression to promote a decrease in fibrosis. Furthermore, this work d...

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“…Coincidentally, both α3β1 and α5β1 are involved in wound healing, where each has been shown to mediate cell migration across newly generated ECM during the re-epithelization process and it stands to reason that α3β1 and α5β1 integrins are likely to play a role in wound healing of the urothelium post-TURBT (19). Therefore, it may be that the therapeutic benefit of VAX014 is also a product of pharmacological activity against the urothelium at the site of resection in vivo, possibly resulting from a VAX014-induced delay in ECM deposition and a theoretical reduction in available tumor reattachment sites therewith.…”

Section: Discussionmentioning

confidence: 99%

A Single Intravesical Instillation of VAX014 Inhibits Orthotopic Superficial Bladder Tumor Implantation to Increase Survival

Hancock

McGuire

Tsuji

et al. 2016

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Abstract. Background/Aim: VAX014 minicells (VAX014) Bladder cancer ranks second amongst newly diagnosed urothelial carcinomas worldwide, is the sixth leading cause of cancer death and the fourth most common malignancy of men in developed countries (1). Current estimates suggest that as many as 75-80% of patients with bladder cancer present for the first time with localized non-muscle invasive bladder cancer (NMIBC). It is further estimated that of those newly diagnosed NMIBC cases, 70% present with what the European Association of Urologists classifies as low-risk disease (2).Current recommended clinical practice for the treatment of low-risk NMIBC is cystoscopic transurethral resection of bladder tumor (TURBT) followed by an immediate postoperative intravesical instillation of a chemotherapeutic agent. Without adjuvant treatment, as many as 35.8% of patients treated for low-risk NMIBC will suffer recurrence within 2 years (3). There have been several studies and meta-analyses published indicating that the immediate postoperative instillation of adjuvant therapy may lead to a decrease in the overall risk of recurrence of up to 39%, with absolute reduction in recurrence rates as high as 17% (4). While clearly effective in reducing recurrence, several recently conducted surveys have revealed that immediate single-dose post-operative adjuvant therapy is not consistently administered (5, 6). A prominently cited reason among those clinicians who do not administer immediate post-operative chemotherapy is that the potential for systemic exposure and agent-associated toxicity outweighs the clinical benefit, especially in cases where bladder perforation is suspected. The perceived clinical benefit-torisk ratio argument seems justified given that while patients with low-and intermediate-risk NMIBC have a high rate of recurrence, the initial risk of progression is low (0.8% and 6% at 5 years, respectively) (2). However, the risk of progression increases with the number and interval of recurrences, so any initial prevention or delay of recurrence would be of clear benefit (2). Moreover, because of the high rate of recurrence, frequent monitoring and treatment are required, making NMIBC one of the most expensive cancer types to treat over the course of the disease (7). Therefore, an effective agent for use in the immediate post-operative setting would impart considerable pharmacoeconomic benefit. Recent failures in mid-and late-stage clinical trials highlight the unmet clinical need for the development of new agents that can be safely administered in the immediate post-operative setting (8).

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Integrins in Wound Healing

Cited by 178 publications

References 153 publications

Integrin αIIbβ3 outside-in signaling

Integrin αIIbβ3 outside-in signaling

The impact of quercetin on wound healing relates to changes in αV and β1 integrin expression

A Single Intravesical Instillation of VAX014 Inhibits Orthotopic Superficial Bladder Tumor Implantation to Increase Survival

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