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1
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Schmitter-Sánchez AD, Park S. Immune-Epithelial Cell Interactions during Epidermal Regeneration, Repair, and Inflammatory Diseases. Int J Stem Cells 2025; 18:1-11. [PMID: 38191522 PMCID: PMC11867906 DOI: 10.15283/ijsc23107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 11/09/2023] [Accepted: 12/04/2023] [Indexed: 01/10/2024] Open
Abstract
The multiple layers of the skin cover and protect our entire body. Among the skin layers, the epidermis is in direct contact with the outer environment and serves as the first line of defense. The epidermis functions as a physical and immunological barrier. To maintain barrier function, the epidermis continually regenerates and repairs itself when injured. Interactions between tissue-resident immune cells and epithelial cells are essential to sustain epidermal regeneration and repair. In this review, we will dissect the crosstalk between epithelial cells and specific immune cell populations located in the epidermis during homeostasis and wound repair. In addition, we will analyze the contribution of dysregulated immune-epithelial interactions in chronic inflammatory diseases.
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Affiliation(s)
- Axel D. Schmitter-Sánchez
- Institute for Quantitative Health Science and Engineering (IQ), Michigan State University, East Lansing, MI, USA
- Cell and Molecular Biology Program, College of Natural Science, Michigan State University, East Lansing, MI, USA
| | - Sangbum Park
- Institute for Quantitative Health Science and Engineering (IQ), Michigan State University, East Lansing, MI, USA
- Division of Dermatology, Department of Medicine, College of Human Medicine, Michigan State University, East Lansing, MI, USA
- Department of Pharmacology and Toxicology, College of Human Medicine, Michigan State University, East Lansing, MI, USA
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2
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Rajesh A, Ju EDE, Oxford KA, Harman RM, Van de Walle GR. The mesenchymal stromal cell secretome promotes tissue regeneration and increases macrophage infiltration in acute and methicillin-resistant Staphylococcus aureus-infected skin wounds in vivo. Cytotherapy 2024; 26:1400-1410. [PMID: 38944795 DOI: 10.1016/j.jcyt.2024.06.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Revised: 06/05/2024] [Accepted: 06/05/2024] [Indexed: 07/01/2024]
Abstract
BACKGROUND AIMS The prevalence of chronic wounds continues to be a burden in human medicine. Methicillin-resistant Staphylococcus aureus (MRSA) is commonly isolated from infected wounds. MRSA infections primarily delay healing by impairing local immune cell functions. This study aimed to investigate the potential of mesenchymal stromal cell (MSC)-secreted bioactive factors, defined as the secretome, to improve innate immune responses in vivo. MSCs were isolated from the bone marrow of horses, which serve as valuable translational models for wound healing. The MSC secretome, collected as conditioned medium (CM), was evaluated in vivo using mouse models of acute and MRSA-infected skin wounds. METHODS Punch biopsies were used to create two full-thickness skin wounds on the back of each mouse. Acute wounds were treated daily with control medium or bone marrow-derived MSC (BM-MSC) CM. The antibiotic mupirocin was administered as a positive control for the MRSA-infected wound experiments. Wounds were photographed daily, and wound images were measured to determine the rate of closure. Trichrome staining was carried out to examine wound tissue histologically, and immunofluorescence antibody binding was used to assess immune cell infiltration. Wounds in the MRSA-infected model were swabbed for quantification of bacterial load. RESULTS Acute wounds treated with BM-MSC CM showed accelerated wound closure compared with controls, as illustrated by enhanced granulation tissue formation and resolution, increased vasculature and regeneration of hair follicles. This treatment also led to increased neutrophil and macrophage infiltration. Chronic MRSA-infected wounds treated with BM-MSC CM showed reduced bacterial load accompanied by better resolution of granulation tissue formation and increased infiltration of pro-healing M2 macrophages compared with control-treated infected wounds. CONCLUSIONS Collectively, our findings indicate that BM-MSC CM exerts pro-healing, immunomodulatory and anti-bacterial effects on wound healing in vivo, validating further exploration of the MSC secretome as a novel treatment option to improve healing of both acute and chronic wounds, especially those infected with antibiotic-resistant bacteria.
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Affiliation(s)
- Aarthi Rajesh
- Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA
| | - Esther Da Eun Ju
- Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA
| | - Kelly A Oxford
- Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA
| | - Rebecca M Harman
- Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA
| | - Gerlinde R Van de Walle
- Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.
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3
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Wang ZC, Hu YY, Shen XZ, Tan WQ. Absence of Langerhans cells resulted in over-influx of neutrophils and increased bacterial burden in skin wounds. Cell Death Dis 2024; 15:760. [PMID: 39424788 PMCID: PMC11489468 DOI: 10.1038/s41419-024-07143-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 10/02/2024] [Accepted: 10/08/2024] [Indexed: 10/21/2024]
Abstract
Langerhans cells (LCs) are resident dendritic cells in the epidermis and their roles in presenting antigens derived from microorganisms present in the skin has been well appreciated. However, it is generally thought that incoming neutrophils are mainly responsible for eradicating invading pathogens in the early stage of wounds and a role of LCs in innate immunity is elusive. In the current study, we showed that wounds absent of LCs had a delayed closure. Mechanistically, LCs were the primary cells in warding off bacteria invasion at the early stage of wound healing. Without LCs, commensal bacteria quickly invaded and propagated in the wounded area. keratinocytes surrounding the wounds responded to the excessive bacteria by elevated production of CXCL5, resulting in an over-influx of neutrophils. The over-presence of activated neutrophils, possibly together with the aggravated invasion of bacteria, was detrimental to epidermal progenitor cell propagation and re-epithelialization. These observations underscore an indispensable role of LCs as effective guardians that preclude both bacteria invasion and damages inflicted by secondary inflammation.
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Affiliation(s)
- Zheng-Cai Wang
- Department of Plastic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yan-Yan Hu
- Department of Plastic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiao Z Shen
- Department of Physiology and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
| | - Wei-Qiang Tan
- Department of Plastic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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Cioce A, Cavani A, Cattani C, Scopelliti F. Role of the Skin Immune System in Wound Healing. Cells 2024; 13:624. [PMID: 38607063 PMCID: PMC11011555 DOI: 10.3390/cells13070624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 03/21/2024] [Accepted: 03/31/2024] [Indexed: 04/13/2024] Open
Abstract
Wound healing is a dynamic and complex process, characterized by the coordinated activities of multiple cell types, each with distinct roles in the stages of hemostasis, inflammation, proliferation, and remodeling. The cells of the immune system not only act as sentinels to monitor the skin and promote homeostasis, but they also play an important role in the process of skin wound repair. Skin-resident and recruited immune cells release cytokines and growth factors that promote the amplification of the inflammatory process. They also work with non-immune cells to remove invading pathogens and debris, as well as guide the regeneration of damaged host tissues. Dysregulation of the immune system at any stage of the process may lead to a prolongation of the inflammatory phase and the development of a pathological condition, such as a chronic wound. The present review aims to summarize the roles of different immune cells, with special emphasis on the different stages of the wound healing process.
