The Cell Biology and Immunology of Wound Healing

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (20 October 2022) | Viewed by 37063

Special Issue Editors


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Guest Editor
Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, QLD 4059, Australia
Interests: cell migration; cytokine secretion; inflammation; tissue repair; wound healing; macrophages; intracellular trafficking; MMP secretion

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Guest Editor
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
Interests: nano(bio)technology; nanomedicine; biomaterials; tissue engineering; cardiovascular regenerative medicine; stem cells; 3D bioprinting; wound healing; drug delivery; antimicrobial materials; hydrogels; electrospun scaffolds; materials science and engineering
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Guest Editor
Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
Interests: tissue injury; repair; inflammation; kidney; wound healing; signaling
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Regenerative Medicine, Future Industries Institute, Mawson Lakes, University of South Australia, Adelaide, SA 5095, Australia
Interests: wound healing; cytoskeleton; inflammation; stem cell therapy; immunotherapy
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Department of Biomedical Engineering, University of Melbourne, Melbourne, VIC 3010, Australia
Interests: wound healing; tissue remodelling; mast cells; progeotlycans; glycosaminoclycans; biomaterials; tissue engineering & regeneration

Special Issue Information

Dear Colleagues,

Wound healing is a dynamic process consisting of a complex series of co-ordinated events that work quickly to restore the skin’s protective barrier. This requires the concerted efforts of often distinct but interlinked processes and includes processes such as coagulation, migration, initiation of an inflammatory response, proliferation, regeneration and extracellular matrix (ECM) remodelling. These events must occur in the proper sequence, in a specific time frame and for a precise amount of time for an effective repair process to occur. Numerous cell types in and surrounding the injured skin work together with immune cells that are recruited to the site of injury to orchestrate this repair process. Their sequential and often overlapping actions occur over the course of seconds to months, depending on their precise roles in the repair process, with their numerous molecules, molecular signalling pathways and cues in the extracellular matrix directing how and when wounds heal.

The normal repair process can be dysregulated by changes in these cells that alter the outcome of wound healing. Additionally, other factors, such as age, bacterial infection or maybe be an underlying co-morbidity like diabetes, can alter cellular function, especially immune cell function and inflammation in wounds.  This can have a major impact, particularly in areas such as scar formation and alterations in the time it takes for a wound to heal. Our knowledge in these areas is ever expanding as new mechanisms come to light.

This Special Issue of Cells will highlight the cell biology and immunology of wound healing in a collection of original research articles, reviews, and communications. Topics include the physiological and pathophysiological roles that cells in the site of injury or their components released into the wound environment and signalling pathways have on the outcomes of wound healing.

Dr. Rachael Z Murray
Dr. Ebrahim Mostafavi
Dr. Pei-Hui Lin
Prof. Dr. Allison Cowin
Dr. Brooke Farrugia
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • wound
  • immune cell
  • inflammation
  • tissue repair
  • skin
  • macrophage
  • neutrophil
  • mast cell
  • T cell
  • dendritic cell
  • extracellular matrix
  • signalling pathway
  • cytokine
  • growth factor
  • keratinocyte
  • fibroblast
  • scarring
  • ulcer
  • chronic wound
  • fibrosis

Published Papers (8 papers)

