SERPINE1: A Molecular Switch in the Proliferation-Migration Dichotomy in Wound-“Activated” Keratinocytes

Simone, Tessa M.; Higgins, Craig E.; Czekay, Ralf-Peter; Law, Brian K.; Higgins, Stephen P.; Archambeault, Jaclyn; Kutz, Stacie M.; Higgins, Paul J.

doi:10.1089/wound.2013.0512

Cited by 70 publications

(75 citation statements)

References 61 publications

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“…This process involves extensive remodeling of the extracellular matrix (ECM) to regulate cellular responses such as apoptosis, proliferation, migration and differentiation (Calve et al, 2010;Lu et al, 2011). ECM remodeling is regulated via activation of specific enzymes such as Serpins (Simone et al, 2014) and TIMPs (Arpino et al, 2015), which inhibit peptidases that degrade structural ECM proteins. We observed strong enrichment of the GO categories ʻpeptidase inhibitor' and ʻnegative regulation of peptidase activity' at later stages of regeneration, particularly at D8 (Fig.…”

Section: Discussion Molecular Signatures Indicate Conserved Features mentioning

confidence: 99%

A microRNA-mRNA expression network during oral siphon regeneration in Ciona

et al. 2017

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Here we present a parallel study of mRNA and microRNA expression during oral siphon (OS) regeneration in Ciona robusta, and the derived network of their interactions. In the process of identifying 248 mRNAs and 15 microRNAs as differentially expressed, we also identified 57 novel microRNAs, several of which are among the most highly differentially expressed. Analysis of functional categories identified enriched transcripts related to stress responses and apoptosis at the wound healing stage, signaling pathways including Wnt and TGFβ during early regrowth, and negative regulation of extracellular proteases in late stage regeneration. Consistent with the expression results, we found that inhibition of TGFβ signaling blocked OS regeneration. A correlation network was subsequently inferred for all predicted microRNA-mRNA target pairs expressed during regeneration. Network-based clustering associated transcripts into 22 non-overlapping groups, the functional analysis of which showed enrichment of stress response, signaling pathway and extracellular protease categories that could be related to specific microRNAs. Predicted targets of the miR-9 cluster suggest a role in regulating differentiation and the proliferative state of neural progenitors through regulation of the cytoskeleton and cell cycle.

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Section: Discussion Molecular Signatures Indicate Conserved Features mentioning

confidence: 99%

A microRNA-mRNA expression network during oral siphon regeneration in Ciona

et al. 2017

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“…The available evidence suggests that the expression and antiproteolytic activity of PAI-1 dictates the physiological and pathophysiological cellular responses to injury. Indeed, several factors (including PAI-1) that are involved in cell motility participate in the regulation of growth arrest in the "go or grow" proliferation/migration dichotomy [28][29][30]. PAI-1 is deposited into cellular migration "trails" while knockdown approaches, PAI-1 add-back rescue as well as use of neutralizing antibodies and PAI-1 −/− keratinocytes confirmed the requirement for PAI-1 in optimal monolayer wound repair [31,32].…”

Section: Pai-1 In Cellular Mechanisms Of Disease Progressionmentioning

confidence: 91%

“…Independent of its function as a protease inhibitor, PAI-1 binds to the endocytic low-density lipoprotein receptor-related protein-1 (LRP1) where it triggers JAK/STAT1-mediated signaling and migration [30]. All three conformations of PAI-1 (active, latent, substrate/cleaved) bind LRP1 and activate the downstream JAK/STAT1 pathway to drive cell migration [44][45][46].…”

Section: Pai-1 As a Multifunctional Signaling "Ligand"mentioning

confidence: 99%

Inhibition of SERPINE1 Function Attenuates Wound Closure in Response to Tissue Injury: A Role for PAI-1 in Re-Epithelialization and Granulation Tissue Formation

Simone

Higgins

2015

JDB

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Plasminogen activator inhibitor-1 (PAI-1; SERPINE1) is a prominent member of the serine protease inhibitor superfamily (SERPIN) and a causative factor of multi-organ fibrosis as well as a key regulator of the tissue repair program. PAI-1 attenuates pericellular proteolysis by inhibiting the catalytic activity of both urokinase and tissue-type protease activators (uPA and tPA) effectively modulating, thereby, plasmin-mediated fibrinolysis and the overall pericellular proteolytic cascade. PAI-1 also impacts cellular responses to tissue injury and stress situations (growth, survival, migration) by titering the locale and temporal activation of multimeric cell-surface signaling complexes. This review will describe PAI-1 structure and function and detail the role of PAI-1 in the tissue repair program with an emphasis on cutaneous wound healing.

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“…Fine control of proteolysis reorganizes ECM architecture which affects the dynamics of cell-ECM interactions involving integrins, releases bioactive ECM molecules such as collagen fragments, and activates growth factors including IGF-1 and FGF-7 which stimulate cellular migratory and proliferative behavior [34] [35]. Current data suggests PAI-1 may function as a rheostat to regulate the spatial-temporal control of pericellular proteolysis in response to tissue injury [36]. Hence, PAI-1 may orchestrate the local proteolysis necessary for visceral skin graft maturation and separation.…”

Section: Discussionmentioning

confidence: 99%

Investigation of Open Abdomen Visceral Skin Graft Revascularization and Separation from Peritoneal Contents

Clark¹,

Coffman²,

Brandenburg³

et al. 2018

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Background: Despite increasing survival following damage control laparotomy and open abdomen technique, little is known about the biology of visceral skin graft revascularization and separation from peritoneal contents. Methods: Following laparotomy for trauma, patients with visceral edema preventing fascial closure underwent Vicryl mesh closure followed by visceral split-thickness skin grafting and readmission graft excision and abdominal wall reconstruction. Utilizing laser speckle contrast imaging, immunochemical staining of histologic sections, and RT-PCR array technology, we examined the revascularization, microvascular anatomy, morphology, and change in gene expression of visceral skin grafts. Results: Ten patients ranging in age from 25 to 46 years underwent visceral grafting for cutaneous coverage of an open abdomen. Skin graft perfusion peaked at a mean of 350 PU by post-operative day 14 synchronous with closure of meshed interstices, and remained constant until excision. Time to graft excision ranged from 6 to 18 months. CD-31 immunostaining documented a significant (p = 0.04) increase in vascular surface area in excised grafts compared to control skin. Trichrome staining revealed an 8-fold increase in excised graft thickness. Mesothelial cells were identified within the dermal matrix of excised grafts. RT-PCR demonstrated significant up-regulation of genes involved in matrix structure and remodeling, cytoskeleton regulation, and WNT signaling; and down-regulation of genes involved in inflammation and matrix proteolysis in excised grafts compared to control skin. Conclusion: Our data document early visceral skin graft perfusion and a plateau in revascularization. Histology reveals a robust dermal matrix populated by fibroblasts and mesothelial cells within a complex supporting vascular network. Genetic analysis of excised grafts reveals growth factor, collagen, and matrix remodeling gene expression.

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SERPINE1: A Molecular Switch in the Proliferation-Migration Dichotomy in Wound-“Activated” Keratinocytes

Cited by 70 publications

References 61 publications

A microRNA-mRNA expression network during oral siphon regeneration in Ciona

A microRNA-mRNA expression network during oral siphon regeneration in Ciona

Inhibition of SERPINE1 Function Attenuates Wound Closure in Response to Tissue Injury: A Role for PAI-1 in Re-Epithelialization and Granulation Tissue Formation

Investigation of Open Abdomen Visceral Skin Graft Revascularization and Separation from Peritoneal Contents

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