scholarly journals Spatiotemporal dynamics of PIEZO1 localization controls keratinocyte migration during wound healing

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Jesse R Holt ◽  
Wei-Zheng Zeng ◽  
Elizabeth L Evans ◽  
Seung-Hyun Woo ◽  
Shang Ma ◽  
...  
Keyword(s):  
Wound Healing ◽  
Molecular Mechanisms ◽  
Wound Closure ◽  
Chemical Activation ◽  
Spatiotemporal Dynamics ◽  
Collective Migration ◽  
Wound Edge ◽  
Keratinocyte Migration ◽  
Predominant Cell Type ◽  
Spatiotemporal Localization

Keratinocytes, the predominant cell type of the epidermis, migrate to reinstate the epithelial barrier during wound healing. Mechanical cues are known to regulate keratinocyte re-epithelialization and wound healing however, the underlying molecular transducers and biophysical mechanisms remain elusive. Here, we show through molecular, cellular and organismal studies that the mechanically-activated ion channel PIEZO1 regulates keratinocyte migration and wound healing. Epidermal-specific Piezo1 knockout mice exhibited faster wound closure while gain-of-function mice displayed slower wound closure compared to littermate controls. By imaging the spatiotemporal localization dynamics of endogenous PIEZO1 channels we find that channel enrichment at some regions of the wound edge induces a localized cellular retraction that slows keratinocyte collective migration. In migrating single keratinocytes, PIEZO1 is enriched at the rear of the cell, where maximal retraction occurs, and we find that chemical activation of PIEZO1 enhances retraction during single as well as collective migration. Our findings uncover novel molecular mechanisms underlying single and collective keratinocyte migration that may suggest a potential pharmacological target for wound treatment. More broadly, we show that nanoscale spatiotemporal dynamics of Piezo1 channels can control tissue-scale events, a finding with implications beyond wound healing to processes as diverse as development, homeostasis, disease and repair.

scholarly journals Spatiotemporal dynamics of PIEZO1 localization controls keratinocyte migration during wound healing

2020 ◽  
Author(s):  
Jesse R. Holt ◽  
Wei-Zheng Zeng ◽  
Elizabeth L. Evans ◽  
Seung-Hyun Woo ◽  
Shang Ma ◽  
...  
Keyword(s):  
Wound Healing ◽  
Wound Closure ◽  
Spatiotemporal Dynamics ◽  
Epithelial Barrier ◽  
Wound Treatment ◽  
Cell Type ◽  
Keratinocyte Migration ◽  
Predominant Cell Type ◽  
Pharmacological Target ◽  
Spatiotemporal Localization

AbstractKeratinocytes, the predominant cell type of the epidermis, migrate to reinstate the epithelial barrier during wound healing. Mechanical cues are known to regulate keratinocyte re-epithelization and wound healing however, the underlying molecular transducers and biophysical mechanisms remain elusive. Here, we show through molecular, cellular and organismal studies that the mechanically-activated ion channel PIEZO1 regulates keratinocyte migration and wound healing. Epidermal-specific Piezo1 knockout mice exhibited faster wound closure while gain-of-function mice displayed slower wound closure compared to littermate controls. By imaging the spatiotemporal localization dynamics of endogenous PIEZO1 channels we find that channel enrichment in sub-cellular regions induces a localized cellular retraction that slows keratinocyte migration. Our findings suggest a potential pharmacological target for wound treatment. More broadly, we show that nanoscale spatiotemporal dynamics of Piezo1 channels can control tissue-scale events, a finding with implications beyond wound healing to processes as diverse as development, homeostasis, disease and repair.

scholarly journals Endocytosis-dependent coordination of multiple actin regulators is required for wound healing

2015 ◽  
Vol 210 (3) ◽  
pp. 419-433 ◽  
Author(s):  
Yutaka Matsubayashi ◽  
Camilla Coulson-Gilmer ◽  
Tom H. Millard
Keyword(s):  
Wound Healing ◽  
Drosophila Melanogaster ◽  
Molecular Mechanisms ◽  
Wound Closure ◽  
Adherens Junctions ◽  
Membrane Traffic ◽  
Leading Edge ◽  
Actin Assembly ◽  
Wound Edge ◽  
Actin Protrusions