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Research

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14 pages, 4721 KiB  
Article
DPSC Products Accelerate Wound Healing in Diabetic Mice through Induction of SMAD Molecules
by Carl J. Greene, Sarah Anderson, Derek Barthels, Md Sariful Islam Howlader, Suman Kanji, Jaganmay Sarkar and Hiranmoy Das
Cells 2022, 11(15), 2409; https://doi.org/10.3390/cells11152409 - 4 Aug 2022
Cited by 6 | Viewed by 2511
Abstract
Despite advances in diabetic wound care, many amputations are still needed each year due to their diabetic wounds, so a more effective therapy is warranted. Herein, we show that the dental pulp-derived stem cell (DPSC) products are effective in wound healing in diabetic [...] Read more.
Despite advances in diabetic wound care, many amputations are still needed each year due to their diabetic wounds, so a more effective therapy is warranted. Herein, we show that the dental pulp-derived stem cell (DPSC) products are effective in wound healing in diabetic NOD/SCID mice. Our results showed that the topical application of DPSC secretory products accelerated wound closure by inducing faster re-epithelialization, angiogenesis, and recellularization. In addition, the number of neutrophils producing myeloperoxidase, which mediates persisting inflammation, was also reduced. NFκB and its downstream effector molecules like IL-6 cause sustained pro-inflammatory activity and were reduced after the application of DPSC products in the experimental wounds. Moreover, the DPSC products also inhibited the activation of NFκB, and its translocation to the nucleus, by which it initiates the inflammation. Furthermore, the levels of TGF-β, and IL-10, potent anti-inflammatory molecules, were also increased after the addition of DPSC products. Mechanistically, we showed that this wound-healing process was mediated by the upregulation and activation of Smad 1 and 2 molecules. In sum, we have defined the cellular and molecular mechanisms by which DPSC products accelerated diabetic wound closure, which can be used to treat diabetic wounds in the near future. Full article
(This article belongs to the Special Issue The Cell Biology and Immunology of Wound Healing)
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17 pages, 3998 KiB  
Article
Flightless I Negatively Regulates Macrophage Surface TLR4, Delays Early Inflammation, and Impedes Wound Healing
by Stuart J. Mills, Parinaz Ahangar, Hannah M. Thomas, Benjamin R. Hofma, Rachael Z. Murray and Allison J. Cowin
Cells 2022, 11(14), 2192; https://doi.org/10.3390/cells11142192 - 13 Jul 2022
Cited by 3 | Viewed by 1960
Abstract
TLR4 plays a pivotal role in orchestrating inflammation and tissue repair. Its expression has finally been balanced to initiate the early, robust immune response necessary for efficient repair without excessively amplifying and prolonging inflammation, which impairs healing. Studies show Flightless I (Flii) is [...] Read more.
TLR4 plays a pivotal role in orchestrating inflammation and tissue repair. Its expression has finally been balanced to initiate the early, robust immune response necessary for efficient repair without excessively amplifying and prolonging inflammation, which impairs healing. Studies show Flightless I (Flii) is an immunomodulator that negatively regulates macrophage TLR4 signalling. Using macrophages from Flii+/−, WT, and FliiTg/Tg mice, we have shown that elevated Flii reduces early TLR4 surface expression, delaying and reducing subsequent TNF secretions. In contrast, reduced Flii increases surface TLR4, leading to an earlier robust TNF peak. In Flii+/− mice, TLR4 levels peak earlier during wound repair, and overall healing is accelerated. Fewer neutrophils, monocytes and macrophages are recruited to Flii+/− wounds, leading to fewer TNF-positive macrophages, alongside an early peak and a robust shift to M2 anti-inflammatory, reparative Ym1+ and IL-10+ macrophages. Importantly, in diabetic mice, high Flii levels are found in plasma and unwounded skin, with further increases observed in their wounds, which have impaired healing. Lowering Flii in diabetic mice results in an earlier shift to M2 macrophages and improved healing. Overall, this suggests Flii regulation of TLR4 reduces early inflammation and decreases the M2 macrophage phenotype, leading to impaired healing. Full article
(This article belongs to the Special Issue The Cell Biology and Immunology of Wound Healing)
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14 pages, 4681 KiB  
Article
Post-COVID Complications after Pressure Ulcer Surgery in Patients with Spinal Cord Injury Associate with Creatine Kinase Upregulation in Adipose Tissue
