Research

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15 pages, 3222 KiB

Open AccessArticle

Genetic Background and Kinetics Define Wound Bed Extracellular Vesicles in a Mouse Model of Cutaneous Injury

by Jin Qian, Dong Jun Park, Sophia Perrott, Parth Patel and Brian P. Eliceiri

Int. J. Mol. Sci. 2021, 22(7), 3551; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073551 - 29 Mar 2021

Cited by 4 | Viewed by 2529

Extracellular vesicles (EVs) have an important role in mediating intercellular signaling in inflammation and affect the kinetics of wound healing, however, an understanding of the mechanisms regulating these responses remains limited. Therefore, we have focused on the use of cutaneous injury models in [...] Read more.

Extracellular vesicles (EVs) have an important role in mediating intercellular signaling in inflammation and affect the kinetics of wound healing, however, an understanding of the mechanisms regulating these responses remains limited. Therefore, we have focused on the use of cutaneous injury models in which to study the biology of EVs on the inflammatory phase of wound healing. For this, the foreign body response using sterile subcutaneous polyvinylalcohol (PVA) sponges is ideally suited for the parallel analysis of immune cells and EVs without the need for tissue dissociation, which would introduce additional variables. We have previously used this model to identify mediators of EV biogenesis, establishing that control of how EVs are made affects their payload and biological activity. These studies in normal mice led us to consider how conditions such as immunodeficiency and obsesity affect the profile of immune cells and EVs in this model using genetically defined mutant mice. Since EVs are intrinsically heterogenous in biological fluids, we have focused our studies on a novel technology, vesicle flow cytometry (vFC) to quantify changes in EVs in mouse models. Here, we show that myeloid-derived immune cells and EVs express proteins relevant in antigen presentation in PVA sponge implants that have distinct profiles in wildtype, immune-deficient (NOD scid) vs. diabetic (Lepr^db) mice. Together, these results establish a foundation for the parallel analysis of both immune cells and EVs with technologies that begin to address the heterogeneity of intercellular communication in the wound bed. Full article

(This article belongs to the Special Issue Immune Responses in Wound Healing and Tissue Reconstruction)

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Review

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18 pages, 309 KiB

Open AccessReview

Immune Cells in Cutaneous Wound Healing: A Review of Functional Data from Animal Models

by David M. Chesko and Traci A. Wilgus

Int. J. Mol. Sci. 2022, 23(5), 2444; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23052444 - 23 Feb 2022

Cited by 10 | Viewed by 2481

Abstract

The healing of skin wounds involves the activation and recruitment of various immune cell types, many of which are believed to contribute significantly to different aspects of the repair process. Roles for immune cells have been described in practically all stages of wound [...] Read more.

The healing of skin wounds involves the activation and recruitment of various immune cell types, many of which are believed to contribute significantly to different aspects of the repair process. Roles for immune cells have been described in practically all stages of wound healing, including hemostasis, inflammation, proliferation and scar formation/remodeling. Over the last decade, tools to deplete immune cell populations in animal models have become more advanced, leading to a surge in the number of studies examining the function of specific immune cell types in skin repair. In this review, we will summarize what is known about distinct immune cell types in cutaneous wound healing, with an emphasis on data from animal studies in which specific cell types have been targeted. Full article

(This article belongs to the Special Issue Immune Responses in Wound Healing and Tissue Reconstruction)

25 pages, 10614 KiB

Open AccessReview

TRPV1: Role in Skin and Skin Diseases and Potential Target for Improving Wound Healing

by Michelle D. Bagood and R. Rivkah Isseroff

Int. J. Mol. Sci. 2021, 22(11), 6135; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22116135 - 07 Jun 2021

Cited by 38 | Viewed by 6057

Abstract

Skin is innervated by a multitude of sensory nerves that are important to the function of this barrier tissue in homeostasis and injury. The role of innervation and neuromediators has been previously reviewed so here we focus on the role of the transient [...] Read more.