The ability to heal wounds efficiently is essential for life. After wounding of an epithelium, the cells bordering the wound form dynamic actin protrusions and/or a contractile actomyosin cable, and these actin structures drive wound closure. Despite their importance in wound healing, the molecular mechanisms that regulate the assembly of these actin structures at wound edges are not well understood. In this paper, using Drosophila melanogaster embryos, we demonstrate that Diaphanous, SCAR, and WASp play distinct but overlapping roles in regulating actin assembly during wound healing. Moreover, we show that endocytosis is essential for wound edge actin assembly and wound closure. We identify adherens junctions (AJs) as a key target of endocytosis during wound healing and propose that endocytic remodeling of AJs is required to form “signaling centers” along the wound edge that control actin assembly. We conclude that coordination of actin assembly, AJ remodeling, and membrane traffic is required for the construction of a motile leading edge during wound healing.

scholarly journals EGF hijacks miR-198/FSTL1 wound-healing switch and steers a two-pronged pathway toward metastasis

2017 ◽  
Vol 214 (10) ◽  
pp. 2889-2900 ◽  
Author(s):  
Gopinath M. Sundaram ◽  
Hisyam M. Ismail ◽  
Mohsin Bashir ◽  
Manish Muhuri ◽  
Candida Vaz ◽  
...  
Keyword(s):  
Wound Healing ◽  
Wound Closure ◽  
Prognostic Significance ◽  
Competitive Inhibitor ◽  
Molecular Switch ◽  
Extracellular Signal Regulated Kinase ◽  
Keratinocyte Migration ◽  
Extracellular Signal ◽  
Single Transcript ◽  
Kinase Phosphorylation

Epithelial carcinomas are well known to activate a prolonged wound-healing program that promotes malignant transformation. Wound closure requires the activation of keratinocyte migration via a dual-state molecular switch. This switch involves production of either the anti-migratory microRNA miR-198 or the pro-migratory follistatin-like 1 (FSTL1) protein from a single transcript; miR-198 expression in healthy skin is down-regulated in favor of FSTL1 upon wounding, which enhances keratinocyte migration and promotes re-epithelialization. Here, we reveal a defective molecular switch in head and neck squamous cell carcinoma (HNSCC). This defect shuts off miR-198 expression in favor of sustained FSTL1 translation, driving metastasis through dual parallel pathways involving DIAPH1 and FSTL1. DIAPH1, a miR-198 target, enhances directional migration through sequestration of Arpin, a competitive inhibitor of Arp2/3 complex. FSTL1 blocks Wnt7a-mediated repression of extracellular signal–regulated kinase phosphorylation, enabling production of MMP9, which degrades the extracellular matrix and facilitates metastasis. The prognostic significance of the FSTL1-DIAPH1 gene pair makes it an attractive target for therapeutic intervention.

scholarly journals Tissue Fluidity Promotes Epithelial Wound Healing

2018 ◽  
Author(s):  
Robert J. Tetley ◽  
Michael F. Staddon ◽  
Shiladitya Banerjee ◽  
Yanlan Mao
Keyword(s):  
Wound Healing ◽  
Wound Closure ◽  
Tissue Mechanics ◽  
Animal Tissues ◽  
Wound Edge ◽  
Surrounding Environment ◽  
Epithelial Wound Healing ◽  
Repair Mechanisms ◽  
Tissue Tension

SummaryEpithelial tissues are inevitably damaged from time to time and must therefore have robust repair mechanisms. The behaviour of tissues depends on their mechanical properties and those of the surrounding environment1. However, it remains poorly understood how tissue mechanics regulates wound healing, particularly in in vivo animal tissues. Here we show that by tuning epithelial cell junctional tension, we can alter the rate of wound healing. We observe cells moving past each other at the wound edge by intercalating, like molecules in a fluid, resulting in seamless wound closure. Using a computational model, we counterintuitively predict that an increase in tissue fluidity, via a reduction in junctional tension, can accelerate the rate of wound healing. This is contrary to previous evidence that actomyosin tensile structures are important for wound closure2–6. When we experimentally reduce tissue tension, cells intercalate faster and wounds close in less time. The role we describe for tissue fluidity in wound healing, in addition to its known roles in developing7,8 and mature tissues9, reinforces the importance of the fluid state of a tissue.