by Mario Martínez-Torija, Pedro F. Esteban, Francisco Javier Espino-Rodríguez, Beatriz Paniagua-Torija, Eduardo Molina-Holgado, Silvia Ceruelo, Gemma Barroso-Garcia, Alba G. Arandilla, Luis F. Lopez-Almodovar, Angel Arevalo-Martin, Juan Antonio Moreno, Daniel Garcia-Ovejero, Mª Carmen Durán-Ruiz and Rafael Moreno-Luna
Cells 2022, 11(8), 1282; https://doi.org/10.3390/cells11081282 - 9 Apr 2022
Cited by 2 | Viewed by 4832
Abstract
The risk of complications following surgical procedures is significantly increased in patients with SARS-CoV-2 infection. However, the mechanisms underlying these correlations are not fully known. Spinal cord injury (SCI) patients who underwent reconstructive surgery for pressure ulcers (PUs) before and during the COVID-19 [...] Read more.
The risk of complications following surgical procedures is significantly increased in patients with SARS-CoV-2 infection. However, the mechanisms underlying these correlations are not fully known. Spinal cord injury (SCI) patients who underwent reconstructive surgery for pressure ulcers (PUs) before and during the COVID-19 pandemic were included in this study. The patient’s postoperative progression was registered, and the subcutaneous white adipose tissue (s-WAT) surrounding the ulcers was analyzed by proteomic and immunohistochemical assays to identify the molecular/cellular signatures of impaired recovery. Patients with SCI and a COVID-19-positive diagnosis showed worse recovery and severe postoperative complications, requiring reintervention. Several proteins were upregulated in the adipose tissue of these patients. Among them, CKMT2 and CKM stood out, and CKM increased for up to 60 days after the COVID-19 diagnosis. Moreover, CKMT2 and CKM were largely found in MGCs within the s-WAT of COVID patients. Some of these proteins presented post-translational modifications and were targeted by autoantibodies in the serum of COVID patients. Overall, our results indicate that CKMT2, CKM, and the presence of MGCs in the adipose tissue surrounding PUs in post-COVID patients could be predictive biomarkers of postsurgical complications. These results suggest that the inflammatory response in adipose tissue may underlie the defective repair seen after surgery. Full article
(This article belongs to the Special Issue The Cell Biology and Immunology of Wound Healing)
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21 pages, 1989 KiB  
Article
Macroscopic, Histologic, and Immunomodulatory Response of Limb Wounds Following Intravenous Allogeneic Cord Blood-Derived Multipotent Mesenchymal Stromal Cell Therapy in Horses
by Suzanne J. K. Mund, Daniel J. MacPhee, John Campbell, Ali Honaramooz, Bruce Wobeser and Spencer M. Barber
Cells 2021, 10(11), 2972; https://doi.org/10.3390/cells10112972 - 1 Nov 2021
Cited by 7 | Viewed by 2149
Abstract
Limb wounds are common in horses and often develop complications. Intravenous multipotent mesenchymal stromal cell (MSC) therapy is promising but has risks associated with intravenous administration and unknown potential to improve cutaneous wound healing. The objectives were to determine the clinical safety of [...] Read more.
Limb wounds are common in horses and often develop complications. Intravenous multipotent mesenchymal stromal cell (MSC) therapy is promising but has risks associated with intravenous administration and unknown potential to improve cutaneous wound healing. The objectives were to determine the clinical safety of administering large numbers of allogeneic cord blood-derived MSCs intravenously, and if therapy causes clinically adverse reactions, accelerates wound closure, improves histologic healing, and alters mRNA expression of common wound cytokines. Wounds were created on the metacarpus of 12 horses. Treatment horses were administered 1.51–2.46 × 108 cells suspended in 50% HypoThermosol FRS, and control horses were administered 50% HypoThermosol FRS alone. Epithelialization, contraction, and wound closure rates were determined using planimetric analysis. Wounds were biopsied and evaluated for histologic healing characteristics and cytokine mRNA expression. Days until wound closure was also determined. The results indicate that 3/6 of treatment horses and 1/6 of control horses experienced minor transient reactions. Treatment did not accelerate wound closure or improve histologic healing. Treatment decreased wound size and decreased all measured cytokines except transforming growth factor-β3. MSC intravenous therapy has the potential to decrease limb wound size; however, further work is needed to understand the clinical relevance of adverse reactions. Full article
(This article belongs to the Special Issue The Cell Biology and Immunology of Wound Healing)
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Review

