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Zhu L, Liu L, Wang A, Liu J, Huang X, Zan T. Positive feedback loops between fibroblasts and the mechanical environment contribute to dermal fibrosis. Matrix Biol 2023; 121:1-21. [PMID: 37164179 DOI: 10.1016/j.matbio.2023.05.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 05/06/2023] [Accepted: 05/07/2023] [Indexed: 05/12/2023]
Abstract
Dermal fibrosis is characterized by excessive deposition of extracellular matrix in the dermis and affects millions of people worldwide and causes limited movement, disfigurement and psychological distress in patients. Fibroblast dysfunction of plays a central role in the pathogenesis of dermal fibrosis and is controlled by distinct factors. Recent studies support the hypothesis that fibroblasts can drive matrix deposition and stiffening, which in turn can exacerbate the functional dysregulation of fibroblasts. Ultimately, through a positive feedback loop, uncontrolled pathological fibrosis develops. This review aims to summarize the phenomenon and mechanism of the positive feedback loop in dermal fibrosis, and discuss potential therapeutic targets to help further elucidate the pathogenesis of dermal fibrosis and develop therapeutic strategies. In this review, fibroblast-derived compositional and structural changes in the ECM that lead to altered mechanical properties are briefly discussed. We focus on the mechanisms by which mechanical cues participate in dermal fibrosis progression. The mechanosensors discussed in the review include integrins, DDRs, proteoglycans, and mechanosensitive ion channels. The FAK, ERK, Akt, and Rho pathways, as well as transcription factors, including MRTF and YAP/TAZ, are also discussed. In addition, we describe stiffness-induced biological changes in the ECM on fibroblasts that contribute to the formation of a positive feedback loop. Finally, we discuss therapeutic strategies to treat the vicious cycle and present important suggestions for researchers conducting in-depth research.
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Affiliation(s)
- Liang Zhu
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Lechen Liu
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Aoli Wang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Jinwen Liu
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Xin Huang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
| | - Tao Zan
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
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2
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Hernández-Bule ML, Toledano-Macías E, Pérez-González LA, Martínez-Pascual MA, Fernández-Guarino M. Anti-Fibrotic Effects of RF Electric Currents. Int J Mol Sci 2023; 24:10986. [PMID: 37446165 DOI: 10.3390/ijms241310986] [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: 05/10/2023] [Revised: 06/21/2023] [Accepted: 06/29/2023] [Indexed: 07/15/2023] Open
Abstract
Hypertrophic scars and keloids are two different manifestations of excessive dermal fibrosis and are caused by an alteration in the normal wound-healing process. Treatment with radiofrequency (RF)-based therapies has proven to be useful in reducing hypertrophic scars. In this study, the effect of one of these radiofrequency therapies, Capacitive Resistive Electrical Transfer Therapy (CRET) on biomarkers of skin fibrosis was investigated. For this, in cultures of human myofibroblasts treated with CRET therapy or sham-treated, proliferation (XTT Assay), apoptosis (TUNEL Assay), and cell migration (Wound Closure Assay) were analyzed. Furthermore, in these cultures the expression and/or localization of extracellular matrix proteins such as α-SMA, Col I, Col III (immunofluorescence), metalloproteinases MMP1 and MMP9, MAP kinase ERK1/2, and the transcription factor NFκB were also investigated (immunoblot). The results have revealed that CRET decreases the expression of extracellular matrix proteins, modifies the expression of the metalloproteinase MMP9, and reduces the activation of NFκB with respect to controls, suggesting that this therapy could be useful for the treatment of fibrotic pathologies.
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Affiliation(s)
- María Luisa Hernández-Bule
- Bioelectromagnetic Laboratory, Instituto Ramón y Cajal de Investigación Sanitaria (Irycis), Carretera de Colmenar Viejo, km. 9.100, 28034 Madrid, Spain
| | - Elena Toledano-Macías
- Bioelectromagnetic Laboratory, Instituto Ramón y Cajal de Investigación Sanitaria (Irycis), Carretera de Colmenar Viejo, km. 9.100, 28034 Madrid, Spain
| | - Luis Alfonso Pérez-González
- Dermatology Service, Hospital Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (Irycis), Carretera de Colmenar Viejo, km. 9.100, 28034 Madrid, Spain
| | - María Antonia Martínez-Pascual
- Bioelectromagnetic Laboratory, Instituto Ramón y Cajal de Investigación Sanitaria (Irycis), Carretera de Colmenar Viejo, km. 9.100, 28034 Madrid, Spain
| | - Montserrat Fernández-Guarino
- Dermatology Service, Hospital Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (Irycis), Carretera de Colmenar Viejo, km. 9.100, 28034 Madrid, Spain
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Mony MP, Harmon KA, Hess R, Dorafshar AH, Shafikhani SH. An Updated Review of Hypertrophic Scarring. Cells 2023; 12:cells12050678. [PMID: 36899815 PMCID: PMC10000648 DOI: 10.3390/cells12050678] [Citation(s) in RCA: 44] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 02/01/2023] [Accepted: 02/08/2023] [Indexed: 02/24/2023] Open
Abstract
Hypertrophic scarring (HTS) is an aberrant form of wound healing that is associated with excessive deposition of extracellular matrix and connective tissue at the site of injury. In this review article, we provide an overview of normal (acute) wound healing phases (hemostasis, inflammation, proliferation, and remodeling). We next discuss the dysregulated and/or impaired mechanisms in wound healing phases that are associated with HTS development. We next discuss the animal models of HTS and their limitations, and review the current and emerging treatments of HTS.
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Affiliation(s)
- Manjula P. Mony
- Department of Surgery, Division of Plastic & Reconstructive Surgery, Rush University Medical Center, Chicago, IL 60612, USA
| | - Kelly A. Harmon
- Department of Surgery, Division of Plastic & Reconstructive Surgery, Rush University Medical Center, Chicago, IL 60612, USA
| | - Ryan Hess
- Department of Surgery, Division of Plastic & Reconstructive Surgery, Rush University Medical Center, Chicago, IL 60612, USA
| | - Amir H. Dorafshar
- Department of Surgery, Division of Plastic & Reconstructive Surgery, Rush University Medical Center, Chicago, IL 60612, USA
| | - Sasha H. Shafikhani
- Department of Medicine, Division of Hematology and Oncology and Cell Therapy, Rush University Medical Center, Chicago, IL 60612, USA
- Cancer Center, Rush University Medical Center, Chicago, IL 60612, USA
- Correspondence:
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Borrelli MR, Shen AH, Griffin M, Mascharak S, Adem S, Deleon NMD, Ngaage LM, Longaker MT, Wan DC, Lorenz HP. A Novel Xenograft Model Demonstrates Human Fibroblast Behavior During Skin Wound Repair and Fibrosis. Adv Wound Care (New Rochelle) 2022; 11:455-465. [PMID: 34521222 PMCID: PMC9245791 DOI: 10.1089/wound.2020.1392] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 08/31/2021] [Indexed: 11/12/2022] Open
Abstract
Objective: Xenografts of human skin in immunodeficient mice provide a means of assessing human skin physiology and its response to wounding. Approach: We describe a novel xenograft model using full-thickness human neonatal foreskin to examine human skin wound repair. Full-thickness 8 mm human neonatal foreskin biopsies were sutured into the dorsum of NOD scid gamma (NSG; NOD.Cg-Prkdc scidIl2rgtm1Wjl/SzJ) pups as subcutaneous grafts. At postnatal day 21 the subcutaneous grafts were exposed to cutaneous grafts. Following maturation of 2 months, xenografts were then wounded with 5 mm linear incisions and monitored until postwound day (PWD) 14 to study skin repair and fibrosis. To explore whether our model can be used to test the efficacy of topical therapies, wounded xenografts were injected with antifibrotic fibroblast growth factor 2 (FGF2) for the first four consecutive PWDs. Xenografts were harvested for analysis by histology and fluorescence-activated cell sorting (FACS). Results: Xenografts were successfully engrafted with evidence of mouse-human anastomoses and resembled native neonatal foreskin at the gross and microscopic level. Wounded xenografted skin scarred with human collagen and an expansion of CD26-positive human fibroblasts. Collagen scar was quantitated by neural network analysis, which revealed distinct clustering of collagen fiber networks from unwounded skin and wounded skin at PWD7 and PWD14. Collagen fiber networks within FGF2-treated wounds at PWD14 resembled those in untreated wounded xenografts at PWD7, suggesting that FGF2 treatment at time of wounding can reduce fibrosis. Innovation and Conclusion: This novel xenograft model can be used to investigate acute fibrosis, fibroblast heterogeneity, and the efficacy of antifibrotic agents during wound repair in human skin.
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Affiliation(s)
- Mimi R. Borrelli
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California, USA
| | - Abra H. Shen
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California, USA
| | - Michelle Griffin
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California, USA
| | - Shamik Mascharak
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California, USA
| | - Sandeep Adem
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California, USA
| | - Nestor M. Diaz Deleon
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California, USA
| | - Ledibabari Mildred Ngaage
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California, USA
| | - Michael T. Longaker
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California, USA
- Department of Surgery, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Derrick C. Wan
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California, USA
| | - Hermann Peter Lorenz
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California, USA
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Role of Daptomycin in Cutaneous Wound Healing: A Narrative Review. Antibiotics (Basel) 2022; 11:antibiotics11070944. [PMID: 35884198 PMCID: PMC9311791 DOI: 10.3390/antibiotics11070944] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/11/2022] [Accepted: 07/11/2022] [Indexed: 02/06/2023] Open
Abstract
Daptomycin is active against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and the on-label indications for its use include complicated skin and skin structure infections (cSSSI). We performed a narrative review of the literature with the aim to evaluate the role of daptomycin in the skin wound healing process, proposing our point of view on the possible association with other molecules that could improve the skin healing process. Daptomycin may improve wound healing in MRSA-infected burns, surgical wounds, and diabetic feet, but further studies in humans with histological examination are needed. In the future, the combination of daptomycin with other molecules with synergistic action, such as vitamin E and derivates, IB-367, RNA III-inhibiting peptide (RIP), and palladium nanoflowers, may help to improve wound healing and overcome forms of antibiotic resistance.
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Vanderstichele S, Vranckx JJ. Anti-fibrotic effect of adipose-derived stem cells on fibrotic scars. World J Stem Cells 2022; 14:200-213. [PMID: 35432731 PMCID: PMC8963379 DOI: 10.4252/wjsc.v14.i2.200] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 05/01/2021] [Accepted: 02/16/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Sustained injury, through radiotherapy, burns or surgical trauma, can result in fibrosis, displaying an excessive deposition of extracellular matrix (ECM), persisting inflammatory reaction, and reduced vascularization. The increasing recognition of fibrosis as a cause for disease and mortality, and increasing use of radiotherapy causing fibrosis, stresses the importance of a decent anti-fibrotic treatment.
AIM To obtain an in-depth understanding of the complex mechanisms underlying fibrosis, and more specifically, the potential mechanisms-of-action of adipose-derived stomal cells (ADSCs) in realizing their anti-fibrotic effect.
METHODS A systematic review of the literature using PubMed, Embase and Web of Science was performed by two independent reviewers.
RESULTS The injection of fat grafts into fibrotic tissue, releases ADSC into the environment. ADSCs’ capacity to directly differentiate into key cell types (e.g., ECs, fibroblasts), as well as to secrete multiple paracrine factors (e.g., hepatocyte growth factor, basis fibroblast growth factor, IL-10), allows them to alter different mechanisms underlying fibrosis in a combined approach. ADSCs favor ECM degradation by impacting the fibroblast-to-myofibroblast differentiation, favoring matrix metalloproteinases over tissue inhibitors of metalloproteinases, positively influencing collagen organization, and inhibiting the pro-fibrotic effects of transforming growth factor-β1. Furthermore, they impact elements of both the innate and adaptive immune response system, and stimulate angiogenesis on the site of injury (through secretion of pro-angiogenic cytokines like stromal cell-derived factor-1 and vascular endothelial growth factor).
CONCLUSION This review shows that understanding the complex interactions of ECM accumulation, immune response and vascularization, is vital to fibrosis treatments’ effectiveness like fat grafting. It details how ADSCs intelligently steer this complex system in an anti-fibrotic or pro-angiogenic direction, without falling into extreme dilation or stimulation of a single aspect. Detailing this combined approach, has brought fat grafting one step closer to unlocking its full potential as a non-anecdotal treatment for fibrosis.