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Affiliation(s)
| | | | | | - Fernanda Scopelliti
- National Institute for Health, Migration and Poverty INMP/NIHMP, Via di S.Gallicano, 25, 00153 Rome, Italy; (A.C.); (A.C.); (C.C.)
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5
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Lesmanawati FE, Windura CA, Saputro ID, Hariani L. Autologous fat grafting and adipose-derived stem cells therapy for acute burns and burn-related scar: A systematic review. Tzu Chi Med J 2024; 36:203-211. [PMID: 38645780 PMCID: PMC11025588 DOI: 10.4103/tcmj.tcmj_189_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 09/11/2023] [Accepted: 12/01/2023] [Indexed: 04/23/2024] Open
Abstract
Objectives The objective of this study was to analyze all available research on the application of autologous fat grafting (AFG) and adipose-derived stem cells (ADSC) to present evidence-based recommendations, particularly in the clinical treatment of acute burns and burn-related scars. Materials and Methods We conducted a systematic search of PubMed, COCHRANE, and EMBASE, as well as a manual search of previous reviews' reference lists up. The risk of bias (RoB) was assessed using RoB 2.0 and ROBINS-I, where appropriate. Results Six eligible studies were selected (2 randomized clinical trials [RCT], 1 retrospective cohort, and 3 experimental studies) with subjects ranging from 3 to 100. Only one study evaluated the use of AFG for acute burns. Improvements in wound healing, vascularization, scar characteristics, and tissue architecture were generally observed in some studies, supported by molecular markers, while one study reported nonsignificant results. Subjective patient satisfaction was reported to have improved. Functional outcomes improvement in the treated regions was minimal. However, study heterogeneity arose mainly from treatment protocols. Cautious results interpretation due to potential bias, especially in selection and confounding domains, and limited clinical trials are important to note. More studies are needed to evaluate. Conclusion AFG and ADSC hold potential as valuable treatment options for burn-related scars, supported by a body of evidence, but further well-designed RCT are needed. The efficacy of acute burn settings is yet to be further evaluated since evidence is limited.
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Affiliation(s)
- Fanny Evasari Lesmanawati
- Department of Plastic Reconstructive and Aesthetic Surgery, Faculty of Medicine Universitas Airlangga, Dr. Soetomo General Academic Hospital, Surabaya, East Java, Indonesia
| | - Carolus Aldo Windura
- Department of Plastic Reconstructive and Aesthetic Surgery, Faculty of Medicine Universitas Airlangga, Dr. Soetomo General Academic Hospital, Surabaya, East Java, Indonesia
| | - Iswinarno Doso Saputro
- Department of Plastic Reconstructive and Aesthetic Surgery, Faculty of Medicine Universitas Airlangga, Dr. Soetomo General Academic Hospital, Surabaya, East Java, Indonesia
| | - Lynda Hariani
- Department of Plastic Reconstructive and Aesthetic Surgery, Faculty of Medicine Universitas Airlangga, Dr. Soetomo General Academic Hospital, Surabaya, East Java, Indonesia
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6
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Jakovija A, Chtanova T. Skin immunity in wound healing and cancer. Front Immunol 2023; 14:1060258. [PMID: 37398649 PMCID: PMC10312005 DOI: 10.3389/fimmu.2023.1060258] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 05/24/2023] [Indexed: 07/04/2023] Open
Abstract
The skin is the body's largest organ. It serves as a barrier to pathogen entry and the first site of immune defense. In the event of a skin injury, a cascade of events including inflammation, new tissue formation and tissue remodeling contributes to wound repair. Skin-resident and recruited immune cells work together with non-immune cells to clear invading pathogens and debris, and guide the regeneration of damaged host tissues. Disruption to the wound repair process can lead to chronic inflammation and non-healing wounds. This, in turn, can promote skin tumorigenesis. Tumors appropriate the wound healing response as a way of enhancing their survival and growth. Here we review the role of resident and skin-infiltrating immune cells in wound repair and discuss their functions in regulating both inflammation and development of skin cancers.
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Affiliation(s)
- Arnolda Jakovija
- Immunity Theme, Garvan Institute of Medical Research, Sydney, Australia
- St. Vincent’s School of Medicine, Faculty of Medicine, University of New South Wales, Sydney, Australia
| | - Tatyana Chtanova
- Immunity Theme, Garvan Institute of Medical Research, Sydney, Australia
- School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, Australia
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Hong YK, Chang YH, Lin YC, Chen B, Guevara BEK, Hsu CK. Inflammation in Wound Healing and Pathological Scarring. Adv Wound Care (New Rochelle) 2023; 12:288-300. [PMID: 36541356 DOI: 10.1089/wound.2021.0161] [Citation(s) in RCA: 60] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Significance: The aberrant inflammation during wound healing results in pathological scarring, such as hypertrophic scars and keloids. This adversely affects the quality of life of patients due to the disfiguring appearance as well as the symptoms of itch and pain. This review summarizes the up-to-date knowledge of the immunopathogenesis and treatment options for pathological scars. Recent Advances: With the advent of new technologies, combined with in vitro and in vivo wound models, several inflammatory cells have been shown to have both direct and indirect effects on both wound healing and pathological scarring. Critical Issues: Expansion of pro-fibrotic immune cells such as M2 macrophages, dendritic cells, mast cells, and Th2 cells leads to fibroblast transition to myofibroblasts via transforming growth factor-β1 signaling pathway. Appropriate management of such inflammatory responses during wound healing remains a critical issue during clinical practice. Future Directions: Regulating inflammation response during wound healing may be a potential therapeutic option for avoiding or reducing pathological scars.