scholarly journals Leader cell positioning drives wound-directed collective migration in TGFβ-stimulated epithelial sheets

2014 ◽  
Vol 25 (10) ◽  
pp. 1586-1593 ◽  
Author(s):  
Douglas A. Chapnick ◽  
Xuedong Liu
Keyword(s):  
Wound Healing ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Transforming Growth Factor ◽  
Leading Edge ◽  
Transforming Growth Factor Β ◽  
Collective Migration ◽  
Cellular Density ◽  
Collective Group ◽  
Epithelial Sheets

During wound healing and cancer metastasis, cells are frequently observed to migrate in collective groups. This mode of migration relies on the cooperative guidance of leader and follower cells throughout the collective group. The upstream determinants and molecular mechanisms behind such cellular guidance remain poorly understood. We use live-cell imaging to track the behavior of epithelial sheets of keratinocytes in response to transforming growth factor β (TGFβ), which stimulates collective migration primarily through extracellular regulated kinase 1/2 (Erk1/2) activation. TGFβ-treated sheets display a spatial pattern of Erk1/2 activation in which the highest levels of Erk1/2 activity are concentrated toward the leading edge of a sheet. We show that Erk1/2 activity is modulated by cellular density and that this functional relationship drives the formation of patterns of Erk1/2 activity throughout sheets. In addition, we determine that a spatially constrained pattern of Erk1/2 activity results in collective migration that is primarily wound directed. Conversely, global elevation of Erk1/2 throughout sheets leads to stochastically directed collective migration throughout sheets. Our study highlights how the spatial patterning of leader cells (cells with elevated Erk1/2 activity) can influence the guidance of a collective group of cells during wound healing.

scholarly journals Fibroblast growth factor 2 accelerates the epithelial–mesenchymal transition in keratinocytes during wound healing process

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Yuta Koike ◽  
Mariko Yozaki ◽  
Atsushi Utani ◽  
Hiroyuki Murota
Keyword(s):  
Wound Healing ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Wound Closure ◽  
Epithelial Mesenchymal Transition ◽  
Healing Process ◽  
Wound Healing Process ◽  
Fibroblast Growth ◽  
Wound Edge ◽  
Mesenchymal Transition

Abstract In the wound healing process, the morphology of keratinocytes at the wound edge temporarily changes to a spindle morphology, which is thought to occur due to an epithelial–mesenchymal transition (EMT). Fibroblast growth factor (FGF) 2, also called basic FGF, has the potential to accelerate wound closure by activating vascular endothelial cells and fibroblasts. We examined the effects of FGF2 on keratinocyte morphology and EMT in wounded skin. Histological examination of murine wounds treated with FGF2 revealed that wound edge keratinocytes formed thickened and multilayered epithelia. In addition, we detected wound edge keratinocytes migrating individually toward the wound center. These migrating keratinocytes exhibited not only spindle morphology but also down-regulated E-cadherin and up-regulated vimentin expression, which is characteristic of EMT. In FGF2-treated wounds, a PCR array revealed the upregulation of genes related to EMT, including transforming growth factor (TGF) signaling. Further, FGF2-treated wound edge keratinocytes expressed EMT-associated transcription factors, including Snai2, and showed translocation of β-catenin from the cell membrane to the cytoplasm/nucleus. However, in vitro examination of keratinocytes revealed that FGF2 alone did not activate EMT in keratinocytes, but that FGF2 might promote EMT in combination with TGFβ1. These findings suggest that FGF2 treatment of wounds could promote keratinocyte EMT, accelerating wound closure.

scholarly journals A Primary Role for Golgi Positioning in Directed Secretion, Cell Polarity, and Wound Healing

2009 ◽  
Vol 20 (6) ◽  
pp. 1728-1736 ◽  
Author(s):  
Smita Yadav ◽  
Sapna Puri ◽  
Adam D. Linstedt
Keyword(s):  
Wound Healing ◽  
Golgi Apparatus ◽  
Cell Polarity ◽  
Wound Closure ◽  
Active Role ◽  
Primary Role ◽  
Wound Edge ◽  
Cellular Physiology ◽  
Golgi Membranes ◽  
Persistent Cell