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Affiliation(s)
| | - Jan Jeroen Vranckx
- Department of Plastic, Reconstructive Surgery, KU-Leuven University Hospitals, Leuven 3000, Belgium
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Hsiao HY, Lai CY, Liu JW, Yu YY, Chang FCS, Huang JJ. Fate of Fat Grafting In Vivo and In Vitro: Does the Suction-Assisted Lipectomy Device Matter? Aesthet Surg J 2021; 41:NP1323-NP1336. [PMID: 34043750 DOI: 10.1093/asj/sjab231] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND Recently, there has been increasing research interest in identifying the effect of liposuction procedures on fat graft survival in order to clarify whether different harvest techniques affect the quality of fat grafts. OBJECTIVES The aim of this study was to investigate the effect of 2 liposuction methods on the survival and regeneration potential of grafted fat tissue. The proliferation and differentiation potentials of adipose-derived stem cells (ASCs) isolated by both methods was also investigated. METHODS Fat grafts were collected from patients who underwent liposuction procedures by 2 different methods: traditional suction-assisted liposuction (TSAL) and vibration amplification of sound energy at resonance (VASER). One portion of the lipoaspirates was implanted into the subcutaneous layer of nu mice for 4 and 12 weeks. ASCs were isolated from the other portion of the lipoaspirate and subjected to proliferation and differentiation assays. RESULTS Although in vivo fat grafting presented similar adipose tissue survival for the 2 different liposuction methods, more angiogenesis and less fibrosis was observed in the VASER group based on histologic evaluation. Furthermore, VASER-derived ASCs presented better quality in terms of cell differentiation capacity. CONCLUSIONS The in vivo study confirmed better graft angiogenesis with less inflammation, apoptosis, and scar formation in the VASER group. ASCs harvested with VASER exhibited increased differentiation capacity compared with those obtained by TSAL, and represent an excellent source for fat grafting and regenerative medicine.
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Affiliation(s)
- Hui-Yi Hsiao
- Center for Tissue Engineering, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | | | - Jia-Wei Liu
- Center for Tissue Engineering, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Yuan-Yuan Yu
- Center for Tissue Engineering, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Frank Chun-Shin Chang
- Division of Craniofacial Surgery, Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Jung-Ju Huang
- Division of Reconstructive Microsurgery, Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan, Taiwan
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Myofibroblasts: Function, Formation, and Scope of Molecular Therapies for Skin Fibrosis. Biomolecules 2021; 11:biom11081095. [PMID: 34439762 PMCID: PMC8391320 DOI: 10.3390/biom11081095] [Citation(s) in RCA: 123] [Impact Index Per Article: 30.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Revised: 07/16/2021] [Accepted: 07/20/2021] [Indexed: 12/11/2022] Open
Abstract
Myofibroblasts are contractile, α-smooth muscle actin-positive cells with multiple roles in pathophysiological processes. Myofibroblasts mediate wound contractions, but their persistent presence in tissues is central to driving fibrosis, making them attractive cell targets for the development of therapeutic treatments. However, due to shared cellular markers with several other phenotypes, the specific targeting of myofibroblasts has long presented a scientific and clinical challenge. In recent years, myofibroblasts have drawn much attention among scientific research communities from multiple disciplines and specialisations. As further research uncovers the characterisations of myofibroblast formation, function, and regulation, the realisation of novel interventional routes for myofibroblasts within pathologies has emerged. The research community is approaching the means to finally target these cells, to prevent fibrosis, accelerate scarless wound healing, and attenuate associated disease-processes in clinical settings. This comprehensive review article describes the myofibroblast cell phenotype, their origins, and their diverse physiological and pathological functionality. Special attention has been given to mechanisms and molecular pathways governing myofibroblast differentiation, and updates in molecular interventions.
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Human CD206+ Macrophages Show Antifibrotic Effects on Human Fibroblasts through an IL-6-Dependent Mechanism In Vitro. Plast Reconstr Surg 2021; 147:231e-239e. [PMID: 33235042 DOI: 10.1097/prs.0000000000007563] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Pathologic scarring including keloid and hypertrophic scar causes aesthetic and physical problems, and there are clinical difficulties (e.g., posttreatment recurrence) in dealing with pathologic scarring. Understanding the mechanisms that underlie scar control in wound healing will help prevent and treat pathologic scarring. The authors focused on CD206+ macrophages in the wound-healing process, and hypothesized that CD206+ macrophages have antifibrotic effects on fibroblasts. METHODS The authors established a co-culture system for CD206+ macrophages and fibroblasts (cell ratio, 1:1). The authors examined the CD206+ macrophages' antifibrotic effects on fibroblasts after a 72-hour culture, focusing on fibrosis-related genes. To identify key factor(s) in the interaction between CD206+ macrophages and fibroblasts, the authors analyzed cytokines in a conditioned medium of the co-culture system. RESULTS Under co-culture with CD206+ macrophages, expression of the following in the fibroblasts was significantly down-regulated: type 1 (fold change, 0.38) and type 3 collagen (0.45), alpha smooth muscle actin (0.24), connective tissue growth factor (0.40), and transforming growth factor-beta (0.66); the expression of matrix metalloproteinase 1 was significantly up-regulated (1.92). Conditioned medium in the co-culture showed a high interleukin (IL)-6 concentration (419 ± 88 pg/ml). When IL-6 was added to fibroblasts, antifibrotic changes in gene expression (as observed under the co-culture) occurred in the fibroblasts. CONCLUSIONS The authors' in vitro results revealed that CD206+ macrophages have antifibrotic effects on fibroblasts by means of a paracrine mechanism involving IL-6. Understanding these effects, especially in vivo, will help elucidate the mechanism of scar control in wound healing and contribute to the development of new scar treatments.
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Elbialy ZI, Assar DH, Abdelnaby A, Asa SA, Abdelhiee EY, Ibrahim SS, Abdel-Daim MM, Almeer R, Atiba A. RETRACTED: Healing potential of Spirulina platensis for skin wounds by modulating bFGF, VEGF, TGF-ß1 and α-SMA genes expression targeting angiogenesis and scar tissue formation in the rat model. Biomed Pharmacother 2021; 137:111349. [PMID: 33567349 DOI: 10.1016/j.biopha.2021.111349] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 01/16/2021] [Accepted: 01/27/2021] [Indexed: 02/06/2023] Open
Abstract
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief. The journal was alerted to an associated PubPeer post in which suspected duplicated features were identified within Figure 4 B1, and the histological image in Figure 3 A1 appears to have been previously published in another article, as detailed here: https://pubpeer.com/publications/E5658B7B735FF993AA795A5F14C086. The journal performed independent analysis and identified additional suspected image duplications between the images of mice in Figure 1 A+B and images of mice in Figure 6 A+B from Elbialy et al., BMC Veterinary Research (2020). The journal requested the authors provide an explanation to these concerns and associated raw data, but this request was not satisfactorily fulfilled. The Editor-in-Chief assessed the case and decided to retract the article.
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Affiliation(s)
- Zizy I Elbialy
- Fish Processing and Biotechnology Department, Faculty of Fisheries Sciences and Aquaculture, Kafrelsheikh University, Kafrelsheikh 33516, Egypt.
| | - Doaa H Assar
- Clinical Pathology Department, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh 33516, Egypt.
| | - Aml Abdelnaby
- Fish Processing and Biotechnology Department, Faculty of Fisheries Sciences and Aquaculture, Kafrelsheikh University, Kafrelsheikh 33516, Egypt
| | - Samah Abu Asa
- Pathology Department, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh 33516, Egypt
| | - Ehab Y Abdelhiee
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Matrouh University, Matrouh, Egypt
| | - Samar S Ibrahim
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Benha University, Egypt
| | - Mohamed M Abdel-Daim
- Department of Zoology, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia; Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, Ismailia 41522, Egypt
| | - Rafa Almeer
- Department of Zoology, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
| | - Ayman Atiba
- Department of Surgery, Anesthesiology, and Radiology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh 33516, Egypt
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12
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Zhang C, Wang J, Xie Y, Wang L, Yang L, Yu J, Miyamoto A, Sun F. Development of FGF-2-loaded electrospun waterborne polyurethane fibrous membranes for bone regeneration. Regen Biomater 2020; 8:rbaa046. [PMID: 33732492 PMCID: PMC7947599 DOI: 10.1093/rb/rbaa046] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 08/06/2020] [Accepted: 09/11/2020] [Indexed: 12/24/2022] Open
Abstract
Guided bone regeneration (GBR) membrane has been used to improve functional outcomes for periodontal regeneration. However, few studies have focused on the biomimetic membrane mimicking the vascularization of the periodontal membrane. This study aimed to fabricate waterborne polyurethane (WPU) fibrous membranes loaded fibroblast growth factor-2 (FGF-2) via emulsion electrospinning, which can promote regeneration of periodontal tissue via the vascularization of the biomimetic GBR membrane. A biodegradable WPU was synthesized by using lysine and dimethylpropionic acid as chain extenders according to the rule of green chemical synthesis technology. The WPU fibers with FGF-2 was fabricated via emulsion electrospinning. The results confirmed that controlled properties of the fibrous membrane had been achieved with controlled degradation, suitable mechanical properties and sustained release of the factor. The immunohistochemical expression of angiogenic-related factors was positive, meaning that FGF-2 loaded in fibers can significantly promote cell vascularization. The fiber scaffold loaded FGF-2 has the potential to be used as a functional GBR membrane to promote the formation of extraosseous blood vessels during periodontal repairing.
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Affiliation(s)
- Chi Zhang
- Department of Rehabilitation, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, P.R. China
| | - Jianxiong Wang
- Department of Rehabilitation, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, P.R. China
| | - Yujie Xie
- Department of Rehabilitation, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, P.R. China
| | - Li Wang
- Department of Rehabilitation, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, P.R. China
| | - Lishi Yang
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, P.R. China
| | - Jihua Yu
- Department of Rehabilitation, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, P.R. China
| | - Akira Miyamoto
- Faculty of Rehabilitation, Department of Physical Therapy, Kobe International University, Kobe, Japan
| | - Fuhua Sun
- Department of Rehabilitation, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, P.R. China
- Correspondence address. Department of Rehabilitation, The Affiliated Hospital of Southwest Medical University, Taiping Street 25, Luzhou 646000, P.R. China. Tel.: +81-18428397607; E-mail:
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Fan C, El Andaloussi S, Lehto T, Kong KW, Seow Y. Smad‑binding decoy reduces extracellular matrix expression in human hypertrophic scar fibroblasts. Mol Med Rep 2020; 22:4589-4600. [PMID: 33173952 PMCID: PMC7646840 DOI: 10.3892/mmr.2020.11549] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Accepted: 08/05/2020] [Indexed: 12/14/2022] Open
Abstract
The exact mechanisms underlying hypertrophic scarring is yet to be fully understood. However, excessive collagen deposition by fibroblasts has been demonstrated to result in hypertrophic scar formation, and collagen synthesis in dermal fibroblasts is regulated by the transforming growth factor-β1/Smad signaling pathway. In view of this, a Smad-binding decoy was designed and its effects on hypertrophic scar-derived human skin fibroblasts was evaluated. The results of the present study revealed that the Smad decoy attenuates the total amount of collagen, collagen I and Smad2/3 expression in scar fibroblasts. Data from RNA sequencing indicated that the Smad decoy induced more than 4-fold change in 178 genes, primarily associated with to the extracellular matrix, compared with the untreated control. In addition, results from quantitative real-time polymerase chain reaction further confirmed that the Smad decoy significantly attenuated the expression of extracellular matrix-related genes, including COL1A1, COL1A2 and COL3A1. Furthermore, the Smad decoy reduced transforming growth factor-β1-induced collagen deposition in scar fibroblasts. Data generated from the present study provide evidence supporting the use of the Smad decoy as a potential hypertrophic scar treatment.
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Affiliation(s)
- Chen Fan
- Skin Research Institute of Singapore, Agency for Science, Technology and Research (A STAR), Singapore 138648, Republic of Singapore
| | - Samir El Andaloussi
- Department of Laboratory Medicine, Center for Advanced Therapies, Karolinska Institute, Stockholm 14186, Sweden
| | - Taavi Lehto
- Department of Laboratory Medicine, Center for Advanced Therapies, Karolinska Institute, Stockholm 14186, Sweden
| | - Kiat Whye Kong
- Molecular Engineering Laboratory, Institute of Bioengineering and Nanotechnology, A STAR, Singapore 138669, Republic of Singapore
| | - Yiqi Seow
- Molecular Engineering Laboratory, Institute of Bioengineering and Nanotechnology, A STAR, Singapore 138669, Republic of Singapore
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Modulation of Extracellular Matrix by Scrophularia striata Extract in Vitro: A Potential Antiscarring Agent. Jundishapur J Nat Pharm Prod 2020. [DOI: 10.5812/jjnpp.95301] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Background: Hypertrophic scars are the consequences of the aberration of normal wound healing. To date, therapeutic strategies for abnormal scarring have been unsuccessful. The abnormal extracellular matrix is one of the most important contributing factors to hypertrophic scars. Scrophularia striata has been used in Iranian folk medicine for the treatment of burn wounds. The plant extract accelerates wound healing and attenuates scar formation. Objectives: The study was performed to investigate the effects of Scrophularia striata hydroalcoholic extract (SSE) on MMP1, MMP8, fibronectin, collagen type I, and total collagen produced by human skin fibroblasts in the culture medium. Methods: The effects of SSE on the expression of MMP1, MMP8, fibronectin, and collagen type I in human skin fibroblast (HSF) were evaluated using Q-PCR and Western blotting methods. In addition, the effect of SSE on the total collagen content was measured in cultured HSF using Red Sirius Kit. Results: SSE significantly induced the expression of MMP1 and suppressed the production of fibronectin at the mRNA and protein levels. The total collagen content was significantly lower in SSE-treated cells than in untreated cells. SSE did not have any significant effect on MMP8 and collagen type I expression. Conclusions: The results of this study revealed that SSE could modulate the extracellular matrix turnover and had the potential for the prevention and treatment of hypertrophic scars.
