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Kheradmandi R, Zamani S, Farahani MK, Ehterami A, Salehi M. Harnessing Nature's Power: Plant and Polymeric-Based Antibacterials as Potential Therapeutics for Infectious Skin Wound Healing. Biopolymers 2025; 116:e70007. [PMID: 40033706 DOI: 10.1002/bip.70007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 02/10/2025] [Accepted: 02/12/2025] [Indexed: 03/05/2025]
Abstract
This comprehensive review explores the potential of plant- and biopolymeric-based antibacterials as innovative therapeutic agents for infectious skin wound healing. By researching the antibacterial properties of various plants, the review highlights their application in skin tissue engineering. Beyond reviewing antibacterial plant extracts, the article delves into the limitations these natural compounds face, such as hydrophilicity, drug release rates, cell attachment, and scaffold stability when integrated into tissue engineering constructs. The review also emphasizes the role of biopolymeric materials, hydrogel optimization, and crosslinkers to improve scaffold performance. This review provides a roadmap for future research by addressing critical factors in scaffold construction. In the end, it aims to guide the development of more effective wound dressings and tissue scaffolds, combining the natural power of plants with advanced biopolymeric materials for enhanced wound healing therapies.
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Affiliation(s)
- Rasoul Kheradmandi
- Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Sepehr Zamani
- Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | | | - Arian Ehterami
- Institute for Regenerative Medicine (IREM), University of Zurich, Zurich, Switzerland
| | - Majid Salehi
- Regenerative Medicine Research Center, Shahroud University of Medical Sciences, Shahroud, Iran
- Department of Tissue Engineering, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
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Gomes MLNP, Krijnen PAJ, Middelkoop E, Niessen HWM, Boekema BKHL. Fetal Skin Wound Healing: Key Extracellular Matrix Components and Regulators in Scarless Healing. J Invest Dermatol 2025; 145:280-302. [PMID: 39152955 DOI: 10.1016/j.jid.2024.05.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 05/28/2024] [Accepted: 05/30/2024] [Indexed: 08/19/2024]
Abstract
Fetal skin at early gestational stage is able to regenerate and heal rapidly after wounding. The exact mechanisms and molecular pathways involved in this process are however still largely unknown. The numerous differences in the skin of the early fetus versus skin in later developmental stages might provide clues for the mechanisms of scarless healing. This review summarizes the differences between mammalian fetal skin and the skin at later developmental phases in healthy and wounded conditions, focusing on extracellular matrix components, which are crucial factors in the microenvironment that direct cells and tissue functions and hence the wound healing process.
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Affiliation(s)
- Madalena Lopes Natário Pinto Gomes
- Department of Plastic, Reconstructive and Hand Surgery, Amsterdam UMC (Location VUmc), Amsterdam, The Netherlands; Preclinical Research, Association of Dutch Burn Centres (ADBC), Beverwijk, The Netherlands; Department of Pathology, Amsterdam UMC Location AMC, Amsterdam, The Netherlands; Tissue Function & Regeneration, Amsterdam Movement Sciences, Amsterdam UMC (Location VUmc), Amsterdam, The Netherlands
| | - Paul A J Krijnen
- Department of Pathology, Amsterdam UMC Location AMC, Amsterdam, The Netherlands; Amsterdam Cardiovascular Sciences Institute, Amsterdam UMC, Amsterdam, The Netherlands
| | - Esther Middelkoop
- Department of Plastic, Reconstructive and Hand Surgery, Amsterdam UMC (Location VUmc), Amsterdam, The Netherlands; Preclinical Research, Association of Dutch Burn Centres (ADBC), Beverwijk, The Netherlands; Tissue Function & Regeneration, Amsterdam Movement Sciences, Amsterdam UMC (Location VUmc), Amsterdam, The Netherlands; Burn Centre, Red Cross Hospital, Beverwijk, The Netherlands
| | - Hans W M Niessen
- Department of Pathology, Amsterdam UMC Location AMC, Amsterdam, The Netherlands; Amsterdam Cardiovascular Sciences Institute, Amsterdam UMC, Amsterdam, The Netherlands; Department of Cardio-thoracic Surgery, Amsterdam UMC (Location VUmc), Amsterdam, The Netherlands
| | - Bouke K H L Boekema
- Department of Plastic, Reconstructive and Hand Surgery, Amsterdam UMC (Location VUmc), Amsterdam, The Netherlands; Preclinical Research, Association of Dutch Burn Centres (ADBC), Beverwijk, The Netherlands.
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Santamaria MP, Mathias-Santamaria IF, Ferreira Bonafé AC, Gonzalez OA, Kirakodu S, Monteiro MDF, Casarin RCV, Shaddox LM, Miguel MMV. Microbiome and Inflammatory Biomarkers Associated With Palatal Wound Healing. J Periodontal Res 2025. [PMID: 39801488 DOI: 10.1111/jre.13373] [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: 09/13/2024] [Revised: 11/20/2024] [Accepted: 11/21/2024] [Indexed: 01/18/2025]
Abstract
AIM The clinical outcomes of a variety of surgical procedures highly depend on tissue repair and show high variability among patients. There is a gap in the literature on how the host inflammatory response, the microbiome, and the interplay between them can influence oral mucosa healing. In this pilot study, we aimed to evaluate the microbiome and biomarkers profiles in patients who had desired versus undesired wound healing in the palatal mucosa. METHODS Seventeen patients underwent a free gingival graft (FGG) for socket preservation. Palatal wound closure (WC) and epithelization (EPT) were assessed clinically. Biofilm from the palatal wound was collected before the surgical procedure and 3, 7, 14, and 30 days postoperatively. The inflammatory exudate was sampled on Days 3 and 7. At 14 days posttreatment, patients were classified into two groups based on EPT rates: (1) undesired healing (UH) and (2) desired healing (DH). RESULTS No difference was observed in alfa diversity over time or between groups. In beta diversity, both UH and DH showed microbiome changes on Days 3-7 and 7, respectively, compared with the baseline (p = 0.01), returning to its initial condition 30 days later. There was a trend toward a different microbiome profile between groups on Day 7 (p = 0.08). Bacterium composition in DH showed a balance between healthy species and oral pathogens over time, whereas UH composition was characterized by microorganisms correlated with epithelium invasion/cytotoxicity; virulence factor upregulation; and oral diseases, such as periodontitis and aphthous stomatitis, until Day 30. UH showed an increase in IL-6, MCP-1, and MIP-1α over time, and DH showed a decrease in TIMP-1, IL-1β, and MIP-1α. On Days 3 and 7, MIP-1α and MMP-2 showed greater concentrations of DH in the intergroup assessment, and MCP-1 increased on Day 7 in UH. CONCLUSION Specific microbiome/inflammatory profiles are associated with DH and UH. TRIAL REGISTRATION NCT05171400.
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Affiliation(s)
- Mauro Pedrine Santamaria
- College of Dentistry, University of Kentucky, Lexington, Kentucky, USA
- Division of Periodontics, Institute of Science and Technology, São José dos Campos, São Paulo State University (UNESP), São Paulo, Brazil
| | | | - Ana Carolina Ferreira Bonafé
- Division of Periodontics, Institute of Science and Technology, São José dos Campos, São Paulo State University (UNESP), São Paulo, Brazil
| | | | | | | | | | | | - Manuela Maria Viana Miguel
- College of Dentistry, University of Kentucky, Lexington, Kentucky, USA
- Division of Periodontics, Institute of Science and Technology, São José dos Campos, São Paulo State University (UNESP), São Paulo, Brazil
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Takaya K, Imbe Y, Wang Q, Okabe K, Sakai S, Aramaki-Hattori N, Kishi K. Rac1 inhibition regenerates wounds in mouse fetuses via altered actin dynamics. Sci Rep 2024; 14:27213. [PMID: 39516580 PMCID: PMC11549422 DOI: 10.1038/s41598-024-78395-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 10/30/2024] [Indexed: 11/16/2024] Open
Abstract
Mammalian wounds leave visible scars, and there are no methods for complete regeneration. However, mouse fetuses regenerate their skin, including epidermal and dermal structures, up to embryonic day (E)13. This regeneration pattern requires the formation of actin cables in the wound margin epithelium; however, the molecular mechanisms are not fully understood. Rac1 alters actin in cells and is involved in the formation of filopodia. We investigated whether actin remodeling and skin regeneration patterns can be reproduced through the regulation of Rac1 signaling. Rac1 expression was downregulated in E13 wounds and upregulated after E15 when scars remained. NSC23766, a Rac1-specific inhibitor, altered actin dynamics at the cell margin from filopodia formation to cable formation and inhibited the migration of mouse epidermal keratinocyte, PAM212, by Rac1 signaling suppression. NSC23766 suppressed Rac1 activity and completely regenerated the fetal mouse wounds, even at E14, by changing actin dynamics. Knocked-out Rac1 transgenic mice experienced delayed epithelialization of wounds with suppressed epidermal migration in adults; however, in fetuses, complete wound regeneration via Rac1 signal suppression was observed. Therefore, Rac1 suppression in the wound epidermis can achieve regenerative wound healing in fetuses and may be a potential candidate for healing scars.
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Affiliation(s)
- Kento Takaya
- Department of Plastic and Reconstructive Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Yuka Imbe
- Faculty of Pharmacy, Keio University, Shiba, Minatoku, Tokyo, Japan
| | - Qi Wang
- Faculty of Pharmacy, Keio University, Shiba, Minatoku, Tokyo, Japan
| | - Keisuke Okabe
- Department of Plastic and Reconstructive Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Shigeki Sakai
- Department of Plastic and Reconstructive Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Noriko Aramaki-Hattori
- Department of Plastic and Reconstructive Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Kazuo Kishi
- Department of Plastic and Reconstructive Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
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Zhang Y, Guan Z, Gong H, Ni Z, Xiao Q, Guo X, Xu Q. The Role of Progenitor Cells in the Pathogenesis of Arteriosclerosis. CARDIOLOGY DISCOVERY 2024; 4:231-244. [DOI: 10.1097/cd9.0000000000000130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
The increasing incidence of arteriosclerosis has become a significant global health burden. Arteriosclerosis is characterized by the thickening and hardening of arterial walls, which can lead to the narrowing or complete blockage of blood vessels. However, the pathogenesis of the disease remains incompletely understood. Recent research has shown that stem and progenitor cells found in the bone marrow and local vessel walls play a role in the development of arteriosclerosis by differentiating into various types of vascular cells, including endothelial cells, smooth muscle cells, fibroblasts, and inflammatory cells. This review aims to provide a comprehensive understanding of the role of stem and progenitor cells in the pathogenesis of arteriosclerosis, shedding light on the underlying mechanisms and potential therapeutic approaches for this disease.
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Affiliation(s)
- Yuesheng Zhang
- Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China
| | - Ziyin Guan
- Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China
| | - Hui Gong
- Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China
| | - Zhichao Ni
- Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China
| | - Qingzhong Xiao
- Centre for Clinical Pharmacology and Precision Medicine, William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Xiaogang Guo
- Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China
| | - Qingbo Xu
- Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China
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Song Z, Li W, He Q, Xie X, Wang X, Guo J. Natural products - Dawn of keloid treatment. Fitoterapia 2024; 175:105918. [PMID: 38554887 DOI: 10.1016/j.fitote.2024.105918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 03/15/2024] [Accepted: 03/23/2024] [Indexed: 04/02/2024]
Abstract
Keloids are prevalent pathological scars, often leading to cosmetic deformities and hindering joint mobility.They cause discomfort, including burning and itching, while gradually expanding and potentially posing a risk of cancer.Developing effective drugs and treatments for keloids has been a persistent challenge in the medical field. Natural products are an important source of innovative drugs and a breakthrough for many knotty disease.Herein, keywords of "natural, plant, compound, extract" were combined with "keloid" and searched in PubMed and Google Scholar, respectively. A total of 32 natural products as well as 9 extracts possessing the potential for treating keloids were ultimately identified.Current research in this field faces a significant challenge due to the lack of suitable animal models, resulting in a predominant reliance on in vitro studies.In vivo and clinical studies are notably scarce as a result.Moreover, there is a notable deficiency in research focusing on the role of nutrients in keloid formation and treatment.The appropriate dosage form (oral, topical, injectable) is crucial for the development of natural product drugs. Finally, the conclusion was hereby made that natural products, when used as adjuncts to other treatments, hold significant potential in the management of keloids.By summarizing the natural products and elucidating their mechanisms in keloid treatment, the present study aims to stimulate further discoveries and research in drug development for effectively addressing this challenging condition.