Skin is innervated by a multitude of sensory nerves that are important to the function of this barrier tissue in homeostasis and injury. The role of innervation and neuromediators has been previously reviewed so here we focus on the role of the transient receptor potential cation channel, subfamily V member 1 (TRPV1) in wound healing, with the intent of targeting it in treatment of non-healing wounds. TRPV1 structure and function as well as the outcomes of TRPV1-targeted therapies utilized in several diseases and tissues are summarized. In skin, keratinocytes, sebocytes, nociceptors, and several immune cells express TRPV1, making it an attractive focus area for treating wounds. Many intrinsic and extrinsic factors confound the function and targeting of TRPV1 and may lead to adverse or off-target effects. Therefore, a better understanding of what is known about the role of TRPV1 in skin and wound healing will inform future therapies to treat impaired and chronic wounds to improve healing. Full article

(This article belongs to the Special Issue Immune Responses in Wound Healing and Tissue Reconstruction)

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16 pages, 2216 KiB

Open AccessReview

Mechanical and Immunological Regulation in Wound Healing and Skin Reconstruction

by Shun Kimura and Takashi Tsuji

Int. J. Mol. Sci. 2021, 22(11), 5474; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115474 - 22 May 2021

Cited by 23 | Viewed by 6075

Abstract

In the past decade, a new frontier in scarless wound healing has arisen because of significant advances in the field of wound healing realised by incorporating emerging concepts from mechanobiology and immunology. The complete integumentary organ system (IOS) regeneration and scarless wound healing [...] Read more.

In the past decade, a new frontier in scarless wound healing has arisen because of significant advances in the field of wound healing realised by incorporating emerging concepts from mechanobiology and immunology. The complete integumentary organ system (IOS) regeneration and scarless wound healing mechanism, which occurs in specific species, body sites and developmental stages, clearly shows that mechanical stress signals and immune responses play important roles in determining the wound healing mode. Advances in tissue engineering technology have led to the production of novel human skin equivalents and organoids that reproduce cell–cell interactions with tissue-scale tensional homeostasis, and enable us to evaluate skin tissue morphology, functionality, drug response and wound healing. This breakthrough in tissue engineering has the potential to accelerate the understanding of wound healing control mechanisms through complex mechanobiological and immunological interactions. In this review, we present an overview of recent studies of biomechanical and immunological wound healing and tissue remodelling mechanisms through comparisons of species- and developmental stage-dependent wound healing mechanisms. We also discuss the possibility of elucidating the control mechanism of wound healing involving mechanobiological and immunological interaction by using next-generation human skin equivalents. Full article

(This article belongs to the Special Issue Immune Responses in Wound Healing and Tissue Reconstruction)

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26 pages, 6790 KiB

Open AccessReview

Dermal Drivers of Injury-Induced Inflammation: Contribution of Adipocytes and Fibroblasts

by Paula O. Cooper, MaryEllen R. Haas, Satish kumar R. Noonepalle and Brett A. Shook

Int. J. Mol. Sci. 2021, 22(4), 1933; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041933 - 16 Feb 2021

Cited by 21 | Viewed by 4845

Abstract

Irregular inflammatory responses are a major contributor to tissue dysfunction and inefficient repair. Skin has proven to be a powerful model to study mechanisms that regulate inflammation. In particular, skin wound healing is dependent on a rapid, robust immune response and subsequent dampening [...] Read more.

Irregular inflammatory responses are a major contributor to tissue dysfunction and inefficient repair. Skin has proven to be a powerful model to study mechanisms that regulate inflammation. In particular, skin wound healing is dependent on a rapid, robust immune response and subsequent dampening of inflammatory signaling. While injury-induced inflammation has historically been attributed to keratinocytes and immune cells, a vast body of evidence supports the ability of non-immune cells to coordinate inflammation in numerous tissues and diseases. In this review, we concentrate on the active participation of tissue-resident adipocytes and fibroblasts in pro-inflammatory signaling after injury, and how altered cellular communication from these cells can contribute to irregular inflammation associated with aberrant wound healing. Furthering our understanding of how tissue-resident mesenchymal cells contribute to inflammation will likely reveal new targets that can be manipulated to regulate inflammation and repair. Full article

(This article belongs to the Special Issue Immune Responses in Wound Healing and Tissue Reconstruction)

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13 pages, 772 KiB

Open AccessReview

Macrophages in Healing Wounds: Paradoxes and Paradigms

by Luisa A. DiPietro, Traci A. Wilgus and Timothy J. Koh

Int. J. Mol. Sci. 2021, 22(2), 950; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020950 - 19 Jan 2021

Cited by 39 | Viewed by 4993

Abstract

Macrophages are prominent cells in normally healing adult skin wounds, yet their exact functions and functional significance to healing outcomes remain enigmatic. Many functional attributes are ascribed to wound macrophages, including host defense and support of the proliferation of new tissue to replace [...] Read more.