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15
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Zhu J, Sun M, Wang Y, Bi H, Xue C. Gene expression profile analysis on different stages of hypertrophic scarring in a rabbit ear model. Exp Ther Med 2020; 20:1505-1513. [PMID: 32742383 PMCID: PMC7388309 DOI: 10.3892/etm.2020.8879] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Accepted: 12/04/2019] [Indexed: 12/11/2022] Open
Abstract
Hypertrophic scarring (HS) is one of the most common skin disorders. The study aimed to investigate the gene expression profile at day 10 (Stage 1), 21 (Stage 2), and day 40 (Stage 3) post-wounding of HS using RNA-sequencing of a scar model from rabbit ears. A total of 17,386 unigenes were annotated using the eggNOG Functional Category database. The study identified significantly differentially expressed genes (DEGs) including 261, 141, and 247 upregulated ones as well as 253, 272, and 58 downregulated ones in three stages respectively. The DEGs varies among each stage measured by Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. DEGs were enriched in 'immune system process' and 'proteinaceous extracellular matrix' in Stage 1, 'anatomical structure development', 'cell differentiation', 'cell adhesion'and some other terms in Stage 2, 'cancers', 'proteinaceous extracellular matrix' and 'signal transduction' in Stage 3. Furthermore, the Wnt signaling pathway was found to play a pivotal role in regression of HS. In conclusion, we revealed comprehensively the gene expression profiles during HS formation providing probable targets in HS treatment.
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Affiliation(s)
- Ji Zhu
- Department of Plastic Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, P.R. China
| | - Mengyan Sun
- Department of Plastic Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, P.R. China
| | - Yuchong Wang
- Department of Plastic Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, P.R. China
| | - Hongda Bi
- Department of Plastic Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, P.R. China
| | - Chunyu Xue
- Department of Plastic Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, P.R. China
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16
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Abdelhakim M, Lin X, Ogawa R. The Japanese Experience with Basic Fibroblast Growth Factor in Cutaneous Wound Management and Scar Prevention: A Systematic Review of Clinical and Biological Aspects. Dermatol Ther (Heidelb) 2020; 10:569-587. [PMID: 32506250 PMCID: PMC7367968 DOI: 10.1007/s13555-020-00407-6] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Indexed: 01/08/2023] Open
Abstract
INTRODUCTION Basic fibroblast growth factor (bFGF) plays several key roles in wound healing. Over the last 2 decades, clinical and basic research on bFGF has been actively conducted in Japan with reports on its potent efficacy in accelerating the healing of chronic ulcers and burn wounds by stimulating key cellular players in the skin. However, its efficacy remains unrecognized internationally. Thus, this study reviews current knowledge about the therapeutic value of bFGF in wound management and scar prevention accumulated in Japan over the last 2 decades. METHODS We review the Japanese literature that demonstrates the anti-scarring effects of bFGF and exhaustively assess how these effects are exerted. Using the search terms "bFGF OR growth factors AND wound healing in Japan" and "bFGF AND scar prevention in Japan," we conducted a search of the PubMed database for publications on the role of bFGF in wound and scar management in Japan. All eligible papers published between 1988 and December 2019 were retrieved and reviewed. RESULTS Our search yielded 208 articles; 82 were related to the application of bFGF for dermal wound healing in Japan. Of these, 27 fulfilled all inclusion criteria; 11 were laboratory studies, 7 were case reports, 4 were clinical studies, and 5 were randomized controlled trials. CONCLUSION Further research, with recognition of the therapeutic value of bFGF in wound and scar management and its clinical applications, is needed to provide additional clinical advantages while improving wound healing and reducing the risk of post-surgical scar formation.
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Affiliation(s)
- Mohamed Abdelhakim
- Department of Plastic, Reconstructive and Aesthetic Surgery, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan.
| | - Xunxun Lin
- Department of Plastic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China
| | - Rei Ogawa
- Department of Plastic, Reconstructive and Aesthetic Surgery, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan
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17
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Su CC, Ho WT, Peng FT, Gao CM, Jou TS, Wang IJ. Exploring a peptidomimetic approach of N-cadherin in modulating fibroblast growth factor receptor signaling for corneal endothelial regeneration. FASEB J 2020; 34:11698-11713. [PMID: 32654299 DOI: 10.1096/fj.201902525rr] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 06/14/2020] [Accepted: 06/17/2020] [Indexed: 11/11/2022]
Abstract
Endothelial rejection and a critical shortage of corneal transplants present an unmet medical need in corneal regeneration research area. Although basic fibroblast growth factor (bFGF) is a potent mitogenic factor for corneal ex vivo expansion, it is also a morphogen eliciting unfavorable endothelial-mesenchymal transition (EnMT) of corneal endothelial cells. A pharmacological reagent that retains the beneficial proliferative effect while lacking the EnMT effect of bFGF would be of great potential in corneal regeneration. In present study, we demonstrated that bFGF not only activated the canonical fibroblast growth factor receptor 1 (FGFR1) tyrosine kinase pathway, but also further upregulated matrix metalloproteinase activity to cleave N-cadherin into N-terminus and C-terminus fragments, which activated the classical FGFR1 tyrosine kinase pathway and a cryptic β-catenin pathway to affect corneal proliferation and EnMT, respectively. We generated the synthetic peptides resembling a critical motif in the ectodomain of N-cadherin and found these peptides enhanced downstream proliferative signaling of FGFR1 but without seemingly EnMT effect. The potential of these peptides can be demonstrated on both ex vivo cell culture and in vivo rat cryo-injury model. Our study indicated this peptidomimetic approach of N-cadherin can stimulate corneal regeneration and offer a promising therapeutic option to treat corneal endothelial dysfunction.
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Affiliation(s)
- Chien-Chia Su
- Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan R.O.C.,Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan R.O.C.,College of Medicine, National Taiwan University, Taipei, Taiwan R.O.C
| | - Wei-Ting Ho
- Department of Ophthalmology, Far Eastern Memorial Hospital, New Taipei City, Taiwan R.O.C
| | - Fu-Ti Peng
- Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan R.O.C
| | - Chia-Mao Gao
- Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan R.O.C
| | - Tzuu-Shuh Jou
- Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan R.O.C.,College of Medicine, National Taiwan University, Taipei, Taiwan R.O.C.,Center of Precision Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan R.O.C
| | - I-Jong Wang
- Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan R.O.C.,Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan R.O.C.,College of Medicine, National Taiwan University, Taipei, Taiwan R.O.C
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18
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Xia T, Shen Z, Cai J, Pan M, Sun C. ColXV Aggravates Adipocyte Apoptosis by Facilitating Abnormal Extracellular Matrix Remodeling in Mice. Int J Mol Sci 2020; 21:ijms21030959. [PMID: 32024006 PMCID: PMC7037489 DOI: 10.3390/ijms21030959] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 01/25/2020] [Accepted: 01/30/2020] [Indexed: 02/06/2023] Open
Abstract
The extracellular matrix (ECM) is a highly dynamic structural network and plays an essential role in cell behavior and regulation during metabolic homeostasis and obesity progression. Abnormal ECM remodeling impairs adipocyte plasticity required for diverse cellular functions. Collagen XV (ColXV) is a proteoglycan localized to the outermost layer of basement membranes (BMs) and forms a bridge between the BMs and the fibrillar collagen matrix. Nevertheless, how ColXV affects ECM composition and the reason for subsequent adipocyte apoptosis is still unclear. This report found, through RNA-seq data, that ColXV is linked to cell growth and ECM remodeling. Findings show that, in response to excessive expression of extracellular ColXV, the AMPK/mTORC1 pathway is strongly activated and triggers a cascade of mitochondrial apoptosis. This is the first study to make use of ECM three-dimensional reconstruction, based on decellularization in the adipose tissues and the study reveals that ColXV is an activation factor that alters ECM remodeling in adipose tissues. It was also demonstrated that the fibroblast growth factor 2 (FGF2)/fibroblast growth factor receptor 1 (FGFR1) axis involved in ECM remodeling is suppressed by ColXV due to reduction of FGF2 translocation to FGFR1. Furthermore, ColXV induced remodeling of ECM preceding apoptosis and continued to induce apoptosis in adipocytes. Collectively, our findings establish ColXV as a basement membrane collagen with homology to ColXVIII, indicating that it is one of the positive regulators for inducing ECM remodeling and further promoting adipocyte apoptosis.
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19
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Lingzhi Z, Meirong L, Xiaobing F. Biological approaches for hypertrophic scars. Int Wound J 2019; 17:405-418. [PMID: 31860941 DOI: 10.1111/iwj.13286] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Revised: 12/01/2019] [Accepted: 12/05/2019] [Indexed: 12/11/2022] Open
Abstract
Scar formation is usually the pathological consequence of skin trauma. And hypertrophic scars (HSs) frequently occur in people after being injured deeply. HSs are unusually considered as the result of tissue contraction and excessive extracellular matrix component deposition. Myofibroblasts, as the effector cells, mainly differentiated from fibroblasts, play the crucial role in the pathophysiology of HSs. A number of growth factors, inflammatory cytokines involved in the process of HS occurrence. Currently, with in-depth exploration and clinical research of HSs, various creative and effective treatments budded. In here, we summarize the progress in the molecular mechanism of HSs, and review the available biotherapeutic methods for their pathophysiological characteristics. Additionally, we further prospected that the comprehensive therapy may be more suitable for HS treatment.
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Affiliation(s)
- Zhong Lingzhi
- Institute of Basic Medical Science, Chinese PLA General Hospital, Beijing, China
| | - Li Meirong
- Institute of Basic Medical Science, Chinese PLA General Hospital, Beijing, China.,Central Laboratory, Trauma Treatment Center, Chinese PLA General Hospital Hainan Branch, Sanya, China
| | - Fu Xiaobing
- Institute of Basic Medical Science, Chinese PLA General Hospital, Beijing, China
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20
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Fan C, Lim LKP, Loh SQ, Ying Lim KY, Upton Z, Leavesley D. Application of “macromolecular crowding” in vitro to investigate the naphthoquinones shikonin, naphthazarin and related analogues for the treatment of dermal scars. Chem Biol Interact 2019; 310:108747. [DOI: 10.1016/j.cbi.2019.108747] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 06/14/2019] [Accepted: 07/10/2019] [Indexed: 01/05/2023]
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21
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Jezierska-Drutel A, Attaran S, Hopkins BL, Skoko JJ, Rosenzweig SA, Neumann CA. The peroxidase PRDX1 inhibits the activated phenotype in mammary fibroblasts through regulating c-Jun N-terminal kinases. BMC Cancer 2019; 19:812. [PMID: 31419957 PMCID: PMC6697950 DOI: 10.1186/s12885-019-6031-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Accepted: 08/12/2019] [Indexed: 01/11/2023] Open
Abstract
Background Reactive oxygen species (ROS), including hydrogen peroxide, drive differentiation of normal fibroblasts into activated fibroblasts, which can generate high amounts of hydrogen peroxide themselves, thereby increasing oxidative stress in the microenvironment. This way, activated fibroblasts can transition into cancer-associated fibroblasts (CAFs). Methods Mammary fibroblasts from either female 8 weeks old PRDX1 knockout and wildtype mice or Balb/c mice were studied for characteristic protein expression using immunofluorescence and immunoblotting. Cancer-associated fibroblasts was examined by transwell migration and invasion assays. The binding of PRDX1 to JNK1 was assessed by co-immuneprecipitation and JNK regulation of CAF phenotypes was examined using the JNK inhibitor SP600125. Extracellular hydrogen peroxide levels were measured by chemiluminescence via the reaction between hypochlorite and luminol. Statistical analyses were done using Students t-test. Results We show here PRDX1 activity as an essential switch in regulating the activated phenotype as loss of PRDX1 results in the development of a CAF-like phenotype in mammary fibroblasts. We also show that PRDX1 regulates JNK kinase signaling thereby inhibiting CAF-like markers and CAF invasion. Inhibition of JNK activity reduced these behaviors. Conclusions These data suggest that PRDX1 repressed the activated phenotype of fibroblasts in part through JNK inhibition which may present a novel therapeutic option for CAF-enriched cancers such as breast cancer. Electronic supplementary material The online version of this article (10.1186/s12885-019-6031-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Agnieszka Jezierska-Drutel
- Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.,Department of Cell and Molecular Pharmacology & Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Shireen Attaran
- Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.,Women's Cancer Research Center, UPMC Hillman Cancer Center, Pittsburgh, PA, 15213, USA
| | - Barbara L Hopkins
- Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, 15213, USA.,Women's Cancer Research Center, UPMC Hillman Cancer Center, Pittsburgh, PA, 15213, USA
| | - John J Skoko
- Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.,Women's Cancer Research Center, UPMC Hillman Cancer Center, Pittsburgh, PA, 15213, USA
| | - Steven A Rosenzweig
- Department of Cell and Molecular Pharmacology & Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Carola A Neumann
- Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15213, USA. .,Women's Cancer Research Center, UPMC Hillman Cancer Center, Pittsburgh, PA, 15213, USA.