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21 pages, 2223 KiB  
Review
The Complexity of the Post-Burn Immune Response: An Overview of the Associated Local and Systemic Complications
by H. Ibrahim Korkmaz, Gwendolien Flokstra, Maaike Waasdorp, Anouk Pijpe, Stephan G. Papendorp, Evelien de Jong, Thomas Rustemeyer, Susan Gibbs and Paul P. M. van Zuijlen
Cells 2023, 12(3), 345; https://doi.org/10.3390/cells12030345 - 17 Jan 2023
Cited by 21 | Viewed by 5354
Abstract
Burn injury induces a complex inflammatory response, both locally and systemically, and is not yet completely unravelled and understood. In order to enable the development of accurate treatment options, it is of paramount importance to fully understand post-burn immunology. Research in the last [...] Read more.
Burn injury induces a complex inflammatory response, both locally and systemically, and is not yet completely unravelled and understood. In order to enable the development of accurate treatment options, it is of paramount importance to fully understand post-burn immunology. Research in the last decades describes insights into the prolonged and excessive inflammatory response that could exist after both severe and milder burn trauma and that this response differs from that of none-burn acute trauma. Persistent activity of complement, acute phase proteins and pro- and anti-inflammatory mediators, changes in lymphocyte activity, activation of the stress response and infiltration of immune cells have all been related to post-burn local and systemic pathology. This “narrative” review explores the current state of knowledge, focusing on both the local and systemic immunology post-burn, and further questions how it is linked to the clinical outcome. Moreover, it illustrates the complexity of post-burn immunology and the existing gaps in knowledge on underlying mechanisms of burn pathology. Full article
(This article belongs to the Special Issue The Cell Biology and Immunology of Wound Healing)
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24 pages, 1042 KiB  
Review
The Immune and Regenerative Response to Burn Injury
by Matthew Burgess, Franklin Valdera, David Varon, Esko Kankuri and Kristo Nuutila
Cells 2022, 11(19), 3073; https://doi.org/10.3390/cells11193073 - 29 Sep 2022
Cited by 32 | Viewed by 8398
Abstract
Burn are diverse and complex injuries that not only have local effects but also serious systemic consequences through severe and prolonged inflammatory response. They are caused by heat, electricity, friction, chemicals, or radiation and are commonly divided into superficial, superficial partial-, deep partial- [...] Read more.
Burn are diverse and complex injuries that not only have local effects but also serious systemic consequences through severe and prolonged inflammatory response. They are caused by heat, electricity, friction, chemicals, or radiation and are commonly divided into superficial, superficial partial-, deep partial- and full-thickness injuries. The severity of the burn depends mainly on the size and depth of the injury but also on location, age, and underlying systemic diseases. A prolonged and strong immune response makes major burns even worse by causing multiple systemic effects including damage to the heart, lungs, blood vessels, kidneys, and other organs. Burns that do not require surgical excision, superficial and superficial partial-thickness, follow the known progression of wound healing (inflammation, proliferation, remodeling), whilst deep partial- and full thickness injuries requiring excision and grafting do not. For these burns, intervention is required for optimal coverage, function, and cosmesis. Annually millions of people worldwide suffer from burns associated with high morbidity and mortality. Fortunately, over the past decades, burn care has significantly improved. The improvement in understanding the pathophysiology of burn injury and burn wound progression has led to developments in skin grafting, fluid resuscitation, infection control and nutrition This review article focuses on the immune and regenerative responses following burn injury. In the Introduction, we describe the epidemiology of burns and burn pathophysiology. The focus of the following chapter is on systemic responses to burn injury. Next, we define the immune response to burns introducing all the different cell types involved. Subsequently, we discuss the regenerative cell response to burns as well as some of the emerging novel treatments in the battle against burns. Full article