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Affiliation(s)
- Yi-Kai Hong
- Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,International Research Center of Wound Repair and Regeneration (iWRR), National Cheng Kung University, Tainan, Taiwan
| | - Yi-Han Chang
- Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yu-Chen Lin
- Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,International Research Center of Wound Repair and Regeneration (iWRR), National Cheng Kung University, Tainan, Taiwan
| | - Brandon Chen
- Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Bryan Edgar K Guevara
- International Research Center of Wound Repair and Regeneration (iWRR), National Cheng Kung University, Tainan, Taiwan.,Department of Dermatology, Southern Philippines Medical Center, Davao, Philippines
| | - Chao-Kai Hsu
- Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,International Research Center of Wound Repair and Regeneration (iWRR), National Cheng Kung University, Tainan, Taiwan.,Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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8
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Xu Z, Dong M, Yin S, Dong J, Zhang M, Tian R, Min W, Zeng L, Qiao H, Chen J. Why traditional herbal medicine promotes wound healing: Research from immune response, wound microbiome to controlled delivery. Adv Drug Deliv Rev 2023; 195:114764. [PMID: 36841332 DOI: 10.1016/j.addr.2023.114764] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 12/16/2022] [Accepted: 02/19/2023] [Indexed: 02/25/2023]
Abstract
Impaired wound healing in chronic wounds has been a significant challenge for clinicians and researchers for decades. Traditional herbal medicine (THM) has a long history of promoting wound healing, making them culturally accepted and trusted by a great number of people in the world. However, for a long time, the understanding of herbal medicine has been limited and incomplete, particularly in the allopathic medicine-dominated research system. The therapeutic effects of individual components isolated from THM are found less pronounced compared to synthetic chemical medicine, and the clinical efficacy is always inferior to herbs. In the present article, we review and discuss underlying mechanisms of the skin microbiome involved in the wound healing process; THM in regulating immune responses and commensal microbiome. We additionally propose few pioneer ideas and studies in the development of therapeutic strategies for controlled delivery of herbal medicine. This review aims to promote wound care with a focus on wound microbiome, immune response, and topical drug delivery systems. Finally, future development trends, challenges, and research directions are discussed.
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Affiliation(s)
- Zeyu Xu
- Jiangsu Provincial Engineering Research Center of TCM External Medication Development and Application, Nanjing University of Chinese Medicine, Nanjing 210023, PR China; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR China
| | - Mei Dong
- Jiangsu Provincial Engineering Research Center of TCM External Medication Development and Application, Nanjing University of Chinese Medicine, Nanjing 210023, PR China; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR China
| | - Shaoping Yin
- Jiangsu Provincial Engineering Research Center of TCM External Medication Development and Application, Nanjing University of Chinese Medicine, Nanjing 210023, PR China; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR China
| | - Jie Dong
- Jiangsu Provincial Engineering Research Center of TCM External Medication Development and Application, Nanjing University of Chinese Medicine, Nanjing 210023, PR China; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR China
| | - Ming Zhang
- Jiangsu Provincial Engineering Research Center of TCM External Medication Development and Application, Nanjing University of Chinese Medicine, Nanjing 210023, PR China; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR China
| | - Rong Tian
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR China
| | - Wen Min
- Jiangsu Provincial Engineering Research Center of TCM External Medication Development and Application, Nanjing University of Chinese Medicine, Nanjing 210023, PR China; Department of Bone Injury of Traditional Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210004, PR China
| | - Li Zeng
- Jiangsu Provincial Engineering Research Center of TCM External Medication Development and Application, Nanjing University of Chinese Medicine, Nanjing 210023, PR China
| | - Hongzhi Qiao
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR China.
| | - Jun Chen
- Jiangsu Provincial Engineering Research Center of TCM External Medication Development and Application, Nanjing University of Chinese Medicine, Nanjing 210023, PR China; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR China.
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9
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Gao Y, Wang Z, Cui Y, Xu M, Weng L. Emerging Strategies of Engineering and Tracking Dendritic Cells for Cancer Immunotherapy. ACS APPLIED BIO MATERIALS 2023; 6:24-43. [PMID: 36520013 DOI: 10.1021/acsabm.2c00790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Dendritic cells (DCs), a kind of specialized immune cells, play key roles in antitumor immune response and promotion of innate and adaptive immune responses. Recently, many strategies have been developed to utilize DCs in cancer therapy, such as delivering antigens and adjuvants to DCs and using scaffold to recruit and activate DCs. Here we outline how different DC subsets influence antitumor immunity, summarize the FDA-approved vaccines and cancer vaccines under clinical trials, discuss the strategies for engineering DCs and noninvasive tracking of DCs to improve antitumor immunotherapy, and reveal the potential of artificial neural networks for the design of DC based vaccines.
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Affiliation(s)
- Yu Gao
- State Key Laboratory for Organic Electronics and Information Displays & Jiangsu Key Laboratory for Biosensors, Institute of Advanced Materials (IAM), Jiangsu National Synergistic Innovation Center for Advanced Materials (SICAM), Nanjing University of Posts and Telecommunications, 9 Wenyuan Road, Nanjing 210023, China
| | - Zhixuan Wang
- School of Geography and Biological Information, Nanjing University of Posts and Telecommunications, 9 Wenyuan Road, Nanjing 210023, China
| | - Ying Cui
- School of Geography and Biological Information, Nanjing University of Posts and Telecommunications, 9 Wenyuan Road, Nanjing 210023, China
| | - Miaomiao Xu
- School of Geography and Biological Information, Nanjing University of Posts and Telecommunications, 9 Wenyuan Road, Nanjing 210023, China
| | - Lixing Weng
- State Key Laboratory for Organic Electronics and Information Displays & Jiangsu Key Laboratory for Biosensors, Institute of Advanced Materials (IAM), Jiangsu National Synergistic Innovation Center for Advanced Materials (SICAM), Nanjing University of Posts and Telecommunications, 9 Wenyuan Road, Nanjing 210023, China.,School of Geography and Biological Information, Nanjing University of Posts and Telecommunications, 9 Wenyuan Road, Nanjing 210023, China
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10
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Wasko R, Bridges K, Pannone R, Sidhu I, Xing Y, Naik S, Miller-Jensen K, Horsley V. Langerhans cells are essential components of the angiogenic niche during murine skin repair. Dev Cell 2022; 57:2699-2713.e5. [PMID: 36493773 PMCID: PMC10848275 DOI: 10.1016/j.devcel.2022.11.012] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 08/28/2022] [Accepted: 11/16/2022] [Indexed: 12/13/2022]
Abstract
Angiogenesis, the growth of new blood vessels from pre-existing vessels, occurs during development, injury repair, and tumorigenesis to deliver oxygen, immune cells, and nutrients to tissues. Defects in angiogenesis occur in cardiovascular and inflammatory diseases, and chronic, non-healing wounds, yet treatment options are limited. Here, we provide a map of the early angiogenic niche by analyzing single-cell RNA sequencing of mouse skin wound healing. Our data implicate Langerhans cells (LCs), phagocytic, skin-resident immune cells, in driving angiogenesis during skin repair. Using lineage-driven reportersw, three-dimensional (3D) microscopy, and mouse genetics, we show that LCs are situated at the endothelial cell leading edge in mouse skin wounds and are necessary for angiogenesis during repair. These data provide additional future avenues for the control of angiogenesis to treat disease and chronic wounds and extend the function of LCs beyond their canonical role in antigen presentation and T cell immunity.