Macrophages are prominent cells in normally healing adult skin wounds, yet their exact functions and functional significance to healing outcomes remain enigmatic. Many functional attributes are ascribed to wound macrophages, including host defense and support of the proliferation of new tissue to replace that lost by injury. Indeed, the depletion of macrophages is unmistakably detrimental to normal skin healing in adult mammals. Yet in certain systems, dermal wounds seem to heal well with limited or even no functional macrophages, creating an apparent paradox regarding the function of this cell in wounds. Recent advances in our understanding of wound macrophage phenotypes, along with new information about cellular plasticity in wounds, may provide some explanation for the apparently contradictory findings and suggest new paradigms regarding macrophage function in wounds. Continued study of this remarkable cell is needed to develop effective therapeutic options to improve healing outcomes. Full article

(This article belongs to the Special Issue Immune Responses in Wound Healing and Tissue Reconstruction)

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14 pages, 381 KiB

Open AccessReview

Role of microRNAs in Pressure Ulcer Immune Response, Pathogenesis, and Treatment

by Stephen M. Niemiec, Amanda E. Louiselle, Kenneth W. Liechty and Carlos Zgheib

Int. J. Mol. Sci. 2021, 22(1), 64; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010064 - 23 Dec 2020

Cited by 17 | Viewed by 6278

Abstract

Pressure ulcers are preventable, yet highly prevalent, chronic wounds that have significant patient morbidity and high healthcare costs. Like other chronic wounds, they are characterized by impaired wound healing due to dysregulated immune processes. This review will highlight key biochemical pathways in the [...] Read more.

Pressure ulcers are preventable, yet highly prevalent, chronic wounds that have significant patient morbidity and high healthcare costs. Like other chronic wounds, they are characterized by impaired wound healing due to dysregulated immune processes. This review will highlight key biochemical pathways in the pathogenesis of pressure injury and how this signaling leads to impaired wound healing. This review is the first to comprehensively describe the current literature on microRNA (miRNA, miR) regulation of pressure ulcer pathophysiology. Full article

(This article belongs to the Special Issue Immune Responses in Wound Healing and Tissue Reconstruction)

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15 pages, 1446 KiB

Open AccessReview

Skin Resident γδ T Cell Function and Regulation in Wound Repair

by Luis D. Munoz, Michael J. Sweeney and Julie M. Jameson

Int. J. Mol. Sci. 2020, 21(23), 9286; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239286 - 05 Dec 2020

Cited by 25 | Viewed by 4125

Abstract

The skin is a critical barrier that protects against damage and infection. Within the epidermis and dermis reside γδ T cells that play a variety of key roles in wound healing and tissue homeostasis. Skin-resident γδ T cells require T cell receptor (TCR) [...] Read more.

The skin is a critical barrier that protects against damage and infection. Within the epidermis and dermis reside γδ T cells that play a variety of key roles in wound healing and tissue homeostasis. Skin-resident γδ T cells require T cell receptor (TCR) ligation, costimulation, and cytokine reception to mediate keratinocyte activity and inflammatory responses at the wound site for proper wound repair. While both epidermal and dermal γδ T cells regulate inflammatory responses in wound healing, the timing and factors produced are distinct. In the absence of growth factors, cytokines, and chemokines produced by γδ T cells, wound repair is negatively impacted. This disruption in γδ T cell function is apparent in metabolic diseases such as obesity and type 2 diabetes. This review provides the current state of knowledge on skin γδ T cell activation, regulation, and function in skin homeostasis and repair in mice and humans. As we uncover more about the complex roles played by γδ T cells in wound healing, novel targets can be discovered for future clinical therapies. Full article

(This article belongs to the Special Issue Immune Responses in Wound Healing and Tissue Reconstruction)

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26 pages, 1861 KiB

Open AccessReview

The Immune Functions of Keratinocytes in Skin Wound Healing

by Minna Piipponen, Dongqing Li and Ning Xu Landén

Int. J. Mol. Sci. 2020, 21(22), 8790; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228790 - 20 Nov 2020

Cited by 161 | Viewed by 15205

Abstract

As the most dominant cell type in the skin, keratinocytes play critical roles in wound repair not only as structural cells but also exerting important immune functions. This review focuses on the communications between keratinocytes and immune cells in wound healing, which are [...] Read more.

As the most dominant cell type in the skin, keratinocytes play critical roles in wound repair not only as structural cells but also exerting important immune functions. This review focuses on the communications between keratinocytes and immune cells in wound healing, which are mediated by various cytokines, chemokines, and extracellular vesicles. Keratinocytes can also directly interact with T cells via antigen presentation. Moreover, keratinocytes produce antimicrobial peptides that can directly kill the invading pathogens and contribute to wound repair in many aspects. We also reviewed the epigenetic mechanisms known to regulate keratinocyte immune functions, including histone modifications, non-protein-coding RNAs (e.g., microRNAs, and long noncoding RNAs), and chromatin dynamics. Lastly, we summarized the current evidence on the dysregulated immune functions of keratinocytes in chronic nonhealing wounds. Based on their crucial immune functions in skin wound healing, we propose that keratinocytes significantly contribute to the pathogenesis of chronic wound inflammation. We hope this review will trigger an interest in investigating the immune roles of keratinocytes in chronic wound pathology, which may open up new avenues for developing innovative wound treatments. Full article

(This article belongs to the Special Issue Immune Responses in Wound Healing and Tissue Reconstruction)

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16 pages, 1059 KiB

Open AccessReview

The Cutaneous Wound Innate Immunological Microenvironment

by Stephen Kirchner, Vivian Lei and Amanda S. MacLeod

Int. J. Mol. Sci. 2020, 21(22), 8748; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228748 - 19 Nov 2020

Cited by 25 | Viewed by 3653

Abstract

The skin represents the first line of defense and innate immune protection against pathogens. Skin normally provides a physical barrier to prevent infection by pathogens; however, wounds, microinjuries, and minor barrier impediments can present open avenues for invasion through the skin. Accordingly, wound [...] Read more.

The skin represents the first line of defense and innate immune protection against pathogens. Skin normally provides a physical barrier to prevent infection by pathogens; however, wounds, microinjuries, and minor barrier impediments can present open avenues for invasion through the skin. Accordingly, wound repair and protection from invading pathogens are essential processes in successful skin barrier regeneration. To repair and protect wounds, skin promotes the development of a specific and complex immunological microenvironment within and surrounding the disrupted tissue. This immune microenvironment includes both innate and adaptive processes, including immune cell recruitment to the wound and secretion of extracellular factors that can act directly to promote wound closure and wound antimicrobial defense. Recent work has shown that this immune microenvironment also varies according to the specific context of the wound: the microbiome, neuroimmune signaling, environmental effects, and age play roles in altering the innate immune response to wounding. This review will focus on the role of these factors in shaping the cutaneous microenvironment and how this ultimately impacts the immune response to wounding. Full article

(This article belongs to the Special Issue Immune Responses in Wound Healing and Tissue Reconstruction)

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19 pages, 3481 KiB

Open AccessReview

Eicosanoids in Skin Wound Healing

by Ken Yasukawa, Toshiaki Okuno and Takehiko Yokomizo

Int. J. Mol. Sci. 2020, 21(22), 8435; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228435 - 10 Nov 2020

Cited by 22 | Viewed by 4540

Abstract

Wound healing is an important process in the human body to protect against external threats. A dysregulation at any stage of the wound healing process may result in the development of various intractable ulcers or excessive scar formation. Numerous factors such as growth [...] Read more.

Wound healing is an important process in the human body to protect against external threats. A dysregulation at any stage of the wound healing process may result in the development of various intractable ulcers or excessive scar formation. Numerous factors such as growth factors, cytokines, and chemokines are involved in this process and play vital roles in tissue repair. Moreover, recent studies have demonstrated that lipid mediators derived from membrane fatty acids are also involved in the process of wound healing. Among these lipid mediators, we focus on eicosanoids such as prostaglandins, thromboxane, leukotrienes, and specialized pro-resolving mediators, which are produced during wound healing processes and play versatile roles in the process. This review article highlights the roles of eicosanoids on skin wound healing, especially focusing on the biosynthetic pathways and biological functions, i.e., inflammation, proliferation, migration, angiogenesis, remodeling, and scarring. Full article

(This article belongs to the Special Issue Immune Responses in Wound Healing and Tissue Reconstruction)

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