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Affiliation(s)
- Zongzhou Song
- Department of Dermatological, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610036, China
| | - Wenquan Li
- Department of Dermatological, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610036, China
| | - Qingying He
- Department of Dermatological, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610036, China
| | - Xin Xie
- Department of Dermatological, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610036, China
| | - Xurui Wang
- Department of Dermatological, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610036, China
| | - Jing Guo
- Department of Dermatological, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610036, China.
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Ly M, Schimmer C, Hawkins R, E Rothenberg K, Fernandez-Gonzalez R. Integrin-based adhesions promote cell-cell junction and cytoskeletal remodelling to drive embryonic wound healing. J Cell Sci 2024; 137:jcs261138. [PMID: 37970744 DOI: 10.1242/jcs.261138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 11/06/2023] [Indexed: 11/17/2023] Open
Abstract
Embryos repair wounds rapidly, with no inflammation or scarring. Embryonic wound healing is driven by the collective movement of the cells around the lesion. The cells adjacent to the wound polarize the cytoskeletal protein actin and the molecular motor non-muscle myosin II, which accumulate at the wound edge forming a supracellular cable around the wound. Adherens junction proteins, including E-cadherin, are internalized from the wound edge and localize to former tricellular junctions at the wound margin, in a process necessary for cytoskeletal polarity. We found that the cells adjacent to wounds in the Drosophila embryonic epidermis polarized Talin, a core component of cell-extracellular matrix (ECM) adhesions, which preferentially accumulated at the wound edge. Integrin knockdown and inhibition of integrin binding delayed wound closure and reduced actin polarization and dynamics around the wound. Additionally, disrupting integrins caused a defect in E-cadherin reinforcement at tricellular junctions along the wound edge, suggesting crosstalk between integrin-based and cadherin-based adhesions. Our results show that cell-ECM adhesion contributes to embryonic wound repair and reveal an interplay between cell-cell and cell-ECM adhesion in the collective cell movements that drive rapid wound healing.
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Affiliation(s)
- Michelle Ly
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada
- Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, University of Toronto, Toronto, ON M5G 1M1, Canada
| | - Clara Schimmer
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada
- Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, University of Toronto, Toronto, ON M5G 1M1, Canada
| | - Raymond Hawkins
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada
- Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, University of Toronto, Toronto, ON M5G 1M1, Canada
| | - Katheryn E Rothenberg
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada
- Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, University of Toronto, Toronto, ON M5G 1M1, Canada
| | - Rodrigo Fernandez-Gonzalez
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada
- Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, University of Toronto, Toronto, ON M5G 1M1, Canada
- Department of Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada
- Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
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Liu J, Dong J, Pei X. Apoptotic Extracellular Vesicles Derived from Human Umbilical Vein Endothelial Cells Promote Skin Repair by Enhancing Angiogenesis: From Death to Regeneration. Int J Nanomedicine 2024; 19:415-428. [PMID: 38250193 PMCID: PMC10799620 DOI: 10.2147/ijn.s441453] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Accepted: 01/08/2024] [Indexed: 01/23/2024] Open
Abstract
Purpose The promotion of angiogenesis is an effective strategy for skin wound repair. While the transplantation of endothelial cells has shown promise in vascularization, the underlying mechanism remains unclear. Recent studies have suggested that transplanted cells undergo apoptosis in a short period and release apoptotic extracellular vesicles (ApoEVs) that may have therapeutic potential. Methods In this study, we isolated ApoEVs from human umbilical vein endothelial cells (HUVECs) and characterized their properties. In vitro, we assessed the effects of ApoEVs on the proliferation, migration, and differentiation of endothelial cells and fibroblasts. In vivo, we investigated the therapeutic role of ApoEVs-AT in full-thickness skin wounds, evaluating wound closure rate, re-epithelialization, granulation tissue formation, vascularization, scar area, and collagen 3(Col3)/collagen 1(Col 1) ratio. Results ApoEVs derived from HUVECs displayed typical characteristics. In vitro, ApoEVs significantly enhanced the proliferation, migration, tube formation, and expression of angiogenic-related genes in endothelial cells and slightly promoted the proliferation and migration of fibroblasts. In vivo, ApoEVs improved the wound closure rate, re-epithelialization, the formation of granulation tissue, and vascularization. Besides, ApoEVs reduced scar formation, accompanied by an increase in the Col 3/ Col 1 ratio. Conclusion Given their abundant source and effectiveness, this study provided a novel approach for angiogenesis in tissue regeneration and deepened the understanding of from death to regeneration.
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Affiliation(s)
- Jinzhao Liu
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China
- Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China
| | - Jia Dong
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China
| | - Xibo Pei
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China
- Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China
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Chen FZ, Tan PC, Yang Z, Li Q, Zhou SB. Identifying characteristics of dermal fibroblasts in skin homeostasis and disease. Clin Exp Dermatol 2023; 48:1317-1327. [PMID: 37566911 DOI: 10.1093/ced/llad257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 07/11/2023] [Accepted: 07/21/2023] [Indexed: 08/13/2023]
Abstract
Heterogeneous dermal fibroblasts are the main components that constitute the dermis. Distinct fibroblast subgroups show specific characteristics and functional plasticity that determine dermal structure during skin development and wound healing. Although researchers have described the roles of fibroblast subsets, this is not completely understood. We review recent evidence supporting understanding about the heterogeneity of fibroblasts. We summarize the origins and the identified profiles of fibroblast subpopulations. The characteristics of fibroblast subpopulations in both healthy and diseased states are highlighted, and the potential of subpopulations to be involved in wound healing in different ways was discussed. Additionally, we review the plasticity of subpopulations and the underlying signalling mechanisms. This review may provide greater insights into potential novel therapeutic targets and tissue regeneration strategies for the future.
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Affiliation(s)
- Fang-Zhou Chen
- Department of Plastic & Reconstructive Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Ninth People's Hospital, Shanghai, China
| | - Poh-Ching Tan
- Department of Plastic & Reconstructive Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Ninth People's Hospital, Shanghai, China
| | - Zihan Yang
- Department of Plastic & Reconstructive Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Ninth People's Hospital, Shanghai, China
- Department of Plastic and Burn Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Qingfeng Li
- Department of Plastic & Reconstructive Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Ninth People's Hospital, Shanghai, China
| | - Shuang-Bai Zhou
- Department of Plastic & Reconstructive Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Ninth People's Hospital, Shanghai, China
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Spoor JKH, Kik CC, van Veelen MLC, Dirven C, Miller JL, Groves ML, DeKoninck PLJ, Baschat AA, Eggink AJ. Potential higher risk of tethered spinal cord in children after prenatal surgery for myelomeningocele: A systematic review and meta-analysis. PLoS One 2023; 18:e0287175. [PMID: 37379312 DOI: 10.1371/journal.pone.0287175] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 05/31/2023] [Indexed: 06/30/2023] Open
Abstract
INTRODUCTION We performed a systematic review and meta-analysis on the incidence of secondary tethered spinal cord (TSC) between prenatal and postnatal closure in patients with MMC. The objectives was to understand the incidence of secondary TSC after prenatal surgery for MMC compared to postnatal surgery for MMC. MATERIAL AND METHODS On May 4, 2023, a systematic search was conducted in Medline, Embase, and the Cochrane Library to gather relevant data. Primary studies focusing on repair type, lesion level, and TSC were included, while non-English or non-Dutch reports, case reports, conference abstracts, editorials, letters, comments, and animal studies were excluded. Two reviewers assessed the included studies for bias risk, following PRISMA guidelines. TSC frequency in MMC closure types was determined, and the relationship between TSC occurrence and closure technique was analyzed using relative risk and Fisher's exact test. Subgroup analysis revealed relative risk differences based on study designs and follow-up periods. A total of ten studies, involving 2,724 patients, were assessed. Among them, 2,293 patients underwent postnatal closure, while 431 received prenatal closure for the MMC defect. In the prenatal closure group, TSC occurred in 21.6% (n = 93), compared to 18.8% (n = 432) in the postnatal closure group. The relative risk (RR) of TSC in patients with prenatal MMC closure versus postnatal MMC closure was 1.145 (95%CI 0.939 to 1.398). Fisher's exact test indicated a statistically non-significant association (p = 0.106) between TSC and closure technique. When considering only RCT and controlled cohort studies, the overall RR for TSC was 1.308 (95%CI 1.007 to 1.698) with a non-significant association (p = .053). For studies focusing on children up until early puberty (maximum 12 years follow-up), the RR for tethering was 1.104 (95%CI 0.876 to 1.391), with a non-significant association (p = 0.409). CONCLUSION AND DISCUSSION This review found no significant increase in relative risk of TSC between prenatal and postnatal closure in MMC patients, but a trend of increased TSC in the prenatal group. More long-term data on TSC after fetal closure is needed for better counseling and outcomes in MMC.
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Affiliation(s)
- Jochem K H Spoor
- Department of Pediatric Neurosurgery, Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Charlotte C Kik
- Department of Pediatric Neurosurgery, Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Marie-Lise C van Veelen
- Department of Pediatric Neurosurgery, Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Clemens Dirven
- Department of Pediatric Neurosurgery, Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Jena L Miller
- Johns Hopkins Center for Fetal Therapy, Department of Gynaecology & Obstetrics, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Mari L Groves
- Department of Neurosurgery, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Philip L J DeKoninck
- Department of Obstetrics and Gynaecology, Division of Obstetrics and Fetal Medicine, Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Ahmet A Baschat
- Johns Hopkins Center for Fetal Therapy, Department of Gynaecology & Obstetrics, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Alex J Eggink
- Department of Obstetrics and Gynaecology, Division of Obstetrics and Fetal Medicine, Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands
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Abstract
The epithelial tissues that line our body, such as the skin and gut, have remarkable regenerative prowess and continually renew throughout our lifetimes. Owing to their barrier function, these tissues have also evolved sophisticated repair mechanisms to swiftly heal and limit the penetration of harmful agents following injury. Researchers now appreciate that epithelial regeneration and repair are not autonomous processes but rely on a dynamic cross talk with immunity. A wealth of clinical and experimental data point to the functional coupling of reparative and inflammatory responses as two sides of the same coin. Here we bring to the fore the immunological signals that underlie homeostatic epithelial regeneration and restitution following damage. We review our current understanding of how immune cells contribute to distinct phases of repair. When unchecked, immune-mediated repair programs are co-opted to fuel epithelial pathologies such as cancer, psoriasis, and inflammatory bowel diseases. Thus, understanding the reparative functions of immunity may advance therapeutic innovation in regenerative medicine and epithelial inflammatory diseases.
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Affiliation(s)
- Laure Guenin-Mace
- Department of Pathology, NYU Langone Health, New York, NY, USA;
- Immunobiology and Therapy Unit, INSERM U1224, Institut Pasteur, Paris, France
| | - Piotr Konieczny
- Department of Pathology, NYU Langone Health, New York, NY, USA;
| | - Shruti Naik
- Department of Pathology, NYU Langone Health, New York, NY, USA;
- Department of Medicine, Ronald O. Perelman Department of Dermatology, and Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA
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Kosykh AV, Tereshina MB, Gurskaya NG. Potential Role of AGR2 for Mammalian Skin Wound Healing. Int J Mol Sci 2023; 24:ijms24097895. [PMID: 37175601 PMCID: PMC10178616 DOI: 10.3390/ijms24097895] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 04/22/2023] [Accepted: 04/24/2023] [Indexed: 05/15/2023] Open
Abstract
The limited ability of mammals to regenerate has garnered significant attention, particularly in regard to skin wound healing (WH), which is a critical step for regeneration. In human adults, skin WH results in the formation of scars following injury or trauma, regardless of severity. This differs significantly from the scarless WH observed in the fetal skin of mammals or anamniotes. This review investigates the role of molecular players involved in scarless WH, which are lost or repressed in adult mammalian WH systems. Specifically, we analyze the physiological role of Anterior Gradient (AGR) family proteins at different stages of the WH regulatory network. AGR is activated in the regeneration of lower vertebrates at the stage of wound closure and, accordingly, is important for WH. Mammalian AGR2 is expressed during scarless WH in embryonic skin, while in adults, the activity of this gene is normally inhibited and is observed only in the mucous epithelium of the digestive tract, which is capable of full regeneration. The combination of AGR2 unique potencies in postnatal mammals makes it possible to consider it as a promising candidate for enhancing WH processes.