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Affiliation(s)
- Renee Wasko
- Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT, USA
| | - Kate Bridges
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA
| | - Rebecca Pannone
- Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT, USA
| | - Ikjot Sidhu
- Department of Pathology, NYU Langone Health, New York, NY, USA
| | - Yue Xing
- Department of Pathology, NYU Langone Health, New York, NY, USA
| | - Shruti Naik
- Department of Pathology, NYU Langone Health, New York, NY, USA
| | - Kathryn Miller-Jensen
- Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT, USA; Department of Biomedical Engineering, Yale University, New Haven, CT, USA.
| | - Valerie Horsley
- Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT, USA; Department of Dermatology, Yale School of Medicine, New Haven, CT, USA.
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11
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Makandar AI, Jain M, Yuba E, Sethi G, Gupta RK. Canvassing Prospects of Glyco-Nanovaccines for Developing Cross-Presentation Mediated Anti-Tumor Immunotherapy. Vaccines (Basel) 2022; 10:vaccines10122049. [PMID: 36560459 PMCID: PMC9784904 DOI: 10.3390/vaccines10122049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 11/18/2022] [Accepted: 11/22/2022] [Indexed: 12/02/2022] Open
Abstract
In view of the severe downsides of conventional cancer therapies, the quest of developing alternative strategies still remains of critical importance. In this regard, antigen cross-presentation, usually employed by dendritic cells (DCs), has been recognized as a potential solution to overcome the present impasse in anti-cancer therapeutic strategies. It has been established that an elevated cytotoxic T lymphocyte (CTL) response against cancer cells can be achieved by targeting receptors expressed on DCs with specific ligands. Glycans are known to serve as ligands for C-type lectin receptors (CLRs) expressed on DCs, and are also known to act as a tumor-associated antigen (TAA), and, thus, can be harnessed as a potential immunotherapeutic target. In this scenario, integrating the knowledge of cross-presentation and glycan-conjugated nanovaccines can help us to develop so called 'glyco-nanovaccines' (GNVs) for targeting DCs. Here, we briefly review and analyze the potential of GNVs as the next-generation anti-tumor immunotherapy. We have compared different antigen-presenting cells (APCs) for their ability to cross-present antigens and described the potential nanocarriers for tumor antigen cross-presentation. Further, we discuss the role of glycans in targeting of DCs, the immune response due to pathogens, and imitative approaches, along with parameters, strategies, and challenges involved in cross-presentation-based GNVs for cancer immunotherapy. It is known that the effectiveness of GNVs in eradicating tumors by inducing strong CTL response in the tumor microenvironment (TME) has been largely hindered by tumor glycosylation and the expression of different lectin receptors (such as galectins) by cancer cells. Tumor glycan signatures can be sensed by a variety of lectins expressed on immune cells and mediate the immune suppression which, in turn, facilitates immune evasion. Therefore, a sound understanding of the glycan language of cancer cells, and glycan-lectin interaction between the cancer cells and immune cells, would help in strategically designing the next-generation GNVs for anti-tumor immunotherapy.
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Affiliation(s)
- Amina I. Makandar
- Protein Biochemistry Research Centre, Dr. D. Y. Patil Biotechnology & Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune 411033, Maharashtra, India
| | - Mannat Jain
- Protein Biochemistry Research Centre, Dr. D. Y. Patil Biotechnology & Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune 411033, Maharashtra, India
| | - Eiji Yuba
- Department of Applied Chemistry, Graduate School of Engineering, Osaka Metropolitan University, 1-1 Gakuen-cho, Naka-ku, Sakai 599-8531, Osaka, Japan
- Correspondence: (E.Y.); (G.S.); or (R.K.G.)
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
- Correspondence: (E.Y.); (G.S.); or (R.K.G.)
| | - Rajesh Kumar Gupta
- Protein Biochemistry Research Centre, Dr. D. Y. Patil Biotechnology & Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune 411033, Maharashtra, India
- Correspondence: (E.Y.); (G.S.); or (R.K.G.)
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Abstract
Chronic wounds are characterized by their inability to heal within an expected time frame and have emerged as an increasingly important clinical problem over the past several decades, owing to their increasing incidence and greater recognition of associated morbidity and socio-economic burden. Even up to a few years ago, the management of chronic wounds relied on standards of care that were outdated. However, the approach to these chronic conditions has improved, with better prevention, diagnosis and treatment. Such improvements are due to major advances in understanding of cellular and molecular aspects of basic science, in innovative and technological breakthroughs in treatment modalities from biomedical engineering, and in our ability to conduct well-controlled and reliable clinical research. The evidence-based approaches resulting from these advances have become the new standard of care. At the same time, these improvements are tempered by the recognition that persistent gaps exist in scientific knowledge of impaired healing and the ability of clinicians to reduce morbidity, loss of limb and mortality. Therefore, taking stock of what is known and what is needed to improve understanding of chronic wounds and their associated failure to heal is crucial to ensuring better treatments and outcomes.
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13
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Maschalidi S, Mehrotra P, Keçeli BN, De Cleene HKL, Lecomte K, Van der Cruyssen R, Janssen P, Pinney J, van Loo G, Elewaut D, Massie A, Hoste E, Ravichandran KS. Targeting SLC7A11 improves efferocytosis by dendritic cells and wound healing in diabetes. Nature 2022; 606:776-784. [PMID: 35614212 DOI: 10.1038/s41586-022-04754-6] [Citation(s) in RCA: 139] [Impact Index Per Article: 46.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 04/11/2022] [Indexed: 02/07/2023]
Abstract
Chronic non-healing wounds are a major complication of diabetes, which affects 1 in 10 people worldwide. Dying cells in the wound perpetuate the inflammation and contribute to dysregulated tissue repair1-3. Here we reveal that the membrane transporter SLC7A11 acts as a molecular brake on efferocytosis, the process by which dying cells are removed, and that inhibiting SLC7A11 function can accelerate wound healing. Transcriptomics of efferocytic dendritic cells in mouse identified upregulation of several SLC7 gene family members. In further analyses, pharmacological inhibition of SLC7A11, or deletion or knockdown of Slc7a11 using small interfering RNA enhanced efferocytosis in dendritic cells. Slc7a11 was highly expressed in dendritic cells in skin, and single-cell RNA sequencing of inflamed skin showed that Slc7a11 was upregulated in innate immune cells. In a mouse model of excisional skin wounding, inhibition or loss of SLC7A11 expression accelerated healing dynamics and reduced the apoptotic cell load in the wound. Mechanistic studies revealed a link between SLC7A11, glucose homeostasis and diabetes. SLC7A11-deficient dendritic cells were dependent on aerobic glycolysis using glucose derived from glycogen stores for increased efferocytosis; also, transcriptomics of efferocytic SLC7A11-deficient dendritic cells identified increased expression of genes linked to gluconeogenesis and diabetes. Further, Slc7a11 expression was higher in the wounds of diabetes-prone db/db mice, and targeting SLC7A11 accelerated their wound healing. The faster healing was also linked to the release of the TGFβ family member GDF15 from efferocytic dendritic cells. In sum, SLC7A11 is a negative regulator of efferocytosis, and removing this brake improves wound healing, with important implications for wound management in diabetes.