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22
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Brazil JC, Quiros M, Nusrat A, Parkos CA. Innate immune cell-epithelial crosstalk during wound repair. J Clin Invest 2019; 129:2983-2993. [PMID: 31329162 PMCID: PMC6668695 DOI: 10.1172/jci124618] [Citation(s) in RCA: 170] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Skin and intestinal epithelial barriers play a pivotal role in protecting underlying tissues from harsh external environments. The protective role of these epithelia is, in part, dependent on a remarkable capacity to restore barrier function and tissue homeostasis after injury. In response to damage, epithelial wounds repair by a series of events that integrate epithelial responses with those of resident and infiltrating immune cells including neutrophils and monocytes/macrophages. Compromise of this complex interplay predisposes to development of chronic nonhealing wounds, contributing to morbidity and mortality of many diseases. Improved understanding of crosstalk between epithelial and immune cells during wound repair is necessary for development of better pro-resolving strategies to treat debilitating complications of disorders ranging from inflammatory bowel disease to diabetes. In this Review we focus on epithelial and innate immune cell interactions that mediate wound healing and restoration of tissue homeostasis in the skin and intestine.
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23
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Akatsu Y, Takahashi N, Yoshimatsu Y, Kimuro S, Muramatsu T, Katsura A, Maishi N, Suzuki HI, Inazawa J, Hida K, Miyazono K, Watabe T. Fibroblast growth factor signals regulate transforming growth factor-β-induced endothelial-to-myofibroblast transition of tumor endothelial cells via Elk1. Mol Oncol 2019; 13:1706-1724. [PMID: 31094056 PMCID: PMC6670013 DOI: 10.1002/1878-0261.12504] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2019] [Revised: 03/31/2019] [Accepted: 05/14/2019] [Indexed: 02/04/2023] Open
Abstract
The tumor microenvironment contains various components, including cancer cells, tumor vessels, and cancer-associated fibroblasts, the latter of which are comprised of tumor-promoting myofibroblasts and tumor-suppressing fibroblasts. Multiple lines of evidence indicate that transforming growth factor-β (TGF-β) induces the formation of myofibroblasts and other types of mesenchymal (non-myofibroblastic) cells from endothelial cells. Recent reports show that fibroblast growth factor 2 (FGF2) modulates TGF-β-induced mesenchymal transition of endothelial cells, but the molecular mechanisms behind the signals that control transcriptional networks during the formation of different groups of fibroblasts remain largely unclear. Here, we studied the roles of FGF2 during the regulation of TGF-β-induced mesenchymal transition of tumor endothelial cells (TECs). We demonstrated that auto/paracrine FGF signals in TECs inhibit TGF-β-induced endothelial-to-myofibroblast transition (End-MyoT), leading to suppressed formation of contractile myofibroblast cells, but on the other hand can also collaborate with TGF-β in promoting the formation of active fibroblastic cells which have migratory and proliferative properties. FGF2 modulated TGF-β-induced formation of myofibroblastic and non-myofibroblastic cells from TECs via transcriptional regulation of various mesenchymal markers and growth factors. Furthermore, we observed that TECs treated with TGF-β were more competent in promoting in vivo tumor growth than TECs treated with TGF-β and FGF2. Mechanistically, we showed that Elk1 mediated FGF2-induced inhibition of End-MyoT via inhibition of TGF-β-induced transcriptional activation of α-smooth muscle actin promoter by myocardin-related transcription factor-A. Our data suggest that TGF-β and FGF2 oppose and cooperate with each other during the formation of myofibroblastic and non-myofibroblastic cells from TECs, which in turn determines the characteristics of mesenchymal cells in the tumor microenvironment.
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Affiliation(s)
- Yuichi Akatsu
- Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Japan.,Biomedicine Group, Pharmaceutical Research Laboratories, Pharmaceutical Group, Nippon Kayaku Co., Ltd., Tokyo, Japan
| | - Naoya Takahashi
- Department of Biochemistry, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Japan
| | - Yasuhiro Yoshimatsu
- Department of Biochemistry, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Japan
| | - Shiori Kimuro
- Department of Biochemistry, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Japan
| | - Tomoki Muramatsu
- Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Japan
| | - Akihiro Katsura
- Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Japan
| | - Nako Maishi
- Department of Vascular Biology and Molecular Pathology, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan
| | - Hiroshi I Suzuki
- Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Japan.,David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Johji Inazawa
- Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Japan
| | - Kyoko Hida
- Department of Vascular Biology and Molecular Pathology, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan
| | - Kohei Miyazono
- Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Japan
| | - Tetsuro Watabe
- Department of Biochemistry, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Japan
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24
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Alemzadeh E, Oryan A, Mohammadi AA. Hyaluronic acid hydrogel loaded by adipose stem cells enhances wound healing by modulating IL-1β, TGF-β1, and bFGF in burn wound model in rat. J Biomed Mater Res B Appl Biomater 2019; 108:555-567. [PMID: 31081996 DOI: 10.1002/jbm.b.34411] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2018] [Revised: 03/17/2019] [Accepted: 04/25/2019] [Indexed: 01/21/2023]
Abstract
Application of hydrogels can be an effective technique in transferring the adipose-derived stem cells (ASCs) to injured tissue and their protection from further complications. Besides, acellular dermal matrix (ADM) has successfully been used in treatment of wounds. In this study, a combination of hylauronic acid (HA) and ASCs (HA/ASCs) was applied on burn wounds and the injured area was then covered by an ADM dressing in a rat model (ADM-HA/ASCs). Wound healing was evaluated by histopathological, histomorphometrical, molecular, biochemical, and scanning electron microscopy assessments on days 7, 14, and 28 post-wounding. ADM-HA/ASCs stimulated healing significantly more than the ADM-HA and ADM treated wounds, as it led to reduced inflammation, and improved angiogenesis and enhanced granulation tissue formation. Expression of interleukin-1β (IL-1β) and transforming growth factor-β1 (TGF-β1) was lower in the ADM-HA/ASCs treated wounds than the ADM-HA and ADM groups, at the seventh post-wounding day. ADM-HA/ASCs also enhanced the expression level of TGF-β1 mRNA at 14 day post-wounding that was parallel to the experimental data from histological and biochemical assessments and confirmed the positive role of ASCs in repair of burn wounds. Additionally, increase in basic fibroblast growth factor (bFGF) expression and decreased TGF-β1 level on the 28th post-wounding day indicated the anti-scarring activity of ASCs. HA loaded by adipose stem cells can represent a promising strategy in accelerating burn wound healing.
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Affiliation(s)
- Esmat Alemzadeh
- Department of Biotechnology, School of Veterinary Medicine, Shiraz University, Shiraz, Iran
| | - Ahmad Oryan
- Department of Pathology, School of Veterinary Medicine, Shiraz University, Shiraz, Iran
| | - Ali A Mohammadi
- Burn and Wound Healing Research Center, Plastic and Reconstructive Ward, Shiraz University of Medical Sciences, Shiraz, Iran
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25
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Euler T, Valesky EM, Meissner M, Hrgovic I, Kaufmann R, Kippenberger S, Zöller NN. Normal and keloid fibroblasts are differentially influenced by IFN-γ and triamcinolone as well as by their combination. Wound Repair Regen 2019; 27:450-461. [PMID: 30994217 DOI: 10.1111/wrr.12722] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Revised: 04/12/2019] [Accepted: 04/15/2019] [Indexed: 12/14/2022]
Abstract
Impaired wound healing as well as imbalanced cell proliferation and extracellular matrix synthesis and degeneration can cause aberrant scarring. The most severe impacts of such scarring on patients' lives are stigmatization and physical restriction. Although, a broad variety of combinatorial approaches with, e.g., glucocorticoids, chemotherapeutics, and immunomodulators are used, there is still a high recurrence rate of keloids. The aim of this study was to investigate which influence interferon γ (IFN-γ, 1.000-10.000 IU/mL) and/or triamcinolone acetonide (TA, 1 μg/mL) have on proliferation, cell viability, collagen type I synthesis, and cytokine secretion in healthy and keloid fibroblasts. It was shown that mono-treatment with IFN-γ or TA for 2 days induced a severe reduction of the proliferative potential in both cell species. The combinatory treatment (IFN-γ plus TA) of keloid fibroblasts enhanced the anti-proliferative effect of the mono-treatments, whereas no additional anti-proliferative effect was observed in normal fibroblasts. Furthermore, we observed that the combinatory treatment regimen reduced the expression of α-smooth muscle actin (α-SMA), an actin isotype contributing to cell-generated mechanical tension, in keloid fibroblasts. In normal fibroblasts, α-SMA was reduced by the mono-treatment with IFN-γ as well as by the combinatory treatment. The analysis of collagen-type I synthesis revealed that TA did not reduce collagen type I synthesis in normal fibroblasts but in keloid fibroblasts. IFN-γ reduced in both cell species the collagen type I synthesis. The combination of TA and IFN-γ intensified the previously observed collagen type I synthesis reduction in keloid fibroblasts. The herein presented data suggest the combinatory application of IFN-γ and TA as a promising therapy concept for keloids.
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Affiliation(s)
- Teresa Euler
- Frankfurt/Main, Department of Dermatology, Venereology and Allergology, University Hospital Frankfurt, Goethe University, Germany
| | - Eva M Valesky
- Frankfurt/Main, Department of Dermatology, Venereology and Allergology, University Hospital Frankfurt, Goethe University, Germany
| | - Markus Meissner
- Frankfurt/Main, Department of Dermatology, Venereology and Allergology, University Hospital Frankfurt, Goethe University, Germany
| | - Igor Hrgovic
- Frankfurt/Main, Department of Dermatology, Venereology and Allergology, University Hospital Frankfurt, Goethe University, Germany
| | - Roland Kaufmann
- Frankfurt/Main, Department of Dermatology, Venereology and Allergology, University Hospital Frankfurt, Goethe University, Germany
| | - Stefan Kippenberger
- Frankfurt/Main, Department of Dermatology, Venereology and Allergology, University Hospital Frankfurt, Goethe University, Germany
| | - Nadja N Zöller
- Frankfurt/Main, Department of Dermatology, Venereology and Allergology, University Hospital Frankfurt, Goethe University, Germany
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26
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Zhao C, Dai L, Wang J, Jian Y, Mei Z, Pei X, Xiong X, Yuan W, Wu F. Beneficial Effects of Lipoic Acid on Post-burn Hypertrophic
Scarring Model. INT J PHARMACOL 2018. [DOI: 10.3923/ijp.2018.733.739] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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27
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Piperigkou Z, Götte M, Theocharis AD, Karamanos NK. Insights into the key roles of epigenetics in matrix macromolecules-associated wound healing. Adv Drug Deliv Rev 2018; 129:16-36. [PMID: 29079535 DOI: 10.1016/j.addr.2017.10.008] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 10/14/2017] [Accepted: 10/20/2017] [Indexed: 02/08/2023]
Abstract
Extracellular matrix (ECM) is a dynamic network of macromolecules, playing a regulatory role in cell functions, tissue regeneration and remodeling. Wound healing is a tissue repair process necessary for the maintenance of the functionality of tissues and organs. This highly orchestrated process is divided into four temporally overlapping phases, including hemostasis, inflammation, proliferation and tissue remodeling. The dynamic interplay between ECM and resident cells exerts its critical role in many aspects of wound healing, including cell proliferation, migration, differentiation, survival, matrix degradation and biosynthesis. Several epigenetic regulatory factors, such as the endogenous non-coding microRNAs (miRNAs), are the drivers of the wound healing response. microRNAs have pivotal roles in regulating ECM composition during wound healing and dermal regeneration. Their expression is associated with the distinct phases of wound healing and they serve as target biomarkers and targets for systematic regulation of wound repair. In this article we critically present the importance of epigenetics with particular emphasis on miRNAs regulating ECM components (i.e. glycoproteins, proteoglycans and matrix proteases) that are key players in wound healing. The clinical relevance of miRNA targeting as well as the delivery strategies designed for clinical applications are also presented and discussed.