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Affiliation(s)
- Anastasiya V Kosykh
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, 117997 Moscow, Russia
| | - Maria B Tereshina
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, 117997 Moscow, Russia
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, 117997 Moscow, Russia
| | - Nadya G Gurskaya
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, 117997 Moscow, Russia
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, 117997 Moscow, Russia
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13
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Ghatak S, Khanna S, Roy S, Thirunavukkarasu M, Pradeep SR, Wulff BC, El Masry MS, Sharma A, Palakurti R, Ghosh N, Xuan Y, Wilgus TA, Maulik N, Yoder MC, Sen CK. Driving adult tissue repair via re-engagement of a pathway required for fetal healing. Mol Ther 2023; 31:454-470. [PMID: 36114673 PMCID: PMC9931555 DOI: 10.1016/j.ymthe.2022.09.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 08/16/2022] [Accepted: 09/06/2022] [Indexed: 02/07/2023] Open
Abstract
Fetal cutaneous wound closure and repair differ from that in adulthood. In this work, we identify an oxidant stress sensor protein, nonselenocysteine-containing phospholipid hydroperoxide glutathione peroxidase (NPGPx), that is abundantly expressed in normal fetal epidermis (and required for fetal wound closure), though not in adult epidermis, but is variably re-induced upon adult tissue wounding. NPGPx is a direct target of the miR-29 family. Following injury, abundance of miR-29 is lowered, permitting a prompt increase in NPGPx transcripts and protein expression in adult wound-edge tissue. NPGPx expression was required to mediate increased keratinocyte migration induced by miR-29 inhibition in vitro and in vivo. Increased NPGPx expression induced increased SOX2 expression and β-catenin nuclear localization in keratinocytes. Augmenting physiologic NPGPx expression via experimentally induced miR-29 suppression, using cutaneous tissue nanotransfection or targeted lipid nanoparticle delivery of anti-sense oligonucleotides, proved to be sufficient to overcome the deleterious effects of diabetes on this specific pathway to enhance tissue repair.
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Affiliation(s)
- Subhadip Ghatak
- Indiana Center for Regenerative Medicine & Engineering, Indiana University Health Comprehensive Wound Center, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Savita Khanna
- Indiana Center for Regenerative Medicine & Engineering, Indiana University Health Comprehensive Wound Center, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Sashwati Roy
- Indiana Center for Regenerative Medicine & Engineering, Indiana University Health Comprehensive Wound Center, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Mahesh Thirunavukkarasu
- Department of Surgery, Molecular Cardiology and Angiogenesis Laboratory, University of Connecticut Health, Farmington, CT 06030, USA
| | - Seetur R Pradeep
- Department of Surgery, Molecular Cardiology and Angiogenesis Laboratory, University of Connecticut Health, Farmington, CT 06030, USA
| | - Brian C Wulff
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Mohamed S El Masry
- Indiana Center for Regenerative Medicine & Engineering, Indiana University Health Comprehensive Wound Center, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Plastic Surgery, Zagazig University, Zagazig 44519, Egypt
| | - Anu Sharma
- Indiana Center for Regenerative Medicine & Engineering, Indiana University Health Comprehensive Wound Center, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Ravichand Palakurti
- Indiana Center for Regenerative Medicine & Engineering, Indiana University Health Comprehensive Wound Center, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Nandini Ghosh
- Indiana Center for Regenerative Medicine & Engineering, Indiana University Health Comprehensive Wound Center, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Yi Xuan
- Indiana Center for Regenerative Medicine & Engineering, Indiana University Health Comprehensive Wound Center, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA
| | - Traci A Wilgus
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Nilanjana Maulik
- Department of Surgery, Molecular Cardiology and Angiogenesis Laboratory, University of Connecticut Health, Farmington, CT 06030, USA
| | - Mervin C Yoder
- Indiana Center for Regenerative Medicine & Engineering, Indiana University Health Comprehensive Wound Center, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Chandan K Sen
- Indiana Center for Regenerative Medicine & Engineering, Indiana University Health Comprehensive Wound Center, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA.
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14
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Gong Y, Jiang Y, Huang J, He Z, Tang Q. Moist exposed burn ointment accelerates diabetes-related wound healing by promoting re-epithelialization. Front Med (Lausanne) 2023; 9:1042015. [PMID: 36703885 PMCID: PMC9871640 DOI: 10.3389/fmed.2022.1042015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 12/23/2022] [Indexed: 01/11/2023] Open
Abstract
Background The incidence of diabetes-related wounds is widespread, and the treatment is challenging. We found that Moist Exposed Burn Ointment (MEBO) promotes the healing of diabetes-related wounds, but the mechanism is not clear. Methods This study aimed to explore the mechanism of MEBO on diabetic wound healing, which may be related to the promotion of re-epithelialization. A full-thickness skin resection model was established in streptozotocin (STZ)-induced diabetic mice. MEBO and Kangfuxin (KFX) were applied to the wound area, and the wound healing rate was analyzed by photographing. The granulation tissue and epidermal thickness, the collagen remodeling rate, and the expression of cytokeratin 10 (CK10), cytokeratin 14 (CK14), Ki67, Collagen I, and Collagen III in the regenerated skin were detected by H&E staining, Masson staining, and immunofluorescence staining, respectively. MEBO and KFX were applied to human immortalized keratinocytes (HaCaT), mouse dermal fibrolasts (MDF) cells, and cell viability, cell migration, and differentiation were determined by CCK-8, scratching assay, RT-qPCR, and Western blot (WB), respectively. Results We found that MEBO significantly promoted the formation of wound granulation tissue and collagen remodeling in diabetic mice. The application of MEBO to diabetic wounds not only promoted the formation of hair follicles and sebaceous glands but also promoted the expression of Ki67, CK10, and CK14 in epidermal cells. MEBO had no significant effect on the differentiation process of keratinocytes. Conclusion Our study further proved that MEBO plays a positive role in diabetic wound healing, and its excellent ability to promote re-epithelialization may be an important reason for promoting wound healing.
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Affiliation(s)
- Yuanxun Gong
- College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China,Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Yan Jiang
- West Guangxi Key Laboratory for Prevention and Treatment of High-Incidence Diseases, Youjiang Medical University for Nationalities, Baise, China
| | - Jinmei Huang
- Graduate School, Guangxi University of Chinese Medicine, Nanning, China
| | - Zuofen He
- Graduate School, YouJiang Medical University for Nationalities, Baise, China
| | - Qianli Tang
- College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China,Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China,*Correspondence: Qianli Tang,
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15
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Wang B, Pang M, Song Y, Wang H, Qi P, Bai S, Lei X, Wei S, Zong Z, Lin S, Zhang X, Cen X, Wang X, Yang Y, Li Y, Wang Y, Xu H, Huang L, Tortorella M, Cheng B, Lee Y, Qin D, Li G. Human fetal mesenchymal stem cells secretome promotes scarless diabetic wound healing through heat-shock protein family. Bioeng Transl Med 2023; 8:e10354. [PMID: 36684113 PMCID: PMC9842061 DOI: 10.1002/btm2.10354] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 05/11/2022] [Accepted: 05/13/2022] [Indexed: 01/25/2023] Open
Abstract
The high mortality rate of patients with diabetic foot ulcers is urging the appearance of an effective biomedical drug. Senescence is one of the major reasons of aging-induced decline in the diabetic wound. Our previous studies have demonstrated the anti-senescence effect of secretomes derived from human fetal mesenchymal stem cells (hfMSC). The present study tends to explore the potential role of hfMSC secretome (HFS) in wound healing through anti-aging. Meanwhile, we try to overcome several obstacles in the clinical application of stem cell secretome. A verticle bioreactor and microcarriers are employed to expand hfMSC and produce the HFS on a large scale. The HFS was then subjected to lyophilization (L-HFS). The PLGA (poly lactic-co-glycolic acid) particles were used to encapsulate and protect L-HFS from degradation in the streptozotocin (STZ)-induced diabetic rat model. Results showed that HFS-PLGA significantly enhanced wound healing by promoting vascularization and inhibiting inflammation in the skin wound bed. We further analyzed the contents of HFS. Isobaric tag for relative and absolute quantitation (ITRAQ) and label-free methods were used to identify peptides in the secretome. Bioinformatics analysis indicated that exosome production-related singling pathways and heat-shock protein family could be used as bio-functional markers and quality control for stem cell secretome production.
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Affiliation(s)
- Bin Wang
- Innovation Centre for Advanced Interdisciplinary Medicine, Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education InstitutesThe Fifth Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina
- The Chinese University of Hong Kong (CUHK)‐Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GDL) Advanced Institute for Regenerative MedicineBioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory)GuangzhouChina
| | - Mengru Pang
- Department of Burn and Plastic SurgeryThe Affiliated Hospital of Guizhou Medical UniversityGuiyangGuizhouChina
| | - Yancheng Song
- Department of orthopedicsThe Affiliated Hospital of Guangdong Pharmaceutical UniversityGuangzhouChina
| | - Haixing Wang
- Department of Orthopaedics and Traumatology, Stem Cells, and Regenerative Medicine LaboratoryLi Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales HospitalShatinHong Kong
| | - Pan Qi
- Department of Orthopaedics and Traumatology, Stem Cells, and Regenerative Medicine LaboratoryLi Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales HospitalShatinHong Kong
| | - Shanshan Bai
- Department of Orthopaedics and Traumatology, Stem Cells, and Regenerative Medicine LaboratoryLi Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales HospitalShatinHong Kong
| | - Xiaoxuan Lei
- Department of Oral and Maxillofacial Surgery/PathologyAmsterdam UMC and Academic Center for Dentistry Amsterdam (ACTA), Vrije Universiteit Amsterdam, Amsterdam Movement ScienceAmsterdamThe Netherlands
| | - Shikun Wei
- Department of Plastic SurgeryGeneral Hospital of Southern Theater Command, PLAGuangzhouChina
| | - Zhixian Zong
- Department of Orthopaedics and Traumatology, Stem Cells, and Regenerative Medicine LaboratoryLi Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales HospitalShatinHong Kong
| | - Sien Lin
- Department of Orthopaedics and Traumatology, Stem Cells, and Regenerative Medicine LaboratoryLi Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales HospitalShatinHong Kong
| | - Xiaoting Zhang
- Department of Orthopaedics and Traumatology, Stem Cells, and Regenerative Medicine LaboratoryLi Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales HospitalShatinHong Kong
| | - Xiaotong Cen
- Innovation Centre for Advanced Interdisciplinary Medicine, Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education InstitutesThe Fifth Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina
- The Chinese University of Hong Kong (CUHK)‐Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GDL) Advanced Institute for Regenerative MedicineBioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory)GuangzhouChina
| | - Xia Wang
- Innovation Centre for Advanced Interdisciplinary Medicine, Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education InstitutesThe Fifth Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina
- The Chinese University of Hong Kong (CUHK)‐Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GDL) Advanced Institute for Regenerative MedicineBioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory)GuangzhouChina
| | - Yongkang Yang
- Department of Orthopaedics and Traumatology, Stem Cells, and Regenerative Medicine LaboratoryLi Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales HospitalShatinHong Kong
| | - Yuan Li
- Department of Orthopaedics and Traumatology, Stem Cells, and Regenerative Medicine LaboratoryLi Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales HospitalShatinHong Kong
| | - Yan Wang
- Department of Burn and Plastic SurgeryThe Affiliated Hospital of Guizhou Medical UniversityGuiyangGuizhouChina
| | - Hongjie Xu
- Innovation Centre for Advanced Interdisciplinary Medicine, Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education InstitutesThe Fifth Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina
- The Chinese University of Hong Kong (CUHK)‐Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GDL) Advanced Institute for Regenerative MedicineBioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory)GuangzhouChina
| | - Lin Huang
- Division of Plastic, Reconstructive and Aesthetic Surgery, Department of SurgeryThe Chinese University of Hong Kong, Prince of Wales HospitalShatinHong Kong
| | - Micky Tortorella
- Centre for Regenerative Medicine and HealthHong Kong Institute of Science and Innovation, Chinese Academy of SciencesHong KongChina
| | - Biao Cheng
- Department of Plastic SurgeryGeneral Hospital of Southern Theater Command, PLAGuangzhouChina
| | - Yukwai Lee
- Department of Orthopaedics and Traumatology, Stem Cells, and Regenerative Medicine LaboratoryLi Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales HospitalShatinHong Kong
| | - Dajiang Qin
- Innovation Centre for Advanced Interdisciplinary Medicine, Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education InstitutesThe Fifth Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina
- The Chinese University of Hong Kong (CUHK)‐Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GDL) Advanced Institute for Regenerative MedicineBioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory)GuangzhouChina
| | - Gang Li
- Department of Orthopaedics and Traumatology, Stem Cells, and Regenerative Medicine LaboratoryLi Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales HospitalShatinHong Kong
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16
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Sinha S, Sparks HD, Labit E, Robbins HN, Gowing K, Jaffer A, Kutluberk E, Arora R, Raredon MSB, Cao L, Swanson S, Jiang P, Hee O, Pope H, Workentine M, Todkar K, Sharma N, Bharadia S, Chockalingam K, de Almeida LGN, Adam M, Niklason L, Potter SS, Seifert AW, Dufour A, Gabriel V, Rosin NL, Stewart R, Muench G, McCorkell R, Matyas J, Biernaskie J. Fibroblast inflammatory priming determines regenerative versus fibrotic skin repair in reindeer. Cell 2022; 185:4717-4736.e25. [PMID: 36493752 PMCID: PMC9888357 DOI: 10.1016/j.cell.2022.11.004] [Citation(s) in RCA: 65] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 08/24/2022] [Accepted: 11/02/2022] [Indexed: 12/13/2022]
Abstract
Adult mammalian skin wounds heal by forming fibrotic scars. We report that full-thickness injuries of reindeer antler skin (velvet) regenerate, whereas back skin forms fibrotic scar. Single-cell multi-omics reveal that uninjured velvet fibroblasts resemble human fetal fibroblasts, whereas back skin fibroblasts express inflammatory mediators mimicking pro-fibrotic adult human and rodent fibroblasts. Consequently, injury elicits site-specific immune responses: back skin fibroblasts amplify myeloid infiltration and maturation during repair, whereas velvet fibroblasts adopt an immunosuppressive phenotype that restricts leukocyte recruitment and hastens immune resolution. Ectopic transplantation of velvet to scar-forming back skin is initially regenerative, but progressively transitions to a fibrotic phenotype akin to the scarless fetal-to-scar-forming transition reported in humans. Skin regeneration is diminished by intensifying, or enhanced by neutralizing, these pathologic fibroblast-immune interactions. Reindeer represent a powerful comparative model for interrogating divergent wound healing outcomes, and our results nominate decoupling of fibroblast-immune interactions as a promising approach to mitigate scar.