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Affiliation(s)
- Sophia Maschalidi
- Unit for Cell Clearance in Health and Disease, VIB Center for Inflammation Research, Ghent, Belgium. .,Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
| | - Parul Mehrotra
- Unit for Cell Clearance in Health and Disease, VIB Center for Inflammation Research, Ghent, Belgium.,Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Burcu N Keçeli
- Unit for Cell Clearance in Health and Disease, VIB Center for Inflammation Research, Ghent, Belgium.,Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Hannah K L De Cleene
- Unit for Cell Clearance in Health and Disease, VIB Center for Inflammation Research, Ghent, Belgium.,Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Kim Lecomte
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.,Unit for Cellular and Molecular Pathophysiology, VIB Center for Inflammation Research, Ghent, Belgium
| | - Renée Van der Cruyssen
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.,Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Ghent University Hospital, Ghent, Belgium
| | - Pauline Janssen
- Laboratory of Neuro-Aging and Viro-Immunotherapy, Center for Neurosciences (C4N), Vrije Universiteit Brussel, Brussels, Belgium
| | - Jonathan Pinney
- The Center for Cell Clearance, University of Virginia, Charlottesville, VA, USA.,Department of Microbiology, Immunology, and Cancer Biology, and the Center for Cell Clearance, University of Virginia, Charlottesville, VA, USA
| | - Geert van Loo
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.,Unit for Cellular and Molecular Pathophysiology, VIB Center for Inflammation Research, Ghent, Belgium
| | - Dirk Elewaut
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.,Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Ghent University Hospital, Ghent, Belgium
| | - Ann Massie
- Laboratory of Neuro-Aging and Viro-Immunotherapy, Center for Neurosciences (C4N), Vrije Universiteit Brussel, Brussels, Belgium
| | - Esther Hoste
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.,Unit for Cellular and Molecular Pathophysiology, VIB Center for Inflammation Research, Ghent, Belgium
| | - Kodi S Ravichandran
- Unit for Cell Clearance in Health and Disease, VIB Center for Inflammation Research, Ghent, Belgium. .,Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium. .,The Center for Cell Clearance, University of Virginia, Charlottesville, VA, USA. .,Department of Microbiology, Immunology, and Cancer Biology, and the Center for Cell Clearance, University of Virginia, Charlottesville, VA, USA. .,Division of Immunobiology, Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA.
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14
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Rosin FCP, Borges G, Pelissari C, Buck MGT, Dos Santos AF, Rodrigues L, Luz JGC, Corrêa L. Effect of chronic ethanol ingestion on dendritic cell population during oral mucosal repair: An experimental study. Eur J Oral Sci 2022; 130:e12865. [PMID: 35482465 DOI: 10.1111/eos.12865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 03/09/2022] [Indexed: 11/30/2022]
Abstract
The aim of this study was to analyze the effect of chronic ethanol ingestion on dendritic cell repopulation during the repair process of rat oral mucosa and in the rat spleen by analyzing the immunohistochemical expression of dendritic cell markers. Wistar rats ingested 20% ethanol solution for 28 days; a surgical wound was performed on the rat tongue after this period. The repair process and the number of CD1a+, CD11c+, and CD207+ cells in the regions adjacent to the wound were determined at day 1, 3, and 7 following the wound as well as in the rat spleen. The wound-only group (no ethanol exposure) had complete reepithelization after 7 days, but this did not occur in the ethanol + wound group at this time point. The inflammatory infiltrate was significantly reduced in animals exposed to ethanol, which also showed significantly lower counts of CD1a+, CD11c+, and CD207+ cells than the wound-only group at all experimental time points. In addition, ethanol exposure also resulted in lower densities of CD11c+ and CD207+ cells in the rat spleen. In conclusion, chronic ethanol intake had a negative impact on dendritic cell numbers, a fact that may contribute to delay in oral mucosa repair.
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Affiliation(s)
| | - Giuliana Borges
- General Pathology Department, School of Dentistry, University of São Paulo, São Paulo, Brazil
| | - Cibele Pelissari
- Oral Pathology Department, School of Dentistry, University of São Paulo, São Paulo, Brazil
| | | | | | - Lucimar Rodrigues
- Oral Surgery Department, School of Dentistry, University of São Paulo, São Paulo, Brazil
| | - João Gualberto C Luz
- Oral Surgery Department, School of Dentistry, University of São Paulo, São Paulo, Brazil
| | - Luciana Corrêa
- General Pathology Department, School of Dentistry, University of São Paulo, São Paulo, Brazil
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15
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Hu W, Wang Y, Chen J, Yu P, Tang F, Hu Z, Zhou J, Liu L, Qiu W, Ye Y, Jia Y, Zhou S, Long J, Zeng Z. Regulation of biomaterial implantation-induced fibrin deposition to immunological functions of dendritic cells. Mater Today Bio 2022. [PMID: 35252832 DOI: 10.1016/j.mtadv.2022.100224] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/14/2023] Open
Abstract
The performance of implanted biomaterials is largely determined by their interaction with the host immune system. As a fibrous-like 3D network, fibrin matrix formed at the interfaces of tissue and material, whose effects on dendritic cells (DCs) remain unknown. Here, a bone plates implantation model was developed to evaluate the fibrin matrix deposition and DCs recruitment in vivo. The DCs responses to fibrin matrix were further analyzed by a 2D and 3D fibrin matrix model in vitro. In vivo results indicated that large amount of fibrin matrix deposited on the interface between the tissue and bone plates, where DCs were recruited. Subsequent in vitro testing denoted that DCs underwent significant shape deformation and cytoskeleton reorganization, as well as mechanical property alteration. Furthermore, the immune function of imDCs and mDCs were negatively and positively regulated, respectively. The underlying mechano-immunology coupling mechanisms involved RhoA and CDC42 signaling pathways. These results suggested that fibrin plays a key role in regulating DCs immunological behaviors, providing a valuable immunomodulatory strategy for tissue healing, regeneration and implantation.
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Affiliation(s)
- Wenhui Hu
- School of Basic Medical Sciences / School of Biology & Engineering, Guizhou Medical University, Guiyang, 550025, PR China
- Key Laboratory of Infectious Immunity and Antibody Engineering in Guizhou Province, Guiyang, 550025, PR China
| | - Yun Wang
- School of Basic Medical Sciences / School of Biology & Engineering, Guizhou Medical University, Guiyang, 550025, PR China
- Key Laboratory of Infectious Immunity and Antibody Engineering in Guizhou Province, Guiyang, 550025, PR China
| | - Jin Chen
- School of Basic Medical Sciences / School of Biology & Engineering, Guizhou Medical University, Guiyang, 550025, PR China
- Key Laboratory of Infectious Immunity and Antibody Engineering in Guizhou Province, Guiyang, 550025, PR China
| | - Peng Yu
- School of Basic Medical Sciences / School of Biology & Engineering, Guizhou Medical University, Guiyang, 550025, PR China
- Key Laboratory of Infectious Immunity and Antibody Engineering in Guizhou Province, Guiyang, 550025, PR China
| | - Fuzhou Tang
- School of Basic Medical Sciences / School of Biology & Engineering, Guizhou Medical University, Guiyang, 550025, PR China
- Key Laboratory of Infectious Immunity and Antibody Engineering in Guizhou Province, Guiyang, 550025, PR China
| | - Zuquan Hu
- School of Basic Medical Sciences / School of Biology & Engineering, Guizhou Medical University, Guiyang, 550025, PR China
- Key Laboratory of Infectious Immunity and Antibody Engineering in Guizhou Province, Guiyang, 550025, PR China
| | - Jing Zhou
- School of Basic Medical Sciences / School of Biology & Engineering, Guizhou Medical University, Guiyang, 550025, PR China
- Key Laboratory of Infectious Immunity and Antibody Engineering in Guizhou Province, Guiyang, 550025, PR China
| | - Lina Liu
- School of Basic Medical Sciences / School of Biology & Engineering, Guizhou Medical University, Guiyang, 550025, PR China
- Key Laboratory of Infectious Immunity and Antibody Engineering in Guizhou Province, Guiyang, 550025, PR China
| | - Wei Qiu
- School of Basic Medical Sciences / School of Biology & Engineering, Guizhou Medical University, Guiyang, 550025, PR China
- Key Laboratory of Infectious Immunity and Antibody Engineering in Guizhou Province, Guiyang, 550025, PR China
| | - Yuannong Ye
- School of Basic Medical Sciences / School of Biology & Engineering, Guizhou Medical University, Guiyang, 550025, PR China
- Key Laboratory of Infectious Immunity and Antibody Engineering in Guizhou Province, Guiyang, 550025, PR China
| | - Yi Jia
- School of Basic Medical Sciences / School of Biology & Engineering, Guizhou Medical University, Guiyang, 550025, PR China
- Key Laboratory of Infectious Immunity and Antibody Engineering in Guizhou Province, Guiyang, 550025, PR China
| | - Shi Zhou
- Department of Interventional Radiology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, PR China
| | - Jinhua Long
- Department of Head & Neck, Affiliated Tumor Hospital of Guizhou Medical University, Guiyang, 550004, PR China
| | - Zhu Zeng
- School of Basic Medical Sciences / School of Biology & Engineering, Guizhou Medical University, Guiyang, 550025, PR China
- Key Laboratory of Infectious Immunity and Antibody Engineering in Guizhou Province, Guiyang, 550025, PR China
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education, Guizhou Medical University, Guiyang 550004, Guizhou, PR China
- State Key Laboratory of Functions & Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550004, PR China
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16
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Immune Cells in Cutaneous Wound Healing: A Review of Functional Data from Animal Models. Int J Mol Sci 2022; 23:ijms23052444. [PMID: 35269586 PMCID: PMC8910456 DOI: 10.3390/ijms23052444] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 02/10/2022] [Accepted: 02/18/2022] [Indexed: 11/17/2022] Open
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 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.
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17
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Hu W, Wang Y, Chen J, Yu P, Tang F, Hu Z, Zhou J, Liu L, Qiu W, Ye Y, Jia Y, Zhou S, Long J, Zeng Z. Regulation of biomaterial implantation-induced fibrin deposition to immunological functions of dendritic cells. Mater Today Bio 2022; 14:100224. [PMID: 35252832 PMCID: PMC8894278 DOI: 10.1016/j.mtbio.2022.100224] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 02/16/2022] [Accepted: 02/18/2022] [Indexed: 11/04/2022] Open
Abstract
The performance of implanted biomaterials is largely determined by their interaction with the host immune system. As a fibrous-like 3D network, fibrin matrix formed at the interfaces of tissue and material, whose effects on dendritic cells (DCs) remain unknown. Here, a bone plates implantation model was developed to evaluate the fibrin matrix deposition and DCs recruitment in vivo. The DCs responses to fibrin matrix were further analyzed by a 2D and 3D fibrin matrix model in vitro. In vivo results indicated that large amount of fibrin matrix deposited on the interface between the tissue and bone plates, where DCs were recruited. Subsequent in vitro testing denoted that DCs underwent significant shape deformation and cytoskeleton reorganization, as well as mechanical property alteration. Furthermore, the immune function of imDCs and mDCs were negatively and positively regulated, respectively. The underlying mechano-immunology coupling mechanisms involved RhoA and CDC42 signaling pathways. These results suggested that fibrin plays a key role in regulating DCs immunological behaviors, providing a valuable immunomodulatory strategy for tissue healing, regeneration and implantation.
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18
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Skin Wound Healing: Normal Macrophage Function and Macrophage Dysfunction in Diabetic Wounds. Molecules 2021; 26:molecules26164917. [PMID: 34443506 PMCID: PMC8398285 DOI: 10.3390/molecules26164917] [Citation(s) in RCA: 199] [Impact Index Per Article: 49.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 07/29/2021] [Accepted: 08/11/2021] [Indexed: 12/16/2022] Open
Abstract
Macrophages play a prominent role in wound healing. In the early stages, they promote inflammation and remove pathogens, wound debris, and cells that have apoptosed. Later in the repair process, they dampen inflammation and secrete factors that regulate the proliferation, differentiation, and migration of keratinocytes, fibroblasts, and endothelial cells, leading to neovascularisation and wound closure. The macrophages that coordinate this repair process are complex: they originate from different sources and have distinct phenotypes with diverse functions that act at various times in the repair process. Macrophages in individuals with diabetes are altered, displaying hyperresponsiveness to inflammatory stimulants and increased secretion of pro-inflammatory cytokines. They also have a reduced ability to phagocytose pathogens and efferocytose cells that have undergone apoptosis. This leads to a reduced capacity to remove pathogens and, as efferocytosis is a trigger for their phenotypic switch, it reduces the number of M2 reparative macrophages in the wound. This can lead to diabetic foot ulcers (DFUs) forming and contributes to their increased risk of not healing and becoming infected, and potentially, amputation. Understanding macrophage dysregulation in DFUs and how these cells might be altered, along with the associated inflammation, will ultimately allow for better therapies that might complement current treatment and increase DFU’s healing rates.
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19
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Hade MD, Suire CN, Suo Z. Mesenchymal Stem Cell-Derived Exosomes: Applications in Regenerative Medicine. Cells 2021; 10:1959. [PMID: 34440728 PMCID: PMC8393426 DOI: 10.3390/cells10081959] [Citation(s) in RCA: 273] [Impact Index Per Article: 68.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/27/2021] [Accepted: 07/30/2021] [Indexed: 12/12/2022] Open
Abstract
Exosomes are a type of extracellular vesicles, produced within multivesicular bodies, that are then released into the extracellular space through a merging of the multivesicular body with the plasma membrane. These vesicles are secreted by almost all cell types to aid in a vast array of cellular functions, including intercellular communication, cell differentiation and proliferation, angiogenesis, stress response, and immune signaling. This ability to contribute to several distinct processes is due to the complexity of exosomes, as they carry a multitude of signaling moieties, including proteins, lipids, cell surface receptors, enzymes, cytokines, transcription factors, and nucleic acids. The favorable biological properties of exosomes including biocompatibility, stability, low toxicity, and proficient exchange of molecular cargos make exosomes prime candidates for tissue engineering and regenerative medicine. Exploring the functions and molecular payloads of exosomes can facilitate tissue regeneration therapies and provide mechanistic insight into paracrine modulation of cellular activities. In this review, we summarize the current knowledge of exosome biogenesis, composition, and isolation methods. We also discuss emerging healing properties of exosomes and exosomal cargos, such as microRNAs, in brain injuries, cardiovascular disease, and COVID-19 amongst others. Overall, this review highlights the burgeoning roles and potential applications of exosomes in regenerative medicine.
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Affiliation(s)
| | | | - Zucai Suo
- Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306, USA; (M.D.H.); (C.N.S.)
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20
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Zhu Y, Wang Y, He W. Locally aggressive orbital giant cell reparative granuloma in an infant: case report and literature review. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2021; 14:776-781. [PMID: 34239680 PMCID: PMC8255204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 11/16/2020] [Indexed: 06/13/2023]
Abstract
Giant cell reparative granuloma (GCRG) is a non-neoplastic hyperplasia of bones that mostly happens in the mandible and maxilla in any age group but has a predilection for children and young adults. GCRGs that cause bone destruction are of very low frequency. Orbital-involved cases have been rarely reported since 1981, especially in children. We now report a 1-year-old girl with a rapidly enlarging post-traumatic orbital mass. CT scan and surgical resection showed a well-defined mass occupying the upper right orbit, causing bone destruction. Microscopically there was a proliferation of histocytes and some osteoclast-like multinucleated giant cells with hemosiderin, finally confirmed to be GCRG. 22 months' follow up showed no evidence of recurrence. This case suggests infant orbital GCRG can be locally aggressive.
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Affiliation(s)
- Yanyan Zhu
- Department of Ophthalmology, Ophthalmic Laboratory, West China Hospital, Sichuan University Chengdu, Sichuan, P. R. China
| | - Yujiao Wang
- Department of Ophthalmology, Ophthalmic Laboratory, West China Hospital, Sichuan University Chengdu, Sichuan, P. R. China
| | - Weimin He
- Department of Ophthalmology, Ophthalmic Laboratory, West China Hospital, Sichuan University Chengdu, Sichuan, P. R. China
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21
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Raziyeva K, Kim Y, Zharkinbekov Z, Kassymbek K, Jimi S, Saparov A. Immunology of Acute and Chronic Wound Healing. Biomolecules 2021; 11:700. [PMID: 34066746 PMCID: PMC8150999 DOI: 10.3390/biom11050700] [Citation(s) in RCA: 411] [Impact Index Per Article: 102.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 04/30/2021] [Accepted: 05/03/2021] [Indexed: 12/14/2022] Open
Abstract
Skin wounds greatly affect the global healthcare system, creating a substantial burden on the economy and society. Moreover, the situation is exacerbated by low healing rates, which in fact are overestimated in reports. Cutaneous wounds are generally classified into acute and chronic. The immune response plays an important role during acute wound healing. The activation of immune cells and factors initiate the inflammatory process, facilitate wound cleansing and promote subsequent tissue healing. However, dysregulation of the immune system during the wound healing process leads to persistent inflammation and delayed healing, which ultimately result in chronic wounds. The microenvironment of a chronic wound is characterized by high quantities of pro-inflammatory macrophages, overexpression of inflammatory mediators such as TNF-α and IL-1β, increased activity of matrix metalloproteinases and abundance of reactive oxygen species. Moreover, chronic wounds are frequently complicated by bacterial biofilms, which perpetuate the inflammatory phase. Continuous inflammation and microbial biofilms make it very difficult for the chronic wounds to heal. In this review, we discuss the role of innate and adaptive immunity in the pathogenesis of acute and chronic wounds. Furthermore, we review the latest immunomodulatory therapeutic strategies, including modifying macrophage phenotype, regulating miRNA expression and targeting pro- and anti-inflammatory factors to improve wound healing.
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Affiliation(s)
- Kamila Raziyeva
- Department of Medicine, School of Medicine, Nazarbayev University, Nur-Sultan 010000, Kazakhstan; (K.R.); (Y.K.); (Z.Z.); (K.K.)
| | - Yevgeniy Kim
- Department of Medicine, School of Medicine, Nazarbayev University, Nur-Sultan 010000, Kazakhstan; (K.R.); (Y.K.); (Z.Z.); (K.K.)
| | - Zharylkasyn Zharkinbekov
- Department of Medicine, School of Medicine, Nazarbayev University, Nur-Sultan 010000, Kazakhstan; (K.R.); (Y.K.); (Z.Z.); (K.K.)
| | - Kuat Kassymbek
- Department of Medicine, School of Medicine, Nazarbayev University, Nur-Sultan 010000, Kazakhstan; (K.R.); (Y.K.); (Z.Z.); (K.K.)
| | - Shiro Jimi
- Central Lab for Pathology and Morphology, Faculty of Medicine, Fukuoka University, Fukuoka 814-0180, Japan;
| | - Arman Saparov
- Department of Medicine, School of Medicine, Nazarbayev University, Nur-Sultan 010000, Kazakhstan; (K.R.); (Y.K.); (Z.Z.); (K.K.)