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Chawla S, Ghosh S. Regulation of fibrotic changes by the synergistic effects of cytokines, dimensionality and matrix: Towards the development of an in vitro human dermal hypertrophic scar model. Acta Biomater 2018; 69:131-145. [PMID: 29330036 DOI: 10.1016/j.actbio.2018.01.002] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Revised: 12/23/2017] [Accepted: 01/06/2018] [Indexed: 02/08/2023]
Abstract
Current therapeutic strategies to reduce scarring in full thickness skin defect offer limited success due to poor understanding of scar tissue formation and the underlying signaling pathways. There is an urgent need to develop human cell based in vitro scar tissue models as animal testing is associated with ethical and logistic complications and inter-species variations. Pro-inflammatory cytokines play critical role in regulating scar development through complex interplay and interaction with the ECM and corresponding signaling pathways. In this context, we assessed the responses of cultured fibroblasts with respect to their differentiation into myofibroblasts using optimised cytokines (TGF-β1, IL-6 and IL-8) for scar formation in 2D (tissue culture plate, collagen type I coated plate) vs 3D collagen type I gel based constructs. We attempted to deduce the role of dimensionality of cell culture matrix in modulating differentiation, function and phenotype of cultured fibroblasts. Validation of the developed model showed similarity to etiology and pathophysiology of in vivo hypertrophic scar with respect to several features: 1) transition of fibroblasts to myofibroblasts with convincing expression of α-SMA stress fibers; 2) contraction; 3) excessive collagen and fibronectin secretion; 4) expression of fibrotic ECM proteins (SPARC and Tenascin); 5) low MMP secretion. Most importantly, we elucidated the involvement of TGF-β/SMAD and Wnt/β-catenin pathways in developing in vitro dermal scar. Hence, this relatively simple in vitro human scar tissue equivalent may serve as an alternative for testing and designing of novel therapeutics and help in extending our understanding of the complex interplay of cytokines and related dermal scar specific signaling. STATEMENT OF SIGNIFICANCE Scarring of the skin affects almost millions of people per year in the developed world alone, nevertheless the complex pathophysiology and the precise signaling mechanisms responsible for this phenomenon of skin scarring are still unknown. A number of anti-scar drugs are being developed and being tested on animals and monolayer models. However, testing the efficacy of these drugs on lab based 3D in vitro models may prove extremely useful in recapitulating the 3D microenvironment of the native scar tissue. In that context in this study we have demonstrated the development of 3D in vitro dermal scar model, by optimizing a constellation of factors, such as combination of cytokines (TGF-β1,IL-6,IL-8) and cellular dimensionality in inducing the differentiation of dermal fibroblasts to myofibroblasts. This in vitro scar model was successful in replicating hallmark features of hypertrophic scar such as excessive synthesis of fibrotic extracellular matrix, perturbed matrix homeostasis, contraction, diminished MMP synthesis. The study also highlighted significant involvement of TGF-β/SMAD and Wnt/β-catenin signaling pathways in in vitro scar formation.
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Erickson JR, Echeverri K. Learning from regeneration research organisms: The circuitous road to scar free wound healing. Dev Biol 2018; 433:144-154. [PMID: 29179946 PMCID: PMC5914521 DOI: 10.1016/j.ydbio.2017.09.025] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Revised: 09/15/2017] [Accepted: 09/18/2017] [Indexed: 11/29/2022]
Abstract
The skin is the largest organ in the body and plays multiple essential roles ranging from regulating temperature, preventing infection and ultimately defining who we are physically. It is a highly dynamic organ that constantly replaces the outermost cells throughout life. However, when faced with a major injury, human skin cannot restore a significant lesion to its original functionality, instead a reparative scar is formed. In contrast to this, many other species have the unique ability to regenerate full thickness skin without formation of scar tissue. Here we review recent advances in the field that shed light on how the skin cells in regenerative species react to injury to prevent scar formation versus scar forming humans.
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Affiliation(s)
- Jami R Erickson
- Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, USA
| | - Karen Echeverri
- Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, USA.
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Mohd Nafi SN, Idris F, Jaafar H. Cellular and Molecular Changes in MNU-Induced Breast Tumours Injected with PF4 or bFGF. Asian Pac J Cancer Prev 2017; 18:3231-3238. [PMID: 29281877 PMCID: PMC5980876 DOI: 10.22034/apjcp.2017.18.12.3231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Background: Angiogenic activity has been considered to reflect important molecular events during breast tumour
development. The present study concerned cellular and molecular changes of MNU-induced breast tumours subjected
to promotion and suppression of angiogenesis. Methods: Female Sprague Dawley rats at the age of 21 days received
MNU at the dose 70 mg/kg of body weight by intraperitoneal injection. Three months post-carcinogen initiation,
mammary tumours were palpated and their growth was monitored. When the tumour diameter reached 1.0 ± 0.05 cm,
rats were given bFGF or PF4 intratumourally at a dose of 10 μg/tumour. Entire palpable tumour were subsequently
excised and subjected to histology examination, IHC staining, and RT-PCR. Results: No critical morphological changes
were observed between pro-angiogenic factor, bFGF, and control groups. However, increase of tumour size with more
necrotic and diffuse areas was notable in tumours after anti-angiogenic PF4 intervention. ER and PR mRNA expression
was significantly up- and down-regulated in bFGF and PF4 groups, respectively. The trends were significantly associated
with peri- and intratumoural MVD counts. However, irrespective of whether we promoted or inhibited angiogenesis,
the expression of EGFR and ERBB2 continued to be significantly increased but this was not significantly associated
with the MVD score. No significant differences in E-cadherin and LR gene expression were noted between intervention
and control groups. Conclusion: ER and PR receptor expression shows consistent responses when tumour angiogenesis
is manipulated either positively or negatively. Our study adds to current understanding that not only do we need to
target hormonal receptors, as presently practiced, but we also need to target endothelial receptors to successfully treat
breast cancer.
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Affiliation(s)
- Siti Norasikin Mohd Nafi
- Department of Pathology, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, 16150 Kota Bharu, Kelantan, Malaysia.
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31
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Preparation and in vitro evaluation of FGF-2 incorporated carboxymethyl chitosan nanoparticles. Carbohydr Polym 2017; 173:114-120. [DOI: 10.1016/j.carbpol.2017.05.080] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Revised: 05/01/2017] [Accepted: 05/24/2017] [Indexed: 01/09/2023]
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Fukata M, Arita T, Kadota H, Odashiro K, Maruyama T, Akashi K. Successful management of wound dehiscence after implantation of a subcutaneous implantable cardioverter-defibrillator without device removal. HeartRhythm Case Rep 2017; 3:415-417. [PMID: 28948145 PMCID: PMC5601323 DOI: 10.1016/j.hrcr.2017.06.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
- Mitsuhiro Fukata
- Department of Hematology, Oncology and Cardiovascular Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Takeshi Arita
- Department of Hematology, Oncology and Cardiovascular Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Hideki Kadota
- Department of Plastic and Reconstructive Surgery, Kyushu University Hospital, Fukuoka, Japan
| | - Keita Odashiro
- Department of Hematology, Oncology and Cardiovascular Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Toru Maruyama
- Faculty of Art and Science, Kyushu University, Fukuoka, Japan
| | - Koichi Akashi
- Department of Hematology, Oncology and Cardiovascular Medicine, Kyushu University Hospital, Fukuoka, Japan
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Dolivo DM, Larson SA, Dominko T. Fibroblast Growth Factor 2 as an Antifibrotic: Antagonism of Myofibroblast Differentiation and Suppression of Pro-Fibrotic Gene Expression. Cytokine Growth Factor Rev 2017; 38:49-58. [PMID: 28967471 DOI: 10.1016/j.cytogfr.2017.09.003] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2017] [Accepted: 09/22/2017] [Indexed: 02/08/2023]
Abstract
Fibrosis is a pathological condition that is characterized by the replacement of dead or damaged tissue with a nonfunctional, mechanically aberrant scar, and fibrotic pathologies account for nearly half of all deaths worldwide. The causes of fibrosis differ somewhat from tissue to tissue and pathology to pathology, but in general some of the cellular and molecular mechanisms remain constant regardless of the specific pathology in question. One of the common mechanisms underlying fibroses is the paradigm of the activated fibroblast, termed the "myofibroblast," a differentiated mesenchymal cell with demonstrated contractile activity and a high rate of collagen deposition. Fibroblast growth factor 2 (FGF2), one of the members of the mammalian fibroblast growth factor family, is a cytokine with demonstrated antifibrotic activity in non-human animal, human, and in vitro models. FGF2 is highly pleiotropic and its receptors are present on many different cell types throughout the body, lending a great deal of variety to the potential mechanisms of FGF2 effects on fibrosis. However, recent reports demonstrate that a substantial contribution to the antifibrotic effects of FGF2 comes from the inhibitory effects of FGF2 on connective tissue fibroblasts, activated myofibroblasts, and myofibroblast progenitors. FGF2 demonstrates effects antagonistic towards fibroblast activation and towards mesenchymal transition of potential myofibroblast-forming cells, as well as promotes a gene expression paradigm more reminiscent of regenerative healing, such as that which occurs in the fetal wound healing response, than fibrotic resolution. With a better understanding of the mechanisms by which FGF2 alters the wound healing cascade and results in a shift away from scar formation and towards functional tissue regeneration, we may be able to further address the critical need of therapy for varied fibrotic pathologies across myriad tissue types.
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Affiliation(s)
- David M Dolivo
- Worcester Polytechnic Institute, Department of Biology and Biotechnology,100 Institute Road, Worcester, MA, 01609, United States
| | - Sara A Larson
- Worcester Polytechnic Institute, Department of Biology and Biotechnology,100 Institute Road, Worcester, MA, 01609, United States
| | - Tanja Dominko
- Worcester Polytechnic Institute, Department of Biology and Biotechnology,100 Institute Road, Worcester, MA, 01609, United States.
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Dolivo DM, Larson SA, Dominko T. FGF2-mediated attenuation of myofibroblast activation is modulated by distinct MAPK signaling pathways in human dermal fibroblasts. J Dermatol Sci 2017; 88:339-348. [PMID: 28899582 DOI: 10.1016/j.jdermsci.2017.08.013] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Revised: 08/18/2017] [Accepted: 08/25/2017] [Indexed: 12/21/2022]
Abstract
BACKGROUND Previous human and animal studies have demonstrated the ability of exogenously administered basic fibroblast growth factor (FGF2) to act as an antifibrotic agent in the skin. Though the activity of FGF2 as an anti-scarring agent is well-established for fibrotic skin wounds, the mechanisms by which FGF2 exerts these actions are not entirely understood. Canonical FGF2 signaling proceeds in part via FGFR/MAPK pathways in human dermal fibroblasts, and FGF2 has been described to prevent or reverse the fibroblast-to-myofibroblast transition, which is driven by TGFβ signaling and understood to be an important step in the formation of a fibrotic scar in vivo. Thus, we set out to investigate the antagonistic effects of FGF2 on TGFβ signaling as well as the broader effects of MAPK inhibition on the TGFβ-mediated induction of myofibroblast gene expression. OBJECTIVE To better understand the effects of FGF2 signaling pathways on myofibroblastic gene expression and cell phenotypes. METHODS Human dermal fibroblasts were cultured in vitro in the presence of FGF2, TGFβ, and/or MAPK inhibitors, and the effects of these agents were investigated by molecular biology techniques including qRT-PCR, immunofluorescence, Western blot, and flow cytometry. RESULTS FGF2 inhibited TGFβ-mediated fibroblast activation, resulting in more rapidly proliferating, spindle-shaped cells, compared to the more slowly proliferating, flatter TGFβ-treated cells. Treatment with FGF2 also attenuated TGFβ-mediated increase in expression of myofibroblast markers smooth muscle α-actin, calponin, transgelin, connective tissue growth factor, ED-A fibronectin, and collagen I. FGF2-mediated antagonism of the TGFβ-mediated fibroblast-to-myofibroblast transition was reversed by small molecule inhibition of ERK or JNK, and it was potentiated by inhibition of p38. MAPK inhibition was demonstrated to have qualitatively similar effects even in the absence of exogenous FGF2, and small molecule inhibition of p38 MAPK was sufficient to attenuate TGFβ-mediated fibroblast activation. CONCLUSIONS Inhibition of select MAPK signaling pathways can reverse or potentiate anti-fibrotic FGF2 effects on human dermal fibroblasts, as well as exert their effects independently of exogenous FGF2 supplementation.
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Affiliation(s)
- David M Dolivo
- Worcester Polytechnic Institute, Department of Biology and Biotechnology, 100 Institute Road, Worcester, MA, 01609, United States
| | - Sara A Larson
- Worcester Polytechnic Institute, Department of Biology and Biotechnology, 100 Institute Road, Worcester, MA, 01609, United States
| | - Tanja Dominko
- Worcester Polytechnic Institute, Department of Biology and Biotechnology, 100 Institute Road, Worcester, MA, 01609, United States.
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Role of Daptomycin on Burn Wound Healing in an Animal Methicillin-Resistant Staphylococcus aureus Infection Model. Antimicrob Agents Chemother 2017; 61:AAC.00606-17. [PMID: 28696234 DOI: 10.1128/aac.00606-17] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Accepted: 07/02/2017] [Indexed: 12/19/2022] Open
Abstract
Prolonged hospitalization and antibiotic therapy are risk factors for the development of methicillin-resistant Staphylococcus aureus (MRSA) infections in thermal burn patients. We used a rat model to study the in vivo efficacy of daptomycin in the treatment of burn wound infections by S. aureus, and we evaluated the wound healing process through morphological and immunohistochemical analysis. A copper bar heated in boiling water was applied on a paraspinal site of each rat, resulting in two full-thickness burns. A small gauze was placed over each burn and inoculated with 5 × 107 CFU of S. aureus ATCC 43300. The study included two uninfected control groups with and without daptomycin treatment, an infected control group that did not receive any treatment, and two infected groups treated, respectively, with intraperitoneal daptomycin and teicoplanin. The main outcome measures were quantitative culture, histological evaluation of tissue repair, and immunohistochemical expression of wound healing markers: epidermal growth factor receptor (EGFR) and fibroblast growth factor 2 (FGF-2). The highest inhibition of infection was achieved in the group that received daptomycin, which reduced the bacterial load from 107 CFU/ml to about 103 CFU/g (P < 0.01). The groups treated with daptomycin showed better overall healing with epithelialization and significantly higher collagen scores than the other groups, and these findings were also confirmed by immunohistochemical data. In conclusion, our results support the hypothesis that daptomycin is an important modulator of wound repair by possibly reducing hypertrophic burn scar formation.