(This article belongs to the Special Issue The Cell Biology and Immunology of Wound Healing)
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14 pages, 1135 KiB  
Review
Macrophage-Mediated Inflammation in Skin Wound Healing
by Alireza Hassanshahi, Mohammad Moradzad, Saman Ghalamkari, Moosa Fadaei, Allison J. Cowin and Mohammadhossein Hassanshahi
Cells 2022, 11(19), 2953; https://doi.org/10.3390/cells11192953 - 21 Sep 2022
Cited by 63 | Viewed by 6659
Abstract
Macrophages are key immune cells that respond to infections, and modulate pathophysiological conditions such as wound healing. By possessing phagocytic activities and through the secretion of cytokines and growth factors, macrophages are pivotal orchestrators of inflammation, fibrosis, and wound repair. Macrophages orchestrate the [...] Read more.
Macrophages are key immune cells that respond to infections, and modulate pathophysiological conditions such as wound healing. By possessing phagocytic activities and through the secretion of cytokines and growth factors, macrophages are pivotal orchestrators of inflammation, fibrosis, and wound repair. Macrophages orchestrate the process of wound healing through the transitioning from predominantly pro-inflammatory (M1-like phenotypes), which present early post-injury, to anti-inflammatory (M2-like phenotypes), which appear later to modulate skin repair and wound closure. In this review, different cellular and molecular aspects of macrophage-mediated skin wound healing are discussed, alongside important aspects such as macrophage subtypes, metabolism, plasticity, and epigenetics. We also highlight previous studies demonstrating interactions between macrophages and these factors for optimal wound healing. Understanding and harnessing the activity and capability of macrophages may help to advance new approaches for improving healing of the skin. Full article
(This article belongs to the Special Issue The Cell Biology and Immunology of Wound Healing)
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13 pages, 697 KiB  
Review
Emerging Roles of Microglia Depletion in the Treatment of Spinal Cord Injury
by Junhao Deng, Fanqi Meng, Kexue Zhang, Jianpeng Gao, Zhongyang Liu, Ming Li, Xiao Liu, Jiantao Li, Yu Wang, Licheng Zhang and Peifu Tang
Cells 2022, 11(12), 1871; https://doi.org/10.3390/cells11121871 - 9 Jun 2022
Cited by 13 | Viewed by 3470
Abstract
Microglia, as the resident immune cells and first responder to neurological insults, play an extremely important role in the pathophysiological process of spinal cord injury. On the one hand, microglia respond rapidly and gather around the lesion in the early stage of injury [...] Read more.
Microglia, as the resident immune cells and first responder to neurological insults, play an extremely important role in the pathophysiological process of spinal cord injury. On the one hand, microglia respond rapidly and gather around the lesion in the early stage of injury to exert a protective role, but with the continuous stimulation of the injury, the excessive activated microglia secrete a large number of harmful substances, aggravate the injury of spinal cord tissue, and affect functional recovery. The effects of microglia depletion on the repair of spinal cord injury remain unclear, and there is no uniformly accepted paradigm for the removal methods and timing of microglia depletion, but different microglia depletion strategies greatly affect the outcomes after spinal cord injury. Therefore, this review summarizes the physiological and pathological roles of microglia, especially the effects of microglia depletion on spinal cord injury—sustained microglial depletion would aggravate injury and impair functional recovery, while the short-term depletion of microglial population in diseased conditions seems to improve tissue repair and promote functional improvement after spinal cord injury. Furthermore, we discuss the advantages and disadvantages of major strategies and timing of microglia depletion to provide potential strategy for the treatment of spinal cord injury. Full article
(This article belongs to the Special Issue The Cell Biology and Immunology of Wound Healing)
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