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22
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Li Z, Lamb R, Coles MC, Bennett CL, Ambler CA. Inducible ablation of CD11c + cells to determine their role in skin wound repair. Immunology 2021; 163:105-111. [PMID: 33502012 PMCID: PMC8044329 DOI: 10.1111/imm.13312] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 01/11/2021] [Accepted: 01/12/2021] [Indexed: 12/11/2022] Open
Abstract
Whether resident and recruited myeloid cells may impair or aid healing of acute skin wounds remains a debated question. To begin to address this, we examined the importance of CD11c+ myeloid cells in the early activation of skin wound repair. We find that an absence of CD11c+ cells delays wound closure and epidermal proliferation, likely due to defects in the activation of the IL-23-IL-22 axis that is required for wound healing.
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Affiliation(s)
- Zhi Li
- Department of BiosciencesBiophysical Sciences InstituteDurham UniversityDurhamUK
- Department of BiologyCentre for Immunology and InfectionHull York Medical SchoolYorkUK
| | - Rebecca Lamb
- Department of BiosciencesBiophysical Sciences InstituteDurham UniversityDurhamUK
| | - Mark C. Coles
- Department of BiologyCentre for Immunology and InfectionHull York Medical SchoolYorkUK
- Kennedy Institute of RheumatologyUniversity of OxfordOxfordUK
| | - Clare L. Bennett
- Institute of Immunity and TransplantationUniversity College LondonLondonUK
- Division of Cancer StudiesUniversity College LondonLondonUK
| | - Carrie A. Ambler
- Department of BiosciencesBiophysical Sciences InstituteDurham UniversityDurhamUK
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23
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Hirobe S, Susai R, Takeuchi H, Eguchi R, Ito S, Quan YS, Kamiyama F, Okada N. Characteristics of immune induction by transcutaneous vaccination using dissolving microneedle patches in mice. Int J Pharm 2021; 601:120563. [PMID: 33811967 DOI: 10.1016/j.ijpharm.2021.120563] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 03/26/2021] [Accepted: 03/28/2021] [Indexed: 12/23/2022]
Abstract
Transcutaneous immunization (TCI) is an appealing vaccination method. Compared with conventional injectable immunization, TCI is easier and less painful. We previously developed a dissolving microneedle (MN) patch and demonstrated that TCI using MN patches demonstrates high vaccination efficacy without adverse events in humans. In this study, we investigated the immune induction mechanism of TCI using our MN patch, focusing on inflammatory responses in the skin and on the dynamics, activation, and differentiation of various immunocompetent cells in draining lymph nodes (dLNs). We demonstrate that inflammatory cytokines such as IL-6 and TNF-α increased in the skin at an early stage after MN patch application, inducing the infiltration of macrophages and neutrophils and promoting the activation and migration of skin-resident antigen-presenting cells (Langerhans and Langerin- dermal dendritic cells) to dLNs. Moreover, the activated antigen-presenting cells reaching the dLNs enhanced the differentiation of T (Teff, Tem, and Tcm) and B (plasma and memory) cells. This may contribute to the efficient antigen-specific antibody production induced by TCI using MN patches. We believe that our findings reveal a part of the immune induction mechanism by TCI and provide useful information for the development and improvement of TCI formulations based on the immune induction mechanism.
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Affiliation(s)
- Sachiko Hirobe
- Laboratory of Biotechnology and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan; Laboratory of Clinical Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Molecular Pharmaceutical Science, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Pharmacy, Osaka University Hospital, 2-15 Yamadaoka, Suita, Osaka 565-0871, Japan.
| | - Ryo Susai
- Laboratory of Biotechnology and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Honoka Takeuchi
- Laboratory of Biotechnology and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Ryosuke Eguchi
- Laboratory of Biotechnology and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Sayami Ito
- Laboratory of Biotechnology and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan; Project for Vaccine and Immune Regulation, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Ying-Shu Quan
- CosMED Pharmaceutical Co. Ltd., 32 Higashikujokawanishi-cho, Minami-ku, Kyoto 601-8014, Japan
| | - Fumio Kamiyama
- CosMED Pharmaceutical Co. Ltd., 32 Higashikujokawanishi-cho, Minami-ku, Kyoto 601-8014, Japan
| | - Naoki Okada
- Laboratory of Biotechnology and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan; Project for Vaccine and Immune Regulation, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan; Laboratory of Vaccine and Immune Regulation (BIKEN), Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
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Rajesh A, Stuart G, Real N, Tschirley A, Ahn J, Wise L, Hibma M. Skin antigen-presenting cells and wound healing: New knowledge gained and challenges encountered using mouse depletion models. Immunology 2021; 163:98-104. [PMID: 33496963 DOI: 10.1111/imm.13311] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 12/15/2020] [Accepted: 12/23/2020] [Indexed: 12/14/2022] Open
Abstract
The role of antigen-presenting cells in the skin immune system, in particular Langerhans cells and dendritic cells, has not been well defined. We recently published a study in 'Immunology' where we reported that the loss of langerin-positive cells in the skin accelerated wound repair in the Lang-DTR mouse. The study published here by Li, et al. reports delayed wound closure following depletion of CD11c-positive cells in the CD11c-DTR mouse. In this commentary, we attribute the differences between these results to several factors that differ between the studies including the depletion of different cell populations; differences in the age and the sex of mice; differences in antibiotic use between the studies; and differences in the location of the biopsies that were taken. Here, we describe the impact of these differences on wound healing and conclude that further standardization of the wound model, and further characterization of the specific cells that are depleted in these mice, is necessary to better understand how antigen-presenting cells contribute to wound healing.
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Affiliation(s)
- Aarthi Rajesh
- Department of Pathology, Otago Medical School, University of Otago, Dunedin, New Zealand
| | - Gabriella Stuart
- Department of Pharmacology and Toxicology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Nicola Real
- Department of Pharmacology and Toxicology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Allison Tschirley
- Department of Pathology, Otago Medical School, University of Otago, Dunedin, New Zealand
| | - Jenny Ahn
- Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Lyn Wise
- Department of Pharmacology and Toxicology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Merilyn Hibma
- Department of Pathology, Otago Medical School, University of Otago, Dunedin, New Zealand
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