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Rengasamy M, Singh G, Fakharuzi NA, Siddikuzzaman, Balasubramanian S, Swamynathan P, Thej C, Sasidharan G, Gupta PK, Das AK, Rahman AZA, Fakiruddin KS, Nian LM, Zakaria Z, Majumdar AS. Transplantation of human bone marrow mesenchymal stromal cells reduces liver fibrosis more effectively than Wharton's jelly mesenchymal stromal cells. Stem Cell Res Ther 2017; 8:143. [PMID: 28610623 PMCID: PMC5470281 DOI: 10.1186/s13287-017-0595-1] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Revised: 03/23/2017] [Accepted: 05/22/2017] [Indexed: 12/17/2022] Open
Abstract
Background Mesenchymal stromal cells (MSCs) from various tissues have shown moderate therapeutic efficacy in reversing liver fibrosis in preclinical models. Here, we compared the relative therapeutic potential of pooled, adult human bone marrow (BM)- and neonatal Wharton’s jelly (WJ)-derived MSCs to treat CCl4-induced liver fibrosis in rats. Methods Sprague-Dawley rats were injected with CCl4 for 8 weeks to induce irreversible liver fibrosis. Ex-vivo expanded, pooled human MSCs obtained from BM and WJ were intravenously administered into rats with liver fibrosis at a dose of 10 × 106 cells/animal. Sham control and vehicle-treated animals served as negative and disease controls, respectively. The animals were sacrificed at 30 and 70 days after cell transplantation and hepatic-hydroxyproline content, histopathological, and immunohistochemical analyses were performed. Results BM-MSCs treatment showed a marked reduction in liver fibrosis as determined by Masson’s trichrome and Sirius red staining as compared to those treated with the vehicle. Furthermore, hepatic-hydroxyproline content and percentage collagen proportionate area were found to be significantly lower in the BM-MSCs-treated group. In contrast, WJ-MSCs treatment showed less reduction of fibrosis at both time points. Immunohistochemical analysis of BM-MSCs-treated liver samples showed a reduction in α-SMA+ myofibroblasts and increased number of EpCAM+ hepatic progenitor cells, along with Ki-67+ and human matrix metalloprotease-1+ (MMP-1+) cells as compared to WJ-MSCs-treated rat livers. Conclusions Our findings suggest that BM-MSCs are more effective than WJ-MSCs in treating liver fibrosis in a CCl4-induced model in rats. The superior therapeutic activity of BM-MSCs may be attributed to their expression of certain MMPs and angiogenic factors.
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Affiliation(s)
- Mathiyazhagan Rengasamy
- Stempeutics Research Pvt Ltd, Akshay Tech Park, EPIP Zone, Phase-1, Whitefield, Bangalore, 560066, Karnataka, India
| | - Gurbind Singh
- Stempeutics Research Pvt Ltd, Akshay Tech Park, EPIP Zone, Phase-1, Whitefield, Bangalore, 560066, Karnataka, India.,Department of Life Sciences, International Medical University, Bukit Jalil, 57000, Kuala Lumpur, Malaysia
| | - Noor Atiqah Fakharuzi
- Hematology Unit, Cancer Research Centre, Institute for Medical Research, Jalan Pahang, 50588, Kuala Lumpur, Malaysia
| | - Siddikuzzaman
- Stempeutics Research Pvt Ltd, Akshay Tech Park, EPIP Zone, Phase-1, Whitefield, Bangalore, 560066, Karnataka, India
| | - Sudha Balasubramanian
- Stempeutics Research Pvt Ltd, Akshay Tech Park, EPIP Zone, Phase-1, Whitefield, Bangalore, 560066, Karnataka, India
| | - Priyanka Swamynathan
- Stempeutics Research Pvt Ltd, Akshay Tech Park, EPIP Zone, Phase-1, Whitefield, Bangalore, 560066, Karnataka, India
| | - Charan Thej
- Stempeutics Research Pvt Ltd, Akshay Tech Park, EPIP Zone, Phase-1, Whitefield, Bangalore, 560066, Karnataka, India.,Manipal University, Manipal, Karnataka, India
| | - Gopinath Sasidharan
- Stempeutics Research Pvt Ltd, Akshay Tech Park, EPIP Zone, Phase-1, Whitefield, Bangalore, 560066, Karnataka, India
| | - Pawan Kumar Gupta
- Stempeutics Research Pvt Ltd, Akshay Tech Park, EPIP Zone, Phase-1, Whitefield, Bangalore, 560066, Karnataka, India
| | - Anjan Kumar Das
- Stempeutics Research Pvt Ltd, Akshay Tech Park, EPIP Zone, Phase-1, Whitefield, Bangalore, 560066, Karnataka, India.,Department of Surgery, Taylor's University School of Medicine, Selangor, Subang Jaya, Malaysia
| | - Ahmad Zuhairi Abd Rahman
- Hematology Unit, Cancer Research Centre, Institute for Medical Research, Jalan Pahang, 50588, Kuala Lumpur, Malaysia
| | - Kamal Shaik Fakiruddin
- Hematology Unit, Cancer Research Centre, Institute for Medical Research, Jalan Pahang, 50588, Kuala Lumpur, Malaysia
| | - Lim Moon Nian
- Hematology Unit, Cancer Research Centre, Institute for Medical Research, Jalan Pahang, 50588, Kuala Lumpur, Malaysia
| | - Zubaidah Zakaria
- Hematology Unit, Cancer Research Centre, Institute for Medical Research, Jalan Pahang, 50588, Kuala Lumpur, Malaysia
| | - Anish S Majumdar
- Stempeutics Research Pvt Ltd, Akshay Tech Park, EPIP Zone, Phase-1, Whitefield, Bangalore, 560066, Karnataka, India.
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Yanaga H, Udoh Y, Yamamoto M, Yoshii S, Mori S, Yamauchi T, Kiyokawa K, Koga M, Yanaga K. Cryopreserved cultured epithelial allografts for pediatric deep partial dermal burns: Early wound closure and suppression of scarring. Regen Ther 2017; 6:74-82. [PMID: 30271841 PMCID: PMC6134912 DOI: 10.1016/j.reth.2017.03.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Accepted: 03/10/2017] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND In deep partial thickness dermal burns (DDB) where greater than 50% of the dermis is lost, severe pain, scarring and contractures occur. Therefore, skin grafting may be required. In children, scar contracture occurs because scarred skin does not stretch with growth creating the need for additional scar-releasing or skin-grafting surgeries. In order to resolve this problem, we used cryopreserved cultured epithelial allograft (cryopreserved allo-CEG), which can be grafted shortly after sustaining a wound. We reevaluated the promotion of early wound closure of burns and suppression of scarring by this treatment. METHODS Cryopreserved allo-CEGs were used to treat 50 cases of pediatric DDB from 1992 to 2000. These cases were reviewed with regard to the time until epithelialization, take percentage, and pain level. Also, in order to examine why cryopreserved allo-CEG promotes healing of burns and suppresses scarring, growth factors and cytokines in the cryopreserved allo-CEG were measured. Cryopreserved allo-CEG sheets were solubilized and concentrations of TGF-α, TGF-β1, IL-1α, IL-1β, PDGF-AA, VEGF, KGF, IL-6, b-FGF, as well as metalloprotease-1 (MMP-1) and HGF, which are noted to have scarring suppression effects, were measured before grafting. RESULTS Grafting of cryopreserved allo-CEGs in 50 cases of childhood DDB resulted in early epithelialization (9.32 ± 3.63 days on the average) and an almost 100% take rate. Also, pain relief (pain reduction or elimination, reduced need for anesthetics) was seen in all cases. Although 15-23 years have now elapsed, adverse events have not been observed. Cryopreserved allo-CEG contains IL-1α, IL-1β, PDGF-AA, TGF-α, TGF-β1, VEGF, and IL-6 have wound healing effects. The concentration of IL-1α was higher than the concentrations of other components, and this was followed by TGF-α, TGF-β1, b-FGF and VEGF. Although the concentration of MMP-1, which has a scarring suppression effect, was high, HGF was not detected. CONCLUSION Cryopreserved allo-CEG contains growth factors that promote wound healing and factors that suppress scarring. Three effects, namely (1) early wound closure, (2) scarring suppression, and (3) pain relief were seen with grafts of cryopreserved allo-CEG in cases of childhood DDB. These observations show that cryopreserved allo-CEG is clinically useful and effective for the treatment of childhood DDB.
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Affiliation(s)
- Hiroko Yanaga
- Yanaga Clinic and Tissue Culture Laboratory, 1-2-12 Tenjin, Chuo-ku, Fukuoka 810-0001, Japan
| | - Yukihiro Udoh
- Kurume University, Department of Plastic and Reconstructive Surgery and Maxillofacial Surgery, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan
| | - Misa Yamamoto
- Yamaguchi University School of Medicine, Faculty of Health Sciences, 1-1-1 Minami-Ogushi, Ube, Yamaguchi 755-8505, Japan
| | - Satoko Yoshii
- Kurume University, Department of Plastic and Reconstructive Surgery and Maxillofacial Surgery, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan
| | - Seiichiro Mori
- Kurume University, Department of Plastic and Reconstructive Surgery and Maxillofacial Surgery, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan
| | - Toshihiko Yamauchi
- Kurume University, Department of Plastic and Reconstructive Surgery and Maxillofacial Surgery, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan
| | - Kensuke Kiyokawa
- Kurume University, Department of Plastic and Reconstructive Surgery and Maxillofacial Surgery, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan
| | - Mika Koga
- Yanaga Clinic and Tissue Culture Laboratory, 1-2-12 Tenjin, Chuo-ku, Fukuoka 810-0001, Japan
| | - Katsu Yanaga
- Yanaga Clinic and Tissue Culture Laboratory, 1-2-12 Tenjin, Chuo-ku, Fukuoka 810-0001, Japan
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Golberg A, Villiger M, Felix Broelsch G, Quinn KP, Albadawi H, Khan S, Watkins MT, Georgakoudi I, Austen WG, Bei M, Bouma BE, Mihm MC, Yarmush ML. Skin regeneration with all accessory organs following ablation with irreversible electroporation. J Tissue Eng Regen Med 2017; 12:98-113. [PMID: 27976527 DOI: 10.1002/term.2374] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Revised: 11/12/2016] [Accepted: 12/06/2016] [Indexed: 12/21/2022]
Abstract
Skin scar formation is a complex process that results in the formation of dense extracellular matrix (ECM) without normal skin appendages such as hair and glands. The absence of a scarless healing model in adult mammals prevents the development of successful therapies. We show that irreversible electroporation of skin drives its regeneration with all accessory organs in normal adult rats. Pulsed electric fields at 500 V, with 70 μs pulse duration and 1000 pulses delivered at 3 Hz, applied through two electrodes separated by 2 mm lead to massive cell death. However, the ECM architecture of the skin was preserved. Six months after the ablation, the epidermis, sebaceous glands, panniculus carnosus, hair follicles, microvasculature and arrector pili muscle were altogether re-formed in the entire ablated area. These results suggest a key role of the ECM architecture in the differentiation, migration and signalling of cells during scarless wound healing. Copyright © 2016 John Wiley & Sons, Ltd.