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Affiliation(s)
- Sarthak Sinha
- Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada
| | - Holly D Sparks
- Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada
| | - Elodie Labit
- Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada
| | - Hayley N Robbins
- Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada
| | - Kevin Gowing
- Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada
| | - Arzina Jaffer
- Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada
| | - Eren Kutluberk
- Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada
| | - Rohit Arora
- Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada
| | - Micha Sam Brickman Raredon
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA; Vascular Biology and Therapeutics, Yale University, New Haven, CT, USA
| | - Leslie Cao
- Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada
| | | | - Peng Jiang
- Morgridge Institute for Research, Madison, WI, USA
| | - Olivia Hee
- Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada
| | - Hannah Pope
- Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada
| | - Matt Workentine
- Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada
| | - Kiran Todkar
- Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada
| | - Nilesh Sharma
- Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada
| | - Shyla Bharadia
- Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | | | - Luiz G N de Almeida
- McCaig Institute, University of Calgary, Calgary, AB, Canada; Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada
| | - Mike Adam
- Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Laura Niklason
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA; Vascular Biology and Therapeutics, Yale University, New Haven, CT, USA
| | - S Steven Potter
- Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Ashley W Seifert
- Department of Biology, University of Kentucky, Lexington, KY, USA
| | - Antoine Dufour
- McCaig Institute, University of Calgary, Calgary, AB, Canada; Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada
| | - Vincent Gabriel
- Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; McCaig Institute, University of Calgary, Calgary, AB, Canada; Department of Surgery, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4N1, Canada
| | - Nicole L Rosin
- Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada
| | - Ron Stewart
- Morgridge Institute for Research, Madison, WI, USA
| | - Greg Muench
- Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada
| | - Robert McCorkell
- Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada
| | - John Matyas
- Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada; McCaig Institute, University of Calgary, Calgary, AB, Canada
| | - Jeff Biernaskie
- Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada; Department of Surgery, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4N1, Canada; Hotchkiss Brain Institute, Calgary, AB, Canada; Alberta Children's Hospital Research Institute, Calgary, AB, Canada.
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17
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García-Sancha N, Corchado-Cobos R, Gómez-Vecino A, Jiménez-Navas A, Pérez-Baena MJ, Blanco-Gómez A, Holgado-Madruga M, Mao JH, Cañueto J, Castillo-Lluva S, Mendiburu-Eliçabe M, Pérez-Losada J. Evolutionary Origins of Metabolic Reprogramming in Cancer. Int J Mol Sci 2022; 23:12063. [PMID: 36292921 PMCID: PMC9603151 DOI: 10.3390/ijms232012063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 09/29/2022] [Accepted: 10/06/2022] [Indexed: 11/23/2022] Open
Abstract
Metabolic changes that facilitate tumor growth are one of the hallmarks of cancer. These changes are not specific to tumors but also take place during the physiological growth of tissues. Indeed, the cellular and tissue mechanisms present in the tumor have their physiological counterpart in the repair of tissue lesions and wound healing. These molecular mechanisms have been acquired during metazoan evolution, first to eliminate the infection of the tissue injury, then to enter an effective regenerative phase. Cancer itself could be considered a phenomenon of antagonistic pleiotropy of the genes involved in effective tissue repair. Cancer and tissue repair are complex traits that share many intermediate phenotypes at the molecular, cellular, and tissue levels, and all of these are integrated within a Systems Biology structure. Complex traits are influenced by a multitude of common genes, each with a weak effect. This polygenic component of complex traits is mainly unknown and so makes up part of the missing heritability. Here, we try to integrate these different perspectives from the point of view of the metabolic changes observed in cancer.
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Affiliation(s)
- Natalia García-Sancha
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, 37007 Salamanca, Spain
- Instituto de Investigación Biosanitaria de Salamanca (IBSAL), 37007 Salamanca, Spain
| | - Roberto Corchado-Cobos
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, 37007 Salamanca, Spain
- Instituto de Investigación Biosanitaria de Salamanca (IBSAL), 37007 Salamanca, Spain
| | - Aurora Gómez-Vecino
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, 37007 Salamanca, Spain
- Instituto de Investigación Biosanitaria de Salamanca (IBSAL), 37007 Salamanca, Spain
| | - Alejandro Jiménez-Navas
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, 37007 Salamanca, Spain
- Instituto de Investigación Biosanitaria de Salamanca (IBSAL), 37007 Salamanca, Spain
| | - Manuel Jesús Pérez-Baena
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, 37007 Salamanca, Spain
- Instituto de Investigación Biosanitaria de Salamanca (IBSAL), 37007 Salamanca, Spain
| | - Adrián Blanco-Gómez
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, 37007 Salamanca, Spain
- Instituto de Investigación Biosanitaria de Salamanca (IBSAL), 37007 Salamanca, Spain
| | - Marina Holgado-Madruga
- Instituto de Investigación Biosanitaria de Salamanca (IBSAL), 37007 Salamanca, Spain
- Departamento de Fisiología y Farmacología, Universidad de Salamanca, 37007 Salamanca, Spain
- Instituto de Neurociencias de Castilla y León (INCyL), 37007 Salamanca, Spain
| | - Jian-Hua Mao
- Lawrence Berkeley National Laboratory, Biological Systems and Engineering Division, Berkeley, CA 94720, USA
- Berkeley Biomedical Data Science Center, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
| | - Javier Cañueto
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, 37007 Salamanca, Spain
- Instituto de Investigación Biosanitaria de Salamanca (IBSAL), 37007 Salamanca, Spain
- Departamento de Dermatología, Hospital Universitario de Salamanca, Paseo de San Vicente 58-182, 37007 Salamanca, Spain
| | - Sonia Castillo-Lluva
- Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas, Universidad Complutense, 28040 Madrid, Spain
- Instituto de Investigaciones Sanitarias San Carlos (IdISSC), 28040 Madrid, Spain
| | - Marina Mendiburu-Eliçabe
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, 37007 Salamanca, Spain
- Instituto de Investigación Biosanitaria de Salamanca (IBSAL), 37007 Salamanca, Spain
| | - Jesús Pérez-Losada
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, 37007 Salamanca, Spain
- Instituto de Investigación Biosanitaria de Salamanca (IBSAL), 37007 Salamanca, Spain
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18
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Luo H, Wang Z, Qi F, Wang D. Applications of human amniotic fluid stem cells in wound healing. Chin Med J (Engl) 2022; 135:2272-2281. [PMID: 36535008 PMCID: PMC9771343 DOI: 10.1097/cm9.0000000000002076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Indexed: 12/23/2022] Open
Abstract
ABSTRACT Complete wound regeneration preserves skin structure and physiological functions, including sensation and perception of stimuli, whereas incomplete wound regeneration results in fibrosis and scarring. Amniotic fluid stem cells (AFSCs) would be a kind of cell population with self-renewing and non-immunogenic ability that have a considerable role in wound generation. They are easy to harvest, culture, and store; moreover, they are non-tumorigenic and not subject to ethical restrictions. They can differentiate into different kinds of cells that replenish the skin, subcutaneous tissues, and accessory organs. Additionally, AFSCs independently produce paracrine effectors and secrete them in exosomes, thereby modulating local immune cell activity. They demonstrate anti-inflammatory and immunomodulatory properties, regulate the physicochemical microenvironment of the wound, and promote full wound regeneration. Thus, AFSCs are potential resources in stem cell therapy, especially in scar-free wound healing. This review describes the biological characteristics and clinical applications of AFSCs in treating wounds and provide new ideas for the treatment of wound healing.
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Affiliation(s)
- Han Luo
- Department of Plastic Surgery and Burns, The Affiliated Hospital of Zunyl Medical University, Zunyl, Guizhou 563003, China
- Department of Plastic Surgery and Burns, Fuling Central Hospital, Chongqing 408000, China
| | - Zhen Wang
- Department of Plastic Surgery and Burns, The Affiliated Hospital of Zunyl Medical University, Zunyl, Guizhou 563003, China
| | - Fang Qi
- Department of Plastic Surgery and Burns, The Affiliated Hospital of Zunyl Medical University, Zunyl, Guizhou 563003, China
| | - Dali Wang
- Department of Plastic Surgery and Burns, The Affiliated Hospital of Zunyl Medical University, Zunyl, Guizhou 563003, China
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Mascharak S, desJardins-Park HE, Davitt MF, Guardino NJ, Gurtner GC, Wan DC, Longaker MT. Modulating Cellular Responses to Mechanical Forces to Promote Wound Regeneration. Adv Wound Care (New Rochelle) 2022; 11:479-495. [PMID: 34465219 PMCID: PMC9245727 DOI: 10.1089/wound.2021.0040] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 08/23/2021] [Indexed: 12/13/2022] Open
Abstract
Significance: Skin scarring poses a major biomedical burden for hundreds of millions of patients annually. However, this burden could be mitigated by therapies that promote wound regeneration, with full recovery of skin's normal adnexa, matrix ultrastructure, and mechanical strength. Recent Advances: The observation of wound regeneration in several mouse models suggests a retained capacity for postnatal mammalian skin to regenerate under the right conditions. Mechanical forces are a major contributor to skin fibrosis and a prime target for devices and therapeutics that could promote skin regeneration. Critical Issues: Wound-induced hair neogenesis, Acomys "spiny" mice, Murphy Roths Large mice, and mice treated with mechanotransduction inhibitors all show various degrees of wound regeneration. Comparison of regenerating wounds in these models against scarring wounds reveals differences in extracellular matrix interactions and in mechanosensitive activation of key signaling pathways, including Wnt, Sonic hedgehog, focal adhesion kinase, and Yes-associated protein. The advent of single-cell "omics" technologies has deepened this understanding and revealed that regeneration may recapitulate development in certain contexts, although it is unknown whether these mechanisms are relevant to healing in tight-skinned animals such as humans. Future Directions: While early findings in mice are promising, comparison across model systems is needed to resolve conflicting mechanisms and to identify conserved master regulators of skin regeneration. There also remains a dire need for studies on mechanomodulation of wounds in large, tight-skinned animals, such as red Duroc pigs, which better approximate human wound healing.