Peri-centrosomal positioning of the mammalian Golgi apparatus is known to involve microtubule-based motility, but its importance for cellular physiology is a major unanswered question. Here, we identify golgin-160 and GMAP210 as proteins required for centripetal motility of Golgi membranes. In the absence of either golgin, peri-centrosomal positioning of the Golgi apparatus was disrupted while the cytoskeleton remained intact. Although secretion persisted with normal kinetics, it was evenly distributed in response to wounding rather than directed to the wound edge. Strikingly, these cells also completely failed to polarize. Further, directionally persistent cell migration was inhibited such that wound closure was impaired. These findings not only reveal novel roles for golgin-160 and GMAP210 in conferring membrane motility but also indicate that Golgi positioning has an active role in directed secretion, cell polarity, and wound healing.

scholarly journals Glucocorticoid-mediated induction of caveolin-1 disrupts cytoskeletal organization, inhibits cell migration and re-epithelialization of non-healing wounds

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Ivan Jozic ◽  
Beatriz Abdo Abujamra ◽  
Michael H. Elliott ◽  
Tongyu C. Wikramanayake ◽  
Jelena Marjanovic ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Wound Closure ◽  
Chronic Wounds ◽  
Normal Skin ◽  
Cell Movement ◽  
Genomic Comparison ◽  
Cytoskeletal Organization ◽  
Caveolin 1 ◽  
Keratinocyte Migration ◽  
Healing Wounds

AbstractAlthough impaired keratinocyte migration is a recognized hallmark of chronic wounds, the molecular mechanisms underpinning impaired cell movement are poorly understood. Here, we demonstrate that both diabetic foot ulcers (DFUs) and venous leg ulcers (VLUs) exhibit global deregulation of cytoskeletal organization in genomic comparison to normal skin and acute wounds. Interestingly, we found that DFUs and VLUs exhibited downregulation of ArhGAP35, which serves both as an inactivator of RhoA and as a glucocorticoid repressor. Since chronic wounds exhibit elevated levels of cortisol and caveolin-1 (Cav1), we posited that observed elevation of Cav1 expression may contribute to impaired actin-cytoskeletal signaling, manifesting in aberrant keratinocyte migration. We showed that Cav1 indeed antagonizes ArhGAP35, resulting in increased activation of RhoA and diminished activation of Cdc42, which can be rescued by Cav1 disruption. Furthermore, we demonstrate that both inducible keratinocyte specific Cav1 knockout mice, and MβCD treated diabetic mice, exhibit accelerated wound closure. Taken together, our findings provide a previously unreported mechanism by which Cav1-mediated cytoskeletal organization prevents wound closure in patients with chronic wounds.

Comparison of the ficus for the wound healing activity in various species

2020 ◽  
Vol 10 (4) ◽  
pp. 67-70
Author(s):  
Mothilal K ◽  
Akila CR ◽  
Mahender K ◽  
Chaitanya Kumar K ◽  
Ravi D
Keyword(s):  
Wound Healing ◽  
Wound Closure ◽  
Subcutaneous Tissue ◽  
Significant Activity ◽  
Herbal Extracts ◽  
Standard Drug ◽  
Excision Wound ◽  
Injuries And Wounds ◽  
Skin Conditions ◽  
Wound Healing Activity

Injuries and wounds are any sorts of damage to the skin or subcutaneous tissue. Usually, any wounds of such sorts are self-healed. Sometimes, there may be a delay in healing, and that delay is caused due to the functional delays in various processes of wound healing. All the Ficus plants show similar activities like the antioxidant, anti-inflammatory and wound healing properties 7including skin conditions like ulcers and rheumatism. The anthelmintic property and immunomodulatory are also seen. The herbal extracts of the same family of Ficus in different plants were investigated for the wound healing activity in the excision wound method, and the extracts showed significant activity compared to the drug. All the extracts showed a better healing ability, but the extract of FBO-100 showed the highest activity followed by FMO followed by FHO and finally the FRO. Overall, the activity of the extract ointment was comparable and was significant compared to the standard drug ointment. The wound closure of the extract ointment treated groups were better and were completed in 12 days, and the activity was more than 96%. The herbal extracts of the same family of Ficus in different plants were investigated for the wound healing activity in the excision wound method, and the extracts showed significant activity compared to the drug. The plants of microcarpa, benghalensis, religiosa and hispida are compared for the activity, and the order showed for the activity was FBO>FMO>FHO>FRO.

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