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Affiliation(s)
- Alexander Golberg
- Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, and the Shriners Burns Hospital, Boston, MA, 02114, USA.,Porter School of Environmental Studies, Tel Aviv University, Tel Aviv, Israel
| | - Martin Villiger
- Wellman Center for Photomedicine and Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, 50 Blossom Street, Boston, Massachusetts, 02114, USA
| | - G Felix Broelsch
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Kyle P Quinn
- Department of Biomedical Engineering, Tufts University, Medford, MA, 02155, USA.,Department of Biomedical Engineering, University of Arkansas, Fayetteville, AR, 72701, USA
| | - Hassan Albadawi
- Division of Vascular and Endovascular Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Saiqa Khan
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Michael T Watkins
- Division of Vascular and Endovascular Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Irene Georgakoudi
- Department of Biomedical Engineering, Tufts University, Medford, MA, 02155, USA
| | - William G Austen
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Marianna Bei
- Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, and the Shriners Burns Hospital, Boston, MA, 02114, USA
| | - Brett E Bouma
- Wellman Center for Photomedicine and Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, 50 Blossom Street, Boston, Massachusetts, 02114, USA.,Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Cambridge, Massachusetts, 02142, USA
| | - Martin C Mihm
- Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Martin L Yarmush
- Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, and the Shriners Burns Hospital, Boston, MA, 02114, USA.,Department of Biomedical Engineering, Rutgers University, Piscataway, NJ, 08854, USA
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39
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Xiao L, Dudley AC. Fine-tuning vascular fate during endothelial-mesenchymal transition. J Pathol 2017; 241:25-35. [PMID: 27701751 PMCID: PMC5164846 DOI: 10.1002/path.4814] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Revised: 09/09/2016] [Accepted: 09/26/2016] [Indexed: 12/22/2022]
Abstract
In the heart and other organs, endothelial-mesenchymal transition (EndMT) has emerged as an important developmental process that involves coordinated migration, differentiation, and proliferation of the endothelium. In multiple disease states including cancer angiogenesis and cardiovascular disease, the processes that regulate EndMT are recapitulated, albeit in an uncoordinated and dysregulated manner. Members of the transforming growth factor beta (TGFβ) superfamily are well known to impart cellular plasticity during EndMT by the timely activation (or repression) of transcription factors and miRNAs in addition to epigenetic regulation of gene expression. On the other hand, fibroblast growth factors (FGFs) are reported to augment or oppose TGFβ-driven EndMT in specific contexts. Here, we have synthesized the currently understood roles of TGFβ and FGF signalling during EndMT and have provided a new, comprehensive paradigm that delineates how an autocrine and paracrine TGFβ/FGF axis coordinates endothelial cell specification and plasticity. We also provide new guidelines and nomenclature that considers factors such as endothelial cell heterogeneity to better define EndMT across different vascular beds. This perspective should therefore help to clarify why TGFβ and FGF can both cooperate with or oppose one another during the complex process of EndMT in both health and disease. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Lin Xiao
- Department of Cell Biology & Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Andrew C. Dudley
- Department of Microbiology, Immunology, and Cancer Biology, The University of Virginia, Charlottesville, VA 22908, USA
- Emily Couric Cancer Center, The University of Virginia
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40
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Growth factor pathways in hypertrophic scars: Molecular pathogenesis and therapeutic implications. Biomed Pharmacother 2016; 84:42-50. [PMID: 27636511 DOI: 10.1016/j.biopha.2016.09.010] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2016] [Revised: 08/26/2016] [Accepted: 09/05/2016] [Indexed: 01/07/2023] Open
Abstract
Hypertrophic scars represent the most common complication of skin injury and are caused by excessive cutaneous wound healing characterized by hypervascularity and pathological deposition of extracellular matrix (ECM) components. To date, the optimal and specific treatment methods for hypertrophic scars have not been available in the clinic. Current paradigm has established fibroblasts and myofibroblasts as pivotal effector cells in the pathophysiology of wound healing. Their biological properties including origin, proliferation, migration, contraction and ECM regulation have profound impacts on the progression and regression of hypertrophic scars. These complex processes are executed and modulated by a signaling network involving a number of growth factors and cytokines. Of particular importance is transforming growth factor-β, platelet-derived growth factor, connective tissue growth factor, epidermal growth factor, and vascular endothelial growth factor. This review article briefly describes the biological functions of fibroblasts and myofibroblasts during hypertrophic scars, and thereafter examines the up-to-date molecular knowledge on the roles of key growth factor pathways in the pathophysiology of hypertrophic scars. Importantly, the therapeutic implications and future challenges of these molecular discoveries are critically discussed in the hope of advancing therapeutic approaches to limit pathological scar formation.
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41
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Carlsson AH, Rose LF, Fletcher JL, Wu JC, Leung KP, Chan RK. Antecedent thermal injury worsens split-thickness skin graft quality: A clinically relevant porcine model of full-thickness burn, excision and grafting. Burns 2016; 43:223-231. [PMID: 27600980 DOI: 10.1016/j.burns.2016.08.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Revised: 08/01/2016] [Accepted: 08/09/2016] [Indexed: 10/21/2022]
Abstract
Current standard of care for full-thickness burn is excision followed by autologous split-thickness skin graft placement. Skin grafts are also frequently used to cover surgical wounds not amenable to linear closure. While all grafts have potential to contract, clinical observation suggests that antecedent thermal injury worsens contraction and impairs functional and aesthetic outcomes. This study evaluates the impact of antecedent full-thickness burn on split-thickness skin graft scar outcomes and the potential mediating factors. Full-thickness contact burns (100°C, 30s) were created on the backs of anesthetized female Yorkshire Pigs. After seven days, burn eschar was tangentially excised and covered with 12/1000th inch (300μm) split-thickness skin graft. For comparison, unburned wounds were created by sharp excision to fat before graft application. From 7 to 120days post-grafting, planimetric measurements, digital imaging and biopsies for histology, immunohistochemistry and gene expression were obtained. At 120days post-grafting, the Observer Scar Assessment Scale, colorimetry, contour analysis and optical graft height assessments were performed. Twenty-nine porcine wounds were analyzed. All measured metrics of clinical skin quality were significantly worse (p<0.05) in burn injured wounds. Histological analysis supported objective clinical findings with marked scar-like collagen proliferation within the dermis, increased vascular density, and prolonged and increased cellular infiltration. Observed differences in contracture also correlated with earlier and more prominent myofibroblast differentiation as demonstrated by α-SMA staining. Antecedent thermal injury worsens split-thickness skin graft quality, likely by multiple mechanisms including burn-related inflammation, microscopically inadequate excision, and dysregulation of tissue remodeling. A valid, reliable, clinically relevant model of full-thickness burn, excision and skin replacement therapy has been demonstrated. Future research to enhance quality of skin replacement therapies should be directed toward modulation of inflammation and assessments for complete excision.
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Affiliation(s)
- Anders H Carlsson
- Q-SCARR™ (Quality Skin Collaborative for Advanced Reconstruction and Regeneration) Research Program, United States; Dental and Craniofacial Trauma Research and Tissue Regeneration, US Army Institute of Surgical Research, 3650 Chambers Pass, JBSA Fort Sam Houston, TX 78234, United States.
| | - Lloyd F Rose
- Q-SCARR™ (Quality Skin Collaborative for Advanced Reconstruction and Regeneration) Research Program, United States; Dental and Craniofacial Trauma Research and Tissue Regeneration, US Army Institute of Surgical Research, 3650 Chambers Pass, JBSA Fort Sam Houston, TX 78234, United States
| | - John L Fletcher
- Q-SCARR™ (Quality Skin Collaborative for Advanced Reconstruction and Regeneration) Research Program, United States; Dental and Craniofacial Trauma Research and Tissue Regeneration, US Army Institute of Surgical Research, 3650 Chambers Pass, JBSA Fort Sam Houston, TX 78234, United States; Clinical Division and Burn Center, US Army Institute of Surgical Research, 3650 Chambers Pass, JBSA Fort Sam Houston, TX 78234, United States
| | - Jesse C Wu
- Q-SCARR™ (Quality Skin Collaborative for Advanced Reconstruction and Regeneration) Research Program, United States; Dental and Craniofacial Trauma Research and Tissue Regeneration, US Army Institute of Surgical Research, 3650 Chambers Pass, JBSA Fort Sam Houston, TX 78234, United States
| | - Kai P Leung
- Dental and Craniofacial Trauma Research and Tissue Regeneration, US Army Institute of Surgical Research, 3650 Chambers Pass, JBSA Fort Sam Houston, TX 78234, United States
| | - Rodney K Chan
- Q-SCARR™ (Quality Skin Collaborative for Advanced Reconstruction and Regeneration) Research Program, United States; Dental and Craniofacial Trauma Research and Tissue Regeneration, US Army Institute of Surgical Research, 3650 Chambers Pass, JBSA Fort Sam Houston, TX 78234, United States; Clinical Division and Burn Center, US Army Institute of Surgical Research, 3650 Chambers Pass, JBSA Fort Sam Houston, TX 78234, United States
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42
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Mehta M, Branford OA, Rolfe KJ. The evidence for natural therapeutics as potential anti-scarring agents in burn-related scarring. BURNS & TRAUMA 2016; 4:15. [PMID: 27574685 PMCID: PMC4964041 DOI: 10.1186/s41038-016-0040-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Accepted: 04/12/2016] [Indexed: 02/07/2023]
Abstract
Though survival rate following severe thermal injuries has improved, the incidence and treatment of scarring have not improved at the same speed. This review discusses the formation of scars and in particular the formation of hypertrophic scars. Further, though there is as yet no gold standard treatment for the prevention or treatment of scarring, a brief overview is included. A number of natural therapeutics have shown beneficial effects both in vivo and in vitro with the potential of becoming clinical therapeutics in the future. These natural therapeutics include both plant-based products such as resveratrol, quercetin and epigallocatechin gallate as examples and includes the non-plant-based therapeutic honey. The review also includes potential mechanism of action for the therapeutics, any recorded adverse events and current administration of the therapeutics used. This review discusses a number of potential 'treatments' that may reduce or even prevent scarring particularly hypertrophic scarring, which is associated with thermal injuries without compromising wound repair.
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Affiliation(s)
- M. Mehta
- British College of Osteopathic Medicine (BCOM), Finchley Road, London, NW3 5HR UK
| | - O. A. Branford
- The Royal Marsden Hospital, Fulham Rd, London, SW3 6JJ UK
| | - K. J. Rolfe
- British College of Osteopathic Medicine (BCOM), Finchley Road, London, NW3 5HR UK
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43
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Lichtenberger BM, Mastrogiannaki M, Watt FM. Epidermal β-catenin activation remodels the dermis via paracrine signalling to distinct fibroblast lineages. Nat Commun 2016; 7:10537. [PMID: 26837596 PMCID: PMC4742837 DOI: 10.1038/ncomms10537] [Citation(s) in RCA: 90] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2015] [Accepted: 12/23/2015] [Indexed: 01/06/2023] Open
Abstract
Sustained epidermal Wnt/β-catenin signalling expands the stem cell compartment and induces ectopic hair follicles (EFs). This is accompanied by extensive fibroblast proliferation and extracellular matrix (ECM) remodelling in the underlying dermis. Here we show that epidermal Hedgehog (Hh) and Transforming growth factor-beta (TGF-β) signalling mediate the dermal changes. Pharmacological inhibition or genetic deletion of these pathways prevents β-catenin-induced dermal reprogramming and EF formation. Epidermal Shh stimulates proliferation of the papillary fibroblast lineage, whereas TGF-β2 controls proliferation, differentiation and ECM production by reticular fibroblasts. Hh inhibitors do not affect TGF-β target gene expression in reticular fibroblasts, and TGF-β inhibition does not prevent Hh target gene induction in papillary fibroblasts. However, when Hh signalling is inhibited the reticular dermis does not respond to epidermal β-catenin activation. We conclude that the dermal response to epidermal Wnt/β-catenin signalling depends on distinct fibroblast lineages responding to different paracrine signals. The molecular mechanisms regulating skin dermal changes are unclear. Here, the authors show that deletion of Hedgehog (Hh) in the upper dermis alters the response to epidermal Wnt signalling, which, together with changes in extracellular matrix production, influences distinct fibroblast lineages differently.
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Affiliation(s)
- Beate M Lichtenberger
- Centre for Stem Cells and Regenerative Medicine, King's College London, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.,Wellcome Trust Centre for Stem Cell Research, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK
| | - Maria Mastrogiannaki
- Centre for Stem Cells and Regenerative Medicine, King's College London, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK
| | - Fiona M Watt
- Centre for Stem Cells and Regenerative Medicine, King's College London, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK
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44
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Hu M, Hu Y, He J, Li B. Prognostic Value of Basic Fibroblast Growth Factor (bFGF) in Lung Cancer: A Systematic Review with Meta-Analysis. PLoS One 2016; 11:e0147374. [PMID: 26824699 PMCID: PMC4732945 DOI: 10.1371/journal.pone.0147374] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Accepted: 01/04/2016] [Indexed: 12/20/2022] Open
Abstract
Background Basic fibroblast growth factor (bFGF) is known to stimulate angiogenesis and thus to influence the proliferation, migration and survival of tumor cells. Many studies examined the relationship between human bFGF overexpression and survival in lung cancer patients, but the results have been mixed. To systematically summarize the clinical prognostic function of bFGF in lung cancer, we performed this systematic review with meta-analysis. Method Studies were identified by an electronic search of PubMed, EMBASE, China National Knowledge Infrastructure and Wanfang databases, including publications prior toAugust 2014. Pooled hazard ratios (HR) for overall survival (OS) were aggregated and quantitatively analyzed by meta-analysis. Results Twenty-two studies (n = 2154) were evaluated in the meta-analysis. Combined HR suggested that bFGF overexpression had an adverse impact on survival of patients with lung cancer(HR = 1.202,95%CI, 1.022–1.382). Our subgroup analysis revealed that the combined HR evaluating bFGF expression on OS in operable non-small cell lung cancer (NSCLC) was 1.553 (95%CI, 1.120–1.986); the combined HR in small cell lung cancer (SCLC) was 1.667 (95%CI, 1.035–2.299). There was no significant impact of bFGF expression on survival in advanced NSCLC. Conclusion This meta-analysis showed that bFGF overexpression is a potential indicator of worse prognosis for patients with operable NSCLC and SCLC, but is not associated with outcome in advanced NSCLC. The data suggests that high bFGF expression is highly related to poor prognosis. Nevertheless,more high-quality studies should be performed in order to provide additional evidence for the prognostic value of bFGF in lung cancer.
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Affiliation(s)
- Mingming Hu
- Department of General Medicine, Beijing Tuberculosis and Thoracic tumor research Institute/ Beijing Chest Hospital, Capital Medical University, Beijing, 101149, China
| | - Ying Hu
- Department of General Medicine, Beijing Tuberculosis and Thoracic tumor research Institute/ Beijing Chest Hospital, Capital Medical University, Beijing, 101149, China
| | - Jiabei He
- Department of General Medicine, Beijing Tuberculosis and Thoracic tumor research Institute/ Beijing Chest Hospital, Capital Medical University, Beijing, 101149, China
| | - Baolan Li
- Department of General Medicine, Beijing Tuberculosis and Thoracic tumor research Institute/ Beijing Chest Hospital, Capital Medical University, Beijing, 101149, China
- * E-mail:
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45
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Zhu Z, Ding J, Tredget EE. The molecular basis of hypertrophic scars. BURNS & TRAUMA 2016; 4:2. [PMID: 27574672 PMCID: PMC4963951 DOI: 10.1186/s41038-015-0026-4] [Citation(s) in RCA: 78] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Accepted: 12/30/2015] [Indexed: 02/05/2023]
Abstract
Hypertrophic scars (HTS) are caused by dermal injuries such as trauma and burns to the deep dermis, which are red, raised, itchy and painful. They can cause cosmetic disfigurement or contractures if craniofacial areas or mobile region of the skin are affected. Abnormal wound healing with more extracellular matrix deposition than degradation will result in HTS formation. This review will introduce the physiology of wound healing, dermal HTS formation, treatment and difference with keloids in the skin, and it also review the current advance of molecular basis of HTS including the involvement of cytokines, growth factors, and macrophages via chemokine pathway, to bring insights for future prevention and treatment of HTS.
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Affiliation(s)
- Zhensen Zhu
- Wound Healing Research Group, Division of Plastic and Reconstructive Surgery, University of Alberta, Edmonton, Alberta Canada
- Department of Burn and Reconstructive Surgery, 2nd Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong China
| | - Jie Ding
- Wound Healing Research Group, Division of Plastic and Reconstructive Surgery, University of Alberta, Edmonton, Alberta Canada
| | - Edward E. Tredget
- Wound Healing Research Group, Division of Plastic and Reconstructive Surgery, University of Alberta, Edmonton, Alberta Canada
- Division of Plastic Surgery, Department of Surgery, University of Alberta, Edmonton, Alberta Canada
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46
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Sideek MA, Teia A, Kopecki Z, Cowin AJ, Gibson MA. Co-localization of LTBP-2 with FGF-2 in fibrotic human keloid and hypertrophic scar. J Mol Histol 2015; 47:35-45. [PMID: 26644005 DOI: 10.1007/s10735-015-9645-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Accepted: 11/25/2015] [Indexed: 02/06/2023]
Abstract
We have recently shown that Latent transforming growth factor-beta-1 binding protein-2 (LTBP-2) has a single high-affinity binding site for fibroblast growth factor-2 (FGF-2) and that LTBP-2 blocks FGF-2 induced cell proliferation. Both proteins showed strong co-localisation within keloid skin from a single patient. In the current study, using confocal microscopy, we have investigated the distribution of the two proteins in normal and fibrotic skin samples including normal scar tissue, hypertrophic scars and keloids from multiple patients. Consistently, little staining for either protein was detected in normal adult skin and normal scar samples but extensive co-localisation of the two proteins was observed in multiple examples of hypertrophic scars and keloids. LTBP-2 and FGF-2 were co-localised to fine fibrous elements within the extracellular matrix identified as elastic fibres by immunostaining with anti-fibrillin-1 and anti-elastin antibodies. Furthermore, qPCR analysis of RNA samples from multiple patients confirmed dramatically increased expression of LTBP-2 and FGF-2, similar TGF-beta 1, in hypertrophic scar compared to normal skin and scar tissue. Overall the results suggest that elevated LTBP-2 may bind and sequester FGF-2 on elastic fibres in fibrotic tissues and modulate FGF-2's influence on the repair and healing processes.
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Affiliation(s)
- Mohamed A Sideek
- Discipline of Anatomy and Pathology, School of Medicine, University of Adelaide, Adelaide, SA, 5005, Australia.,Department of Biomedical Sciences, Kulliyyah of Allied Health Sciences, International Islamic University Malaysia, 25200, Kuantan, Pahang, Malaysia
| | - Abdulrahman Teia
- Discipline of Anatomy and Pathology, School of Medicine, University of Adelaide, Adelaide, SA, 5005, Australia
| | - Zlatko Kopecki
- Regenerative Medicine, Mawson Institute, University of South Australia, Adelaide, SA, 5095, Australia
| | - Allison J Cowin
- Regenerative Medicine, Mawson Institute, University of South Australia, Adelaide, SA, 5095, Australia
| | - Mark A Gibson
- Discipline of Anatomy and Pathology, School of Medicine, University of Adelaide, Adelaide, SA, 5005, Australia.
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47
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DePaul MA, Lin CY, Silver J, Lee YS. Peripheral Nerve Transplantation Combined with Acidic Fibroblast Growth Factor and Chondroitinase Induces Regeneration and Improves Urinary Function in Complete Spinal Cord Transected Adult Mice. PLoS One 2015; 10:e0139335. [PMID: 26426529 PMCID: PMC4591338 DOI: 10.1371/journal.pone.0139335] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2015] [Accepted: 09/11/2015] [Indexed: 01/08/2023] Open
Abstract
The loss of lower urinary tract (LUT) control is a ubiquitous consequence of a complete spinal cord injury, attributed to a lack of regeneration of supraspinal pathways controlling the bladder. Previous work in our lab has utilized a combinatorial therapy of peripheral nerve autografts (PNG), acidic fibroblast growth factor (aFGF), and chondroitinase ABC (ChABC) to treat a complete T8 spinal cord transection in the adult rat, resulting in supraspinal control of bladder function. In the present study we extended these findings by examining the use of the combinatorial PNG+aFGF+ChABC treatment in a T8 transected mouse model, which more closely models human urinary deficits following spinal cord injury. Cystometry analysis and external urethral sphincter electromyograms reveal that treatment with PNG+aFGF+ChABC reduced bladder weight, improved bladder and external urethral sphincter histology, and significantly enhanced LUT function, resulting in more efficient voiding. Treated mice's injured spinal cord also showed a reduction in collagen scaring, and regeneration of serotonergic and tyrosine hydroxylase-positive axons across the lesion and into the distal spinal cord. Regeneration of serotonin axons correlated with LUT recovery. These results suggest that our mouse model of LUT dysfunction recapitulates the results found in the rat model and may be used to further investigate genetic contributions to regeneration failure.
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Affiliation(s)
- Marc A. DePaul
- Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Ching-Yi Lin
- Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
| | - Jerry Silver
- Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Yu-Shang Lee
- Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
- * E-mail:
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48
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LTBP-2 Has a Single High-Affinity Binding Site for FGF-2 and Blocks FGF-2-Induced Cell Proliferation. PLoS One 2015; 10:e0135577. [PMID: 26263555 PMCID: PMC4532469 DOI: 10.1371/journal.pone.0135577] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2014] [Accepted: 07/24/2015] [Indexed: 12/18/2022] Open
Abstract
Latent transforming growth factor-beta-1 binding protein-2 (LTBP-2) belongs to the fibrillin-LTBP superfamily of extracellular matrix proteins. LTBPs and fibrillins are involved in the sequestration and storage of latent growth factors, particularly transforming growth factor β (TGF-β), in tissues. Unlike other LTBPs, LTBP-2 does not covalently bind TGF-β, and its molecular functions remain unclear. We are screening LTBP-2 for binding to other growth factors and have found very strong saturable binding to fibroblast growth factor-2 (FGF-2) (Kd = 1.1 nM). Using a series of recombinant LTBP-2 fragments a single binding site for FGF-2 was identified in a central region of LTBP-2 consisting of six tandem epidermal growth factor-like (EGF-like) motifs (EGFs 9–14). This region was also shown to contain a heparin/heparan sulphate-binding site. FGF-2 stimulation of fibroblast proliferation was completely negated by the addition of 5-fold molar excess of LTBP-2 to the assay. Confocal microscopy showed strong co-localisation of LTBP-2 and FGF-2 in fibrotic keloid tissue suggesting that the two proteins may interact in vivo. Overall the study indicates that LTBP-2 is a potent inhibitor of FGF-2 that may influence FGF-2 bioactivity during wound repair particularly in fibrotic tissues.
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49
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Lee DE, Trowbridge RM, Ayoub NT, Agrawal DK. High-mobility Group Box Protein-1, Matrix Metalloproteinases, and Vitamin D in Keloids and Hypertrophic Scars. PLASTIC AND RECONSTRUCTIVE SURGERY-GLOBAL OPEN 2015; 3:e425. [PMID: 26180726 PMCID: PMC4494495 DOI: 10.1097/gox.0000000000000391] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Accepted: 04/23/2015] [Indexed: 01/16/2023]
Abstract
Keloids and hypertrophic scars represent excessive wound healing involving high production of collagen by skin fibroblasts. This review focuses on the role of high-mobility group box protein-1 (HMGB-1), matrix metalloproteinases (MMPs), and vitamin D in these conditions. Although the role of HMGB-1 in keloids and hypertrophic scars is unclear, the effect of HMGB-1 on fibroblasts suggests a profibrotic role and a potential contribution to excessive scarring. MMPs contribute extensively to wound healing and characteristically degrade the extracellular matrix. MMP-1 is decreased in keloids and hypertrophic scars. However, other MMPs, including MMP-2, have been found to be increased and are thought to possibly contribute to keloid expansion through peripheral extracellular matrix catabolism. Many novel therapeutic approaches to keloids and hypertrophic scars target MMPs and aim to increase their levels and catabolic activity. The higher prevalence of keloids in darker skin types may partially be due to a tendency for lower vitamin D levels. The physiologically active form of vitamin D, 1,25(OH)2D3, inhibits the proliferation of keloid fibroblasts, and correlations between vitamin D receptor polymorphisms, such as the TaqI CC genotype, and keloid formation have been reported. Additionally, vitamin D may exert an antifibrotic effect partially mediated by MMPs. Here, we critically discuss whether keloid and hypertrophic scar formation could be predicted based on vitamin D status and vitamin D receptor polymorphisms. Specifically, the findings identified HMGB-1, MMPs, and vitamin D as potential avenues for further clinical investigation and potentially novel therapeutic approaches to prevent the development of keloids and hypertrophic scars.
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Affiliation(s)
- Dylan E. Lee
- From the Center for Clinical and Translational Science, Creighton University School of Medicine, Omaha, Neb.; Brigham and Women’s Hospital, Boston, Mass.; and Westfield Plastic Surgery Center, Omaha, Neb
| | - Ryan M. Trowbridge
- From the Center for Clinical and Translational Science, Creighton University School of Medicine, Omaha, Neb.; Brigham and Women’s Hospital, Boston, Mass.; and Westfield Plastic Surgery Center, Omaha, Neb
| | - Nagi T. Ayoub
- From the Center for Clinical and Translational Science, Creighton University School of Medicine, Omaha, Neb.; Brigham and Women’s Hospital, Boston, Mass.; and Westfield Plastic Surgery Center, Omaha, Neb
| | - Devendra K. Agrawal
- From the Center for Clinical and Translational Science, Creighton University School of Medicine, Omaha, Neb.; Brigham and Women’s Hospital, Boston, Mass.; and Westfield Plastic Surgery Center, Omaha, Neb
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50
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van den Broek LJ, van der Veer WM, de Jong EH, Gibbs S, Niessen FB. Suppressed inflammatory gene expression during human hypertrophic scar compared to normotrophic scar formation. Exp Dermatol 2015; 24:623-9. [DOI: 10.1111/exd.12739] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/24/2015] [Indexed: 02/06/2023]
Affiliation(s)
- Lenie J. van den Broek
- Department of Dermatology; VU University Medical Center; Amsterdam The Netherlands
- Research Institute MOVE; Amsterdam The Netherlands
- A-SKIN Nederland BV; Amsterdam The Netherlands
| | - Willem M. van der Veer
- Department of Plastic Reconstructive and Hand Surgery; VU University Medical Center; Amsterdam The Netherlands
| | - Etty H. de Jong
- Department of Plastic and Reconstructive Surgery; University Medical Center Groningen; Groningen The Netherland
| | - Susan Gibbs
- Department of Dermatology; VU University Medical Center; Amsterdam The Netherlands
- Research Institute MOVE; Amsterdam The Netherlands
- Department of Oral Cell Biology; Academic Center for Dentistry Amsterdam (ACTA); Amsterdam The Netherlands
| | - Frank B. Niessen
- Research Institute MOVE; Amsterdam The Netherlands
- Department of Plastic Reconstructive and Hand Surgery; VU University Medical Center; Amsterdam The Netherlands
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