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Affiliation(s)
- Shamik Mascharak
- Division of Plastic and Reconstructive Surgery, Department of Surgery; Stanford, California, USA
- Institute for Stem Cell Biology and Regenerative Medicine; Stanford University School of Medicine, Stanford, California, USA
| | - Heather E. desJardins-Park
- Division of Plastic and Reconstructive Surgery, Department of Surgery; Stanford, California, USA
- Institute for Stem Cell Biology and Regenerative Medicine; Stanford University School of Medicine, Stanford, California, USA
| | - Michael F. Davitt
- Division of Plastic and Reconstructive Surgery, Department of Surgery; Stanford, California, USA
| | - Nicholas J. Guardino
- Division of Plastic and Reconstructive Surgery, Department of Surgery; Stanford, California, USA
| | - Geoffrey C. Gurtner
- Division of Plastic and Reconstructive Surgery, Department of Surgery; Stanford, California, USA
| | - Derrick C. Wan
- Division of Plastic and Reconstructive Surgery, Department of Surgery; Stanford, California, USA
| | - Michael T. Longaker
- Division of Plastic and Reconstructive Surgery, Department of Surgery; Stanford, California, USA
- Institute for Stem Cell Biology and Regenerative Medicine; Stanford University School of Medicine, Stanford, California, USA
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20
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Singer AJ. Healing Mechanisms in Cutaneous Wounds: Tipping the Balance. TISSUE ENGINEERING. PART B, REVIEWS 2022; 28:1151-1167. [PMID: 34915757 PMCID: PMC9587785 DOI: 10.1089/ten.teb.2021.0114] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Acute and chronic cutaneous wounds pose a significant health and economic burden. Cutaneous wound healing is a complex process that occurs in four distinct, yet overlapping, highly coordinated stages: hemostasis, inflammation, proliferation, and remodeling. Postnatal wound healing is reparative, which can lead to the formation of scar tissue. Regenerative wound healing occurs during fetal development and in restricted postnatal tissues. This process can restore the wound to an uninjured state by producing new skin cells from stem cell reservoirs, resulting in healing with minimal or no scarring. Focusing on the pathophysiology of acute burn wounds, this review highlights reparative and regenerative healing mechanisms (including the role of cells, signaling molecules, and the extracellular matrix) and discusses how components of regenerative healing are being used to drive the development of novel approaches and therapeutics aimed at improving clinical outcomes. Important components of regenerative healing, such as stem cells, growth factors, and decellularized dermal matrices, are all being evaluated to recapitulate more closely the natural regenerative healing process.
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Affiliation(s)
- Adam J Singer
- Department of Emergency Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, New York, USA
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Short WD, Wang X, Keswani SG. The Role of T Lymphocytes in Cutaneous Scarring. Adv Wound Care (New Rochelle) 2022; 11:121-131. [PMID: 34238032 PMCID: PMC8742284 DOI: 10.1089/wound.2021.0059] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Accepted: 07/05/2021] [Indexed: 01/14/2023] Open
Abstract
Significance: Cutaneous scarring affects millions of patients worldwide and results in significant financial and psychosocial burdens. Given the immune system's intricate involvement in the initiation and progression of wound healing, it is no surprise that the scarring outcome can be affected by the actions of various immune cells and the cytokines and growth factors they produce. Understanding the role of T cells in regulating immune responses and directing the action of wound mesenchymal cells is essential to developing antifibrotic therapies to reduce the burden of scarring. Recent Advances: As the immune system is intimately involved in wound healing, much work has examined the impact of T cells and their cytokines on the final wound outcome. New innovative tools for studying T cells have resulted in more sophisticated immunophenotyping capabilities and the ability to examine effects of individual cytokines in the wound environment. Critical Issues: Despite continued advances in the study of specific immune cells and their effects on dermal fibrosis, minimal progress has been made to modulate immune responses to result in improved wound cosmesis. Future Directions: The actions of T cells represent potential pharmacologic targets that could lead to novel bioengineered or immunoengineered therapies to improve the lives of people with cutaneous scarring.
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Affiliation(s)
- Walker D. Short
- Department of Surgery, Baylor College of Medicine, Houston, Texas, USA
- Laboratory for Regenerative Tissue Repair, Texas Children's Hospital, Houston, Texas, USA
| | - Xinyi Wang
- Department of Surgery, Baylor College of Medicine, Houston, Texas, USA
- Laboratory for Regenerative Tissue Repair, Texas Children's Hospital, Houston, Texas, USA
| | - Sundeep G. Keswani
- Department of Surgery, Baylor College of Medicine, Houston, Texas, USA
- Laboratory for Regenerative Tissue Repair, Texas Children's Hospital, Houston, Texas, USA
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22
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Choi S, Yoon M, Choi KY. Approaches for Regenerative Healing of Cutaneous Wound with an Emphasis on Strategies Activating the Wnt/β-Catenin Pathway. Adv Wound Care (New Rochelle) 2022; 11:70-86. [PMID: 33573472 PMCID: PMC9831250 DOI: 10.1089/wound.2020.1284] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Significance: In adult mammals, spontaneous repair of a cutaneous wound occurs slowly and leaves a scar with skin adnexa deficiencies. To accelerate cutaneous wound-healing rates and avoid scar formation, current studies have focused on regenerative therapies. Recent Advances: Emerging therapeutics for regenerative wound healing often focus on the use of growth factors and stem cells. However, these therapeutic approaches have limited routine clinical use due to high costs and technical requirements. Critical Issue: Understanding the molecular mechanisms involved in the signaling pathways for cutaneous wound healing and neogenic synthesis of the skin components is important for identification of novel targets for the development of regenerative wound-healing agents. Future Directions: The Wnt/β-catenin pathway is a well-known key player for enhancement of the overall healing process involving tissue regeneration via crosstalk with other signaling pathways. Strategies that activate the Wnt/β-catenin pathway via modulation of the pathway-controlling regulatory factors could provide effective therapeutic approaches for regenerative wound healing.
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Affiliation(s)
- Sehee Choi
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea
| | - Minguen Yoon
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea
| | - Kang-Yell Choi
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.,CK Biotech, Inc., Seodaemun-Gu, Korea.,Correspondence: CK Biotech, Inc., Room 417, Engineering Research Park, 50 Yonsei Ro, Seodaemun-Gu 03722, Korea
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Moretti L, Stalfort J, Barker TH, Abebayehu D. The interplay of fibroblasts, the extracellular matrix, and inflammation in scar formation. J Biol Chem 2022; 298:101530. [PMID: 34953859 PMCID: PMC8784641 DOI: 10.1016/j.jbc.2021.101530] [Citation(s) in RCA: 187] [Impact Index Per Article: 62.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 12/08/2021] [Indexed: 02/06/2023] Open
Abstract
Various forms of fibrosis, comprising tissue thickening and scarring, are involved in 40% of deaths across the world. Since the discovery of scarless functional healing in fetuses prior to a certain stage of development, scientists have attempted to replicate scarless wound healing in adults with little success. While the extracellular matrix (ECM), fibroblasts, and inflammatory mediators have been historically investigated as separate branches of biology, it has become increasingly necessary to consider them as parts of a complex and tightly regulated system that becomes dysregulated in fibrosis. With this new paradigm, revisiting fetal scarless wound healing provides a unique opportunity to better understand how this highly regulated system operates mechanistically. In the following review, we navigate the four stages of wound healing (hemostasis, inflammation, repair, and remodeling) against the backdrop of adult versus fetal wound healing, while also exploring the relationships between the ECM, effector cells, and signaling molecules. We conclude by singling out recent findings that offer promising leads to alter the dynamics between the ECM, fibroblasts, and inflammation to promote scarless healing. One factor that promises to be significant is fibroblast heterogeneity and how certain fibroblast subpopulations might be predisposed to scarless healing. Altogether, reconsidering fetal wound healing by examining the interplay of the various factors contributing to fibrosis provides new research directions that will hopefully help us better understand and address fibroproliferative diseases, such as idiopathic pulmonary fibrosis, liver cirrhosis, systemic sclerosis, progressive kidney disease, and cardiovascular fibrosis.
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Affiliation(s)
- Leandro Moretti
- Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA
| | - Jack Stalfort
- Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA
| | - Thomas Harrison Barker
- Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA
| | - Daniel Abebayehu
- Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA.
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Shibuya Y, Hokugo A, Okawa H, Kondo T, Khalil D, Wang L, Roca Y, Clements A, Sasaki H, Berry E, Nishimura I, Jarrahy R. Therapeutic downregulation of neuronal PAS domain 2 ( Npas2) promotes surgical skin wound healing. eLife 2022; 11:e71074. [PMID: 35040776 PMCID: PMC8789286 DOI: 10.7554/elife.71074] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 01/14/2022] [Indexed: 11/13/2022] Open
Abstract
Attempts to minimize scarring remain among the most difficult challenges facing surgeons, despite the use of optimal wound closure techniques. Previously, we reported improved healing of dermal excisional wounds in circadian clock neuronal PAS domain 2 (Npas2)-null mice. In this study, we performed high-throughput drug screening to identify a compound that downregulates Npas2 activity. The hit compound (Dwn1) suppressed circadian Npas2 expression, increased murine dermal fibroblast cell migration, and decreased collagen synthesis in vitro. Based on the in vitro results, Dwn1 was topically applied to iatrogenic full-thickness dorsal cutaneous wounds in a murine model. The Dwn1-treated dermal wounds healed faster with favorable mechanical strength and developed less granulation tissue than the controls. The expression of type I collagen, Tgfβ1, and α-smooth muscle actin was significantly decreased in Dwn1-treated wounds, suggesting that hypertrophic scarring and myofibroblast differentiation are attenuated by Dwn1 treatment. NPAS2 may represent an important target for therapeutic approaches to optimal surgical wound management.
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Affiliation(s)
- Yoichiro Shibuya
- Regenerative Bioengineering and Repair Laboratory, Division of Plastic and Reconstructive Surgery, Department of Surgery, David Geffen School of MedicineLos AngelesUnited States
- Weintraub Center for Reconstructive BiotechnologyLos AngelesUnited States
- Department of Plastic and Reconstructive Surgery, Faculty of Medicine, University of TsukubaTsukubaJapan
| | - Akishige Hokugo
- Regenerative Bioengineering and Repair Laboratory, Division of Plastic and Reconstructive Surgery, Department of Surgery, David Geffen School of MedicineLos AngelesUnited States
- Weintraub Center for Reconstructive BiotechnologyLos AngelesUnited States
| | - Hiroko Okawa
- Weintraub Center for Reconstructive BiotechnologyLos AngelesUnited States
- Division of Molecular and Regenerative Prosthodontics, Tohoku University Graduate School of DentistryMiyagiJapan
| | - Takeru Kondo
- Weintraub Center for Reconstructive BiotechnologyLos AngelesUnited States
- Division of Molecular and Regenerative Prosthodontics, Tohoku University Graduate School of DentistryMiyagiJapan
| | - Daniel Khalil
- Regenerative Bioengineering and Repair Laboratory, Division of Plastic and Reconstructive Surgery, Department of Surgery, David Geffen School of MedicineLos AngelesUnited States
| | - Lixin Wang
- Regenerative Bioengineering and Repair Laboratory, Division of Plastic and Reconstructive Surgery, Department of Surgery, David Geffen School of MedicineLos AngelesUnited States
| | - Yvonne Roca
- Regenerative Bioengineering and Repair Laboratory, Division of Plastic and Reconstructive Surgery, Department of Surgery, David Geffen School of MedicineLos AngelesUnited States
| | - Adam Clements
- Regenerative Bioengineering and Repair Laboratory, Division of Plastic and Reconstructive Surgery, Department of Surgery, David Geffen School of MedicineLos AngelesUnited States
| | - Hodaka Sasaki
- Weintraub Center for Reconstructive BiotechnologyLos AngelesUnited States
| | - Ella Berry
- Regenerative Bioengineering and Repair Laboratory, Division of Plastic and Reconstructive Surgery, Department of Surgery, David Geffen School of MedicineLos AngelesUnited States
| | - Ichiro Nishimura
- Weintraub Center for Reconstructive BiotechnologyLos AngelesUnited States
| | - Reza Jarrahy
- Regenerative Bioengineering and Repair Laboratory, Division of Plastic and Reconstructive Surgery, Department of Surgery, David Geffen School of MedicineLos AngelesUnited States
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Nozaki R, Kasamatsu A, Moss J, Uzawa K. Lysyl hydroxylase 2 deficiency promotes filopodia formation and fibroblast migration. Biochem Biophys Res Commun 2022; 587:146-152. [PMID: 34875533 PMCID: PMC10020999 DOI: 10.1016/j.bbrc.2021.11.100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Accepted: 11/29/2021] [Indexed: 11/19/2022]
Abstract
Lysyl hydroxylase 2 (LH2) regulates intermolecular cross-linking of collagen molecules. Accumulation of LH2-modified collagen, which is highly stable and resistant to collagenase cleavage, is one cause of fibrosis. We previously demonstrated that conventional LH2 knockout mice showed embryonic lethality. Here we established LH2 conditional knockout mice using a tamoxifen-inducible Cre system. Morphological analysis of LH2-deficient fibroblasts by microscopy showed a dramatic increase in the number of filopodia, the finger-like cell surface projections that enable cell movement. The tips and leading edges of these filopodia exhibited up-regulated expression of Myosin-X (Myo10), a regulator of filopodial integrity. Wound healing assays demonstrated that migration of LH2-deficient cells was significantly faster than that of control cells. Gene expression profiling data also supported this phenotype. Together these findings indicate that LH2 deficiency may prevent fibrosis through decreased accumulation of LH2-cross-linked collagen, and that fibroblasts with faster migration contribute to enhanced wound healing activity. In conclusion, our cellular models provide evidence that LH2 deficiency plays a critical role in cell migration mediated through filopodia formation. Understanding the precise role of this phenotype in LH2-deficient cells may be helpful to define the pathogenesis of fibrosis. As such, detailed analyses of fibrosis and wound healing using LH2-deficient mouse models are needed.
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Affiliation(s)
- Ryunosuke Nozaki
- Department of Oral Science, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Atsushi Kasamatsu
- Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, Chiba, Japan.
| | - Joel Moss
- Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Katsuhiro Uzawa
- Department of Oral Science, Graduate School of Medicine, Chiba University, Chiba, Japan; Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, Chiba, Japan.
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Gait analysis combined with the expression of TGF-β1, TGF-β3 and CREB during Achilles tendon healing in rat. Chin J Traumatol 2021; 24:360-367. [PMID: 34696976 PMCID: PMC8606907 DOI: 10.1016/j.cjtee.2021.10.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 08/14/2021] [Accepted: 09/01/2021] [Indexed: 02/04/2023] Open
Abstract
PURPOSE To observe the changes of gait behavior and the expression of wound healing factors of transforming growth factor-β1 (TGF-β1), TGF-β3 and cAMP response element binding protein-1 (CREB-1) during the healing of Achilles tendon in a rat model, and to investigate whether gait analysis can be used to evaluate the tendon healing. METHODS Achilles tendon of 40 healthy male Sprague-Dawley rats were transected and sutured to establish the Achilles tendon injury (ATI) model. They were randomly divided into 4 groups based on the observational time point at 1, 2, 4 and 6 weeks after injury (n = 10 for each group). Before modeling, 9 rats were randomly selected for CatWalk gait analysis, which contained step cycle, single stance time and average speed. Data were recorded as the normal controls. After then, ATI models were established in the left hind limbs of the all 40 rats (ATI group), while the right hind limbs were only cut and sutured without injury of the Achilles tendon (sham operation group). At 1, 2, 4 and 6 weeks after injury, the gait behavior of the corresponding group of rats (n = 9) as observed and recorded by CatWalk platform. After then, the rats were sacrificed and Achilles tendon of both limbs was harvested. The tendon healing was observed by gross anatomy and histological examination, and the protein and mRNA expression of TGF-β1, TGF-β3, CREB-1 were observed by immunohistochemistry and qPCR. The results of tendon gross grading were analyzed by Wilcoxon rank sum test, and other data were analyzed by one-way analysis of variance among multiple groups. RESULTS Compared with normal controls, all gait indexes (step cycle, single stance time and average speed) were greatly affected following ATI, which however improved with time. The step cycle was significantly lower at 1, 2 and 4 weeks after ATI (compared with normal controls, all p < 0.05), but almost returned to the normal level at 6 weeks ((0.694 ± 0.102) vs. (0.503 ± 0.094) s, p > 0.05). The single stance time of the ATI group was significantly shorter at 1 and 2 weeks after operation ((0.078 ± 0.010) s at 1 week, (0.078 ± 0.020) s at 2 weeks, all p < 0.001) and revealed no significant difference at 4 weeks (p = 0.120). The average speed of ATI group at 1, 2, 4, 6 weeks was significantly lower than that in the normal control group (all p < 0.001). Gross observation showed that the grade of local scar adhesion in ATI group increased significantly at 2, 4 and 6 weeks, compared with the sham operation group (all p < 0.001). Extensive adhesion was formed at 6 weeks after ATI. The results of HE staining showed that the number of fibroblast increased gradually and arranged more orderly in ATI group at 1, 2 and 4 weeks (all p < 0.001), and decreased at 6 weeks, but it was still significantly higher than that of the sham operation group (p < 0.001). Immunohistochemistry showed that the positive expression of TGF-β1, TGF-β3, CREB-1 in ATI group was higher than that in the sham operation group at 4 time points (all p < 0.05), which reached the peak at 2 weeks after operation and decreased at 4 weeks (p = 0.002, p < 0.001, p = 0.041, respectively). The results of qPCR suggested that the mRNA expression of TGF-β1, TGF-β3, CREB-1 in ATI group was higher than that in the sham operation group at all-time points (all p < 0.05), which reached the peak at 2 weeks after operation, decreased at 4 weeks, and significantly decreased at 6 weeks (all p < 0.001). CONCLUSION Gait behavior indexes are associated with Achilles tendon healing. The study gives an insight of TGF-β1, TGF-β3, CREB-1 changes in the coursing of Achilles tendon healing and these cytokines may be able to be used to regulate the Achilles tendon healing.
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Hosseini M, Shafiee A. Engineering Bioactive Scaffolds for Skin Regeneration. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2021; 17:e2101384. [PMID: 34313003 DOI: 10.1002/smll.202101384] [Citation(s) in RCA: 85] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 03/24/2021] [Indexed: 06/13/2023]
Abstract
Large skin wounds pose a major clinical challenge. Scarcity of donor site and postsurgical scarring contribute to the incomplete or partial loss of function and aesthetic concerns in skin wound patients. Currently, a wide variety of skin grafts are being applied in clinical settings. Scaffolds are used to overcome the issues related to the misaligned architecture of the repaired skin tissues. The current review summarizes the contribution of biomaterials to wound healing and skin regeneration and addresses the existing limitations in skin grafting. Then, the clinically approved biologic and synthetic skin substitutes are extensively reviewed. Next, the techniques for modification of skin grafts aiming for enhanced tissue regeneration are outlined, and a summary of different growth factor delivery systems using biomaterials is presented. Considering the significant progress in biomaterial science and manufacturing technologies, the idea of biomaterial-based skin grafts with the ability for scarless wound healing and reconstructing full skin organ is more achievable than ever.
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Affiliation(s)
- Motaharesadat Hosseini
- Institute of Health and Biomedical Innovation, Queensland University of Technology (QUT), Kelvin Grove, Brisbane, QLD, 4059, Australia
| | - Abbas Shafiee
- Herston Biofabrication Institute, Metro North Hospital and Health Service, Brisbane, QLD, 4029, Australia
- Royal Brisbane and Women's Hospital, Metro North Hospital and Health Service, Brisbane, QLD, 4029, Australia
- UQ Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD, 4102, Australia
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Otsuka T, Kan HM, Laurencin CT. Regenerative Engineering Approaches to Scar-Free Skin Regeneration. REGENERATIVE ENGINEERING AND TRANSLATIONAL MEDICINE 2021. [DOI: 10.1007/s40883-021-00229-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Baysal I, Ozcelikay G, Yabanoglu-Ciftci S, Ucar BI, Gencer A, Arica-Yegin B. Nanoparticles and Nanostructured Films with TGF-β3: Preparation, Characterization, and Efficacy. AAPS PharmSciTech 2021; 22:213. [PMID: 34378118 DOI: 10.1208/s12249-021-02097-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 07/13/2021] [Indexed: 11/30/2022] Open
Abstract
TGF-β3 has been reported to have a strong therapeutic efficacy in wound healing when externally administered, but TGF-β3's active form is rapidly metabolized and removed from the body. Therefore, a drug delivery system that can provide a new non-toxic and an effective treatment that could be locally applied and also be able to protect the stability of the protein and provide controlled release is required. The aim of the study is to prepare and characterize nanoparticles and nanostructured films with TGF-β3 and to evaluate in vitro cytotoxicity of the loaded nanoparticles. PCL-based films containing TGF-β3 or TGF-β3-loaded PLGA nanoparticles were prepared with non-toxic modified solvent displacement method. The particle size and protein loading efficiency of TGF-β3-loaded PLGA nanoparticles were 204.9 ± 10.3 nm and 42.42 ± 2.03%, respectively. In vitro release studies of TGF-β3-loaded PLGA nanoparticle formulations revealed that the protein was completely released from the nanoparticles at the end of 24 h. In vitro release profile of film formulation containing TGF-β3-loaded nanoparticles was similar. TGF-β3 released from nanoparticles do not have a significant effect on proliferation of HepG2 cells demonstrating their biocompatibility. Additionally, prepared films were tested with in vivo wound healing mouse model and showed to heal significantly faster and with improved scarring. PCL films loaded with TGF-β3 or TGF-β3 nanoparticles prepared in this study may be an effective treatment approach for wound healing therapy after injury.
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The bright side of fibroblasts: molecular signature and regenerative cues in major organs. NPJ Regen Med 2021; 6:43. [PMID: 34376677 PMCID: PMC8355260 DOI: 10.1038/s41536-021-00153-z] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 07/22/2021] [Indexed: 02/07/2023] Open
Abstract
Fibrosis is a pathologic process characterized by the replacement of parenchymal tissue by large amounts of extracellular matrix, which may lead to organ dysfunction and even death. Fibroblasts are classically associated to fibrosis and tissue repair, and seldom to regeneration. However, accumulating evidence supports a pro-regenerative role of fibroblasts in different organs. While some organs rely on fibroblasts for maintaining stem cell niches, others depend on fibroblast activity, particularly on secreted molecules that promote cell adhesion, migration, and proliferation, to guide the regenerative process. Herein we provide an up-to-date overview of fibroblast-derived regenerative signaling across different organs and discuss how this capacity may become compromised with aging. We further introduce a new paradigm for regenerative therapies based on reverting adult fibroblasts to a fetal/neonatal-like phenotype.
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Durant F, Whited JL. Finding Solutions for Fibrosis: Understanding the Innate Mechanisms Used by Super-Regenerator Vertebrates to Combat Scarring. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:e2100407. [PMID: 34032013 PMCID: PMC8336523 DOI: 10.1002/advs.202100407] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 03/12/2021] [Indexed: 05/08/2023]
Abstract
Soft tissue fibrosis and cutaneous scarring represent massive clinical burdens to millions of patients per year and the therapeutic options available are currently quite limited. Despite what is known about the process of fibrosis in mammals, novel approaches for combating fibrosis and scarring are necessary. It is hypothesized that scarring has evolved as a solution to maximize healing speed to reduce fluid loss and infection. This hypothesis, however, is complicated by regenerative animals, which have arguably the most remarkable healing abilities and are capable of scar-free healing. This review explores the differences observed between adult mammalian healing that typically results in fibrosis versus healing in regenerative animals that heal scarlessly. Each stage of wound healing is surveyed in depth from the perspective of many regenerative and fibrotic healers so as to identify the most important molecular and physiological variances along the way to disparate injury repair outcomes. Understanding how these powerful model systems accomplish the feat of scar-free healing may provide critical therapeutic approaches to the treatment or prevention of fibrosis.
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Affiliation(s)
- Fallon Durant
- Department of Stem Cell and Regenerative BiologyHarvard UniversityCambridgeMA02138USA
| | - Jessica L. Whited
- Department of Stem Cell and Regenerative BiologyHarvard UniversityCambridgeMA02138USA
- The Harvard Stem Cell InstituteCambridgeMA02138USA
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Pereira D, Sequeira I. A Scarless Healing Tale: Comparing Homeostasis and Wound Healing of Oral Mucosa With Skin and Oesophagus. Front Cell Dev Biol 2021; 9:682143. [PMID: 34381771 PMCID: PMC8350526 DOI: 10.3389/fcell.2021.682143] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 06/24/2021] [Indexed: 12/14/2022] Open
Abstract
Epithelial tissues are the most rapidly dividing tissues in the body, holding a natural ability for renewal and regeneration. This ability is crucial for survival as epithelia are essential to provide the ultimate barrier against the external environment, protecting the underlying tissues. Tissue stem and progenitor cells are responsible for self-renewal and repair during homeostasis and following injury. Upon wounding, epithelial tissues undergo different phases of haemostasis, inflammation, proliferation and remodelling, often resulting in fibrosis and scarring. In this review, we explore the phenotypic differences between the skin, the oesophagus and the oral mucosa. We discuss the plasticity of these epithelial stem cells and contribution of different fibroblast subpopulations for tissue regeneration and wound healing. While these epithelial tissues share global mechanisms of stem cell behaviour for tissue renewal and regeneration, the oral mucosa is known for its outstanding healing potential with minimal scarring. We aim to provide an updated review of recent studies that combined cell therapy with bioengineering exporting the unique scarless properties of the oral mucosa to improve skin and oesophageal wound healing and to reduce fibrotic tissue formation. These advances open new avenues toward the ultimate goal of achieving scarless wound healing.
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Affiliation(s)
| | - Inês Sequeira
- Institute of Dentistry, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
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33
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Amer Y, Bridges C, Marathe K. Epidemiology, Pathophysiology, and Management Strategies of Neonatal Wound Care. Neoreviews 2021; 22:e452-e460. [PMID: 34210809 DOI: 10.1542/neo.22-7-e452] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Guidelines for neonatal skin care are scarce, and there is no consensus on the best management practices for neonatal skin breakdown. This review presents the pathology and phases of wound healing, reasons for neonatal skin fragility, and approaches to recognition of commonly encountered neonatal wounds. This review also provides general strategies for neonatal wound prevention, care, dressing, and management to avoid further damage to the fragile neonatal skin. The importance and role of retaining moisture in expediting wound healing is discussed, as well as updated classifications on how to grade and assess pressure ulcers and the role of negative pressure wound therapy and silver dressings. Lastly, this review discusses prevention and treatment options for surgical wounds, intravenous extravasation wounds, congenital wounds, and thermal injuries, in addition to how to differentiate these wounds from the common diaper dermatitis and contact dermatitis.
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Affiliation(s)
- Yomna Amer
- School of Medicine, University of Louisville, Louisville, KY
| | - Catherine Bridges
- Department of Dermatology, University of Cincinnati, Cincinnati, OH.,Department of Dermatology, Cincinnati Children's Hospital, Cincinnati, OH
| | - Kalyani Marathe
- Department of Dermatology, Cincinnati Children's Hospital, Cincinnati, OH
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Machcinska S, Kopcewicz M, Bukowska J, Walendzik K, Gawronska-Kozak B. Impairment of the Hif-1α regulatory pathway in Foxn1-deficient (Foxn1 -/- ) mice affects the skin wound healing process. FASEB J 2021; 35:e21289. [PMID: 33475195 DOI: 10.1096/fj.202001907r] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 11/13/2020] [Accepted: 12/03/2020] [Indexed: 02/06/2023]
Abstract
Hypoxia and hypoxia-regulated factors (eg, hypoxia-inducible factor-1α [Hif-1α], factor inhibiting Hif-1α [Fih-1], thioredoxin-1 [Trx-1], aryl hydrocarbon receptor nuclear translocator 2 [Arnt-2]) have essential roles in skin wound healing. Using Foxn1-/- mice that can heal skin injuries in a unique scarless manner, we investigated the interaction between Foxn1 and hypoxia-regulated factors. The Foxn1-/- mice displayed impairments in the regulation of Hif-1α, Trx-1, and Fih-1 but not Arnt-2 during the healing process. An analysis of wounded skin showed that the skin of the Foxn1-/- mice healed in a scarless manner, displaying rapid re-epithelialization and an increase in transforming growth factor β (Tgfβ-3) and collagen III expression. An in vitro analysis revealed that Foxn1 overexpression in keratinocytes isolated from the skin of the Foxn1-/- mice led to reduced Hif-1α expression in normoxic but not hypoxic cultures and inhibited Fih-1 expression exclusively under hypoxic conditions. These data indicate that in the skin, Foxn1 affects hypoxia-regulated factors that control the wound healing process and suggest that under normoxic conditions, Foxn1 is a limiting factor for Hif-1α.
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Affiliation(s)
- Sylwia Machcinska
- Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland
| | - Marta Kopcewicz
- Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland
| | - Joanna Bukowska
- Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland
| | - Katarzyna Walendzik
- Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland
| | - Barbara Gawronska-Kozak
- Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland
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35
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Correa-Gallegos D, Rinkevich Y. Cutting into wound repair. FEBS J 2021; 289:5034-5048. [PMID: 34137168 DOI: 10.1111/febs.16078] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 06/02/2021] [Accepted: 06/16/2021] [Indexed: 11/28/2022]
Abstract
The skin is home to an assortment of fibroblastic lineages that shape the wound repair response toward scars or regeneration. In this review, we discuss the distinct embryonic origins, anatomic locations, and functions of fibroblastic lineages, and how these distinct lineages of fibroblasts dictate the skin's wound response across injury depths, anatomic locations, and embryonic development to promote either scarring or regeneration. We highlight the supportive role of the fascia in dictating scarring outcomes; we then discuss recent findings that indicate fascia mobilization by its resident fibroblasts supersede the classical de novo deposition program of wound matrix formation. These recent findings reconfigure our traditional view of wound repair and present exciting new therapeutic avenues to treat scarring and fibrosis across a range of medical settings.
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Affiliation(s)
- Donovan Correa-Gallegos
- Institute of Lung Biology and Disease, Comprehensive Pneumology Center, Helmholtz Zentrum München, Munich, Germany
| | - Yuval Rinkevich
- Institute of Regenerative Biology and Medicine, Helmholtz Zentrum München, Munich, Germany
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36
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Belgodere J, Son D, Jeon B, Choe J, Guidry AC, Bao AX, Zamin SA, Parikh UM, Balaji S, Kim M, Jung JP. Attenuating Fibrotic Markers of Patient-Derived Dermal Fibroblasts by Thiolated Lignin Composites. ACS Biomater Sci Eng 2021; 7:2212-2218. [PMID: 33938742 PMCID: PMC8290399 DOI: 10.1021/acsbiomaterials.1c00427] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 04/27/2021] [Indexed: 12/31/2022]
Abstract
We report the use of phenolic functional groups of lignosulfonate to impart antioxidant properties and the cell binding domains of gelatin to enhance cell adhesion for poly(ethylene glycol) (PEG)-based scaffolds. Chemoselective thiol-ene chemistry was utilized to form composites with thiolated lignosulfonate (TLS) and methacrylated fish gelatin (fGelMA). Antioxidant properties of TLS were not altered after thiolation and the levels of antioxidation were comparable to those of L-ascorbic acid. PEG-fGelMA-TLS composites significantly reduced the difference in COL1A1, ACTA2, TGFB1, and HIF1A genes between high-scarring and low-scarring hdFBs, providing the potential utility of TLS to attenuate fibrotic responses.
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Affiliation(s)
- Jorge
A. Belgodere
- Department
of Biological Engineering, Louisiana State
University, Baton
Rouge, Louisiana 70803, United States
| | - Dongwan Son
- Department
of Chemistry and Chemical Engineering, Inha
University, Incheon 22212, Republic of Korea
| | - Bokyoung Jeon
- Department
of Biological Engineering, Louisiana State
University, Baton
Rouge, Louisiana 70803, United States
- Department
of Chemistry and Chemical Engineering, Inha
University, Incheon 22212, Republic of Korea
| | - Jongwon Choe
- Department
of Biological Engineering, Louisiana State
University, Baton
Rouge, Louisiana 70803, United States
- Department
of Chemistry and Chemical Engineering, Inha
University, Incheon 22212, Republic of Korea
| | - Anna C. Guidry
- Department
of Biological Engineering, Louisiana State
University, Baton
Rouge, Louisiana 70803, United States
| | - Adam X. Bao
- Department
of Biological Engineering, Louisiana State
University, Baton
Rouge, Louisiana 70803, United States
| | - Syed A. Zamin
- Department
of Biological Engineering, Louisiana State
University, Baton
Rouge, Louisiana 70803, United States
| | - Umang M. Parikh
- Department
of Pediatric Surgery, Texas Children’s
Hospital and Baylor College of Medicine, Houston, Texas 77030, United States
| | - Swathi Balaji
- Department
of Pediatric Surgery, Texas Children’s
Hospital and Baylor College of Medicine, Houston, Texas 77030, United States
| | - Myungwoong Kim
- Department
of Chemistry and Chemical Engineering, Inha
University, Incheon 22212, Republic of Korea
| | - Jangwook P. Jung
- Department
of Biological Engineering, Louisiana State
University, Baton
Rouge, Louisiana 70803, United States
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Monika P, Waiker PV, Chandraprabha MN, Rangarajan A, Murthy KNC. Myofibroblast progeny in wound biology and wound healing studies. Wound Repair Regen 2021; 29:531-547. [PMID: 34009713 DOI: 10.1111/wrr.12937] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 04/15/2021] [Accepted: 05/07/2021] [Indexed: 12/19/2022]
Abstract
Fibroblasts and myofibroblasts play a myriad of important roles in human tissue function, especially in wound repair and healing. Among all cells, fibroblasts are group of cells that decide the status of wound as they maintain tissue homeostasis. Currently, the increase in the deleterious effects of chronic wound and their morbidity rate has necessitated the need to understand the influence of fibroblasts and myofibroblasts, which chiefly originate locally from tissue-resident fibroblasts to address the same. Wound pathophysiology is complex, herein, we have discussed fibroblast and myofibroblast heterogeneity in skin and different organs by understanding the phenotypical and functional properties of each of its sub-populations in the process of wound healing. Recent advancements in fibroblast activation, differentiation to myofibroblasts, proliferation and migration are discussed in detail. Fibroblasts and myofibroblasts are key players in wound healing and wound remodelling, respectively, and their significance in wound repair is discussed. An increased understanding of their biology during wound healing also gives an opportunity to explore more of fibroblast and myofibroblast focused therapies to treat chronic wounds which are clinical challenges. In this regard, in the current review, we have described the different methods for isolation of primary fibroblasts and myofibroblasts from both animal models and humans, and their characterization. Additionally, we have also provided details on possible molecular targets for better understanding of prognosis, diagnosis and treatment of chronic wounds. Information will help both researchers and clinicians in providing molecular insight that enable them for effective chronic wound management. The knowledge of intimate dialogue between the fibroblast, sub-populations like, myofibroblast and their microenvironment, will serve useful in determining novel, efficient and specific therapeutic targets to treat pathological wound conditions.
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Affiliation(s)
- Prakash Monika
- Department of Biotechnology, M. S. Ramaiah Institute of Technology, Bangalore, India
| | | | | | - Annapoorni Rangarajan
- Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, India
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desJardins-Park HE, Mascharak S, Longaker MT, Wan DC. Endogenous Mechanisms of Craniomaxillofacial Repair: Toward Novel Regenerative Therapies. FRONTIERS IN ORAL HEALTH 2021; 2:676258. [PMID: 35048022 PMCID: PMC8757793 DOI: 10.3389/froh.2021.676258] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 04/14/2021] [Indexed: 12/13/2022] Open
Abstract
In the fields of oral and craniomaxillofacial surgery, regeneration of multiple tissue types-including bone, skin, teeth, and mucosal soft tissue-is often a desired outcome. However, limited endogenous capacity for regeneration, as well as predisposition of many tissues to fibrotic healing, may prevent recovery of normal form and function for patients. Recent basic science research has advanced our understanding of molecular and cellular pathways of repair in the oral/craniofacial region and how these are influenced by local microenvironment and embryonic origin. Here, we review the current state of knowledge in oral and craniomaxillofacial tissue repair/regeneration in four key areas: bone (in the context of calvarial defects and mandibular regeneration during distraction osteogenesis); skin (in the context of cleft lip/palate surgery); oral mucosa (in the context of minimally scarring repair of mucosal injuries); and teeth (in the context of dental disease/decay). These represent four distinct healing processes and outcomes. We will discuss both divergent and conserved pathways of repair in these contexts, with an eye toward fundamental mechanisms of regeneration vs. fibrosis as well as translational research directions. Ultimately, this knowledge can be leveraged to develop new cell-based and molecular treatment strategies to encourage bone and soft tissue regeneration in oral and craniomaxillofacial surgery.
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Affiliation(s)
- Heather E. desJardins-Park
- Division of Plastic and Reconstructive Surgery, Hagey Laboratory for Pediatric Regenerative Medicine, Stanford School of Medicine, Department of Surgery, Stanford, CA, United States
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine, Stanford, CA, United States
| | - Shamik Mascharak
- Division of Plastic and Reconstructive Surgery, Hagey Laboratory for Pediatric Regenerative Medicine, Stanford School of Medicine, Department of Surgery, Stanford, CA, United States
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine, Stanford, CA, United States
| | - Michael T. Longaker
- Division of Plastic and Reconstructive Surgery, Hagey Laboratory for Pediatric Regenerative Medicine, Stanford School of Medicine, Department of Surgery, Stanford, CA, United States
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine, Stanford, CA, United States
| | - Derrick C. Wan
- Division of Plastic and Reconstructive Surgery, Hagey Laboratory for Pediatric Regenerative Medicine, Stanford School of Medicine, Department of Surgery, Stanford, CA, United States
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39
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Wilgus TA. A Murine Incisional Fetal Wound-Healing Model to Study Scarless and Fibrotic Skin Repair. Methods Mol Biol 2021; 2193:13-21. [PMID: 32808254 DOI: 10.1007/978-1-0716-0845-6_2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The ideal response to skin injury is the complete regeneration of normal tissue without scar formation. This regenerative response is known to occur at early stages of embryonic development but is lost as the skin becomes more mature. In more developed skin, the wound-healing response is suboptimal and results in the formation of scar tissue. Scar tissue can be a significant clinical concern, causing skin dysfunction as well as psychosocial issues related to poor aesthetic outcomes. Mouse models of fetal wound healing can be useful for understanding what regulatory pathways lead to skin regeneration and scarless healing in less developed skin or scarring and fibrotic healing in more developed skin. Here, a reproducible incisional wound model in developing mice is described that our lab has used repeatedly to study scarless and fibrotic fetal wound healing.
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Affiliation(s)
- Traci A Wilgus
- Department of Pathology, The Ohio State University, Columbus, OH, USA.
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40
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Shabanzadeh DM, Clausen S, Maigaard K, Fode M. Male Circumcision Complications - A Systematic Review, Meta-Analysis and Meta-Regression. Urology 2021; 152:25-34. [PMID: 33545206 DOI: 10.1016/j.urology.2021.01.041] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 01/13/2021] [Accepted: 01/18/2021] [Indexed: 10/22/2022]
Abstract
OBJECTIVE To determine the risk of complications requiring treatment following male circumcision by health-care professionals and to explore the impact of participant characteristics, type of circumcision and study design. METHODS We identified studies through systematic searches in online databases (MEDLINE, EMBASE and CENTRAL) and hand searches. We performed random-effects meta-analysis to determine risk of circumcision complications and mixed-effects metaregression analyses to explore the impact of participant characteristics, type of circumcision and study design. Methods were prespecified in a registered protocol (Prospero CRD42020116770) and according to PRISMA guidelines. RESULTS We included 351 studies with 4.042.988 participants. Overall complication risk was 3.84% (95% confidence interval 3.35-4.37). Our meta-analysis revealed that therapeutic circumcisions were associated with a 2-fold increase in complications as compared to nontherapeutic (7.47% and 3.34%, respectively). Adhesions, meatal stenosis and infections were the most frequent complication subgroups to therapeutic circumcisions. Bleeding, device removals and infections occurred more frequently in nontherapeutic circumcisions. Additionally, adjusted metaregression analyses revealed that children above 2 years, South American continent, older publication year and smaller study populations increased complication risk. Type of circumcision method, provider and setting were not associated with complication risk. Sensitivity analyses including only better-quality studies reporting indication, age at circumcision, treatment for complications, full-text articles, and adequate follow-up clinically for a minimum of one month or through databases confirmed our main findings while accounting better for heterogeneity. CONCLUSION Circumcision complications occur in about 4 per hundred circumcisions. Higher risks of complications were determined by therapeutic circumcisions and by childhood age when compared to infant. Future studies should assess therapeutic and childhood circumcisions separately.
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Affiliation(s)
- Daniel Mønsted Shabanzadeh
- Department of Gastroenterology, Surgical Unit, Copenhagen University Hospital, Hvidovre, Capital Region of Denmark.
| | - Signe Clausen
- Mental Health Services, Capital Region of Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Capital Region of Denmark
| | | | - Mikkel Fode
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Capital Region of Denmark; Department of Urology, Zealand University Hospital, Roskilde, Capital Region of Denmark
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41
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Wilgus TA. Inflammation as an orchestrator of cutaneous scar formation: a review of the literature. PLASTIC AND AESTHETIC RESEARCH 2020; 7:54. [PMID: 33123623 PMCID: PMC7592345 DOI: 10.20517/2347-9264.2020.150] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Inflammation is a key phase in the cutaneous wound repair process. The activation of inflammatory cells is critical for preventing infection in contaminated wounds and results in the release of an array of mediators, some of which stimulate the activity of keratinocytes, endothelial cells, and fibroblasts to aid in the repair process. However, there is an abundance of data suggesting that the strength of the inflammatory response early in the healing process correlates directly with the amount of scar tissue that will eventually form. This review will summarize the literature related to inflammation and cutaneous scar formation, highlight recent discoveries, and discuss potential treatment modalities that target inflammation to minimize scarring.
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Affiliation(s)
- Traci A Wilgus
- Department of Pathology, Ohio State University, Columbus, OH 43210, USA
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Koudouna E, Spurlin J, Babushkina A, Quantock AJ, Jester JV, Lwigale P. Recapitulation of normal collagen architecture in embryonic wounded corneas. Sci Rep 2020; 10:13815. [PMID: 32796881 PMCID: PMC7427794 DOI: 10.1038/s41598-020-70658-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Accepted: 07/31/2020] [Indexed: 02/06/2023] Open
Abstract
Wound healing is characterized by cell and extracellular matrix changes mediating cell migration, fibrosis, remodeling and regeneration. We previously demonstrated that chick fetal wound healing shows a regenerative phenotype regarding the cellular and molecular organization of the cornea. However, the chick corneal stromal structure is remarkably complex in the collagen fiber/lamellar organization, involving branching and anastomosing of collagen bundles. It is unknown whether the chick fetal wound healing is capable of recapitulating this developmentally regulated organization pattern. The purpose of this study was to examine the three-dimensional collagen architecture of wounded embryonic corneas, whilst identifying temporal and spatial changes in collagen organization during wound healing. Linear corneal wounds that traversed the epithelial layer, Bowman´s layer, and anterior stroma were generated in chick corneas on embryonic day 7. Irregular thin collagen fibers are present in the wounded cornea during the early phases of wound healing. As wound healing progresses, the collagen organization dramatically changes, acquiring an orthogonal arrangement. Fourier transform analysis affirmed this observation and revealed that adjacent collagen lamellae display an angular displacement progressing from the epithelium layer towards the endothelium. These data indicate that the collagen organization of the wounded embryonic cornea recapitulate the native macrostructure.
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Affiliation(s)
- Elena Koudouna
- Gavin Herbert Eye Institute, University of California Irvine, Irvine, CA, USA.,Structural Biophysics Research Group, School of Optometry and Vision Sciences, Cardiff University, Cardiff, Wales, UK
| | - James Spurlin
- Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ, USA
| | - Anna Babushkina
- Department of Biosciences, Rice University, Houston, TX, USA
| | - Andrew J Quantock
- Structural Biophysics Research Group, School of Optometry and Vision Sciences, Cardiff University, Cardiff, Wales, UK
| | - James V Jester
- Gavin Herbert Eye Institute, University of California Irvine, Irvine, CA, USA
| | - Peter Lwigale
- Department of Biosciences, Rice University, Houston, TX, USA.
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Monavarian M, Kader S, Moeinzadeh S, Jabbari E. Regenerative Scar-Free Skin Wound Healing. TISSUE ENGINEERING PART B-REVIEWS 2020; 25:294-311. [PMID: 30938269 DOI: 10.1089/ten.teb.2018.0350] [Citation(s) in RCA: 163] [Impact Index Per Article: 32.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
IMPACT STATEMENT Millions of people every year develop scars in response to skin injuries after surgery, trauma, or burns with significant undesired physical and psychological effects. This review provides an update on engineering strategies for scar-free wound healing and discusses the role of different cell types, growth factors, cytokines, and extracellular components in regenerative wound healing. The use of pro-regenerative matrices combined with engineered cells with less intrinsic potential for fibrogenesis is a promising strategy for achieving scar-free skin tissue regeneration.
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Affiliation(s)
- Mehri Monavarian
- 1Biomimetic Materials and Tissue Engineering Laboratory, Department of Chemical Engineering, University of South Carolina, Columbia, South Carolina
| | - Safaa Kader
- 1Biomimetic Materials and Tissue Engineering Laboratory, Department of Chemical Engineering, University of South Carolina, Columbia, South Carolina.,2Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina
| | - Seyedsina Moeinzadeh
- 1Biomimetic Materials and Tissue Engineering Laboratory, Department of Chemical Engineering, University of South Carolina, Columbia, South Carolina
| | - Esmaiel Jabbari
- 1Biomimetic Materials and Tissue Engineering Laboratory, Department of Chemical Engineering, University of South Carolina, Columbia, South Carolina
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Current potential therapeutic strategies targeting the TGF-β/Smad signaling pathway to attenuate keloid and hypertrophic scar formation. Biomed Pharmacother 2020; 129:110287. [PMID: 32540643 DOI: 10.1016/j.biopha.2020.110287] [Citation(s) in RCA: 227] [Impact Index Per Article: 45.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 05/08/2020] [Accepted: 05/16/2020] [Indexed: 12/12/2022] Open
Abstract
Aberrant scar formation, which includes keloid and hypertrophic scars, is associated with a pathological disorganized wound healing process with chronic inflammation. The TGF-β/Smad signaling pathway is the most canonical pathway through which the formation of collagen in the fibroblasts and myofibroblasts is regulated. Sustained activation of the TGF-β/Smad signaling pathway results in the long-term overactivation of fibroblasts and myofibroblasts, which is necessary for the excessive collagen formation in aberrant scars. There are two categories of therapeutic strategies that aim to target the TGF-β/Smad signaling pathway in fibroblasts and myofibroblasts to interfere with their cellular functions and reduce cell proliferation. The first therapeutic strategy includes medications, and the second strategy is composed of genetic and cellular therapeutics. Therefore, the focus of this review is to critically evaluate these two main therapeutic strategies that target the TGF-β/Smad pathway to attenuate abnormal skin scar formation.
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45
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Paterson YZ, Cribbs A, Espenel M, Smith EJ, Henson FMD, Guest DJ. Genome-wide transcriptome analysis reveals equine embryonic stem cell-derived tenocytes resemble fetal, not adult tenocytes. Stem Cell Res Ther 2020; 11:184. [PMID: 32430075 PMCID: PMC7238619 DOI: 10.1186/s13287-020-01692-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 04/21/2020] [Accepted: 04/28/2020] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Tendon injuries occur frequently in human and equine athletes. Treatment options are limited, and the prognosis is often poor with functionally deficient scar tissue resulting. Fetal tendon injuries in contrast are capable of healing without forming scar tissue. Embryonic stem cells (ESCs) may provide a potential cellular therapeutic to improve adult tendon regeneration; however, whether they can mimic the properties of fetal tenocytes is unknown. To this end, understanding the unique expression profile of normal adult and fetal tenocytes is crucial to allow validation of ESC-derived tenocytes as a cellular therapeutic. METHODS Equine adult, fetal and ESC-derived tenocytes were cultured in a three-dimensional environment, with histological, morphological and transcriptomic differences compared. Additionally, the effects on gene expression of culturing adult and fetal tenocytes in either conventional two-dimensional monolayer culture or three-dimensional culture were compared using RNA sequencing. RESULTS No qualitative differences in three-dimensional tendon constructs generated from adult, fetal and ESCs were found using histological and morphological analysis. However, genome-wide transcriptomic analysis using RNA sequencing revealed that ESC-derived tenocytes' transcriptomic profile more closely resembled fetal tenocytes as opposed to adult tenocytes. Furthermore, this study adds to the growing evidence that monolayer cultured cells' gene expression profiles converge, with adult and fetal tenocytes having only 10 significantly different genes when cultured in this manner. In contrast, when adult and fetal tenocytes were cultured in 3D, large distinctions in gene expression between these two developmental stages were found, with 542 genes being differentially expressed. CONCLUSION The information provided in this study makes a significant contribution to the investigation into the differences between adult reparative and fetal regenerative cells and supports the concept of using ESC-derived tenocytes as a cellular therapy. Comparing two- and three-dimensional culture also indicates three-dimensional culture as being a more physiologically relevant culture system for determining transcriptomic difference between the same cell types from different developmental stages.
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Affiliation(s)
- Y. Z. Paterson
- Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge, CB3 0ES UK
- Centre for Preventive Medicine, Animal Health Trust, Lanwades Park, Kentford, Newmarket, Suffolk, CB8 7UU UK
| | - A. Cribbs
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, OX3 7LD UK
| | - M. Espenel
- Centre for Preventive Medicine, Animal Health Trust, Lanwades Park, Kentford, Newmarket, Suffolk, CB8 7UU UK
| | - E. J. Smith
- Centre for Preventive Medicine, Animal Health Trust, Lanwades Park, Kentford, Newmarket, Suffolk, CB8 7UU UK
| | - F. M. D. Henson
- Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge, CB3 0ES UK
- Centre for Preventive Medicine, Animal Health Trust, Lanwades Park, Kentford, Newmarket, Suffolk, CB8 7UU UK
| | - D. J. Guest
- Centre for Preventive Medicine, Animal Health Trust, Lanwades Park, Kentford, Newmarket, Suffolk, CB8 7UU UK
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Botting RA, Haniffa M. The developing immune network in human prenatal skin. Immunology 2020; 160:149-156. [PMID: 32173857 PMCID: PMC7218404 DOI: 10.1111/imm.13192] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 03/09/2020] [Accepted: 03/10/2020] [Indexed: 02/06/2023] Open
Abstract
Establishment of a well‐functioning immune network in skin is crucial for its barrier function. This begins in utero alongside the structural differentiation and maturation of skin, and continues to expand and diversify across the human lifespan. The microenvironment of the developing human skin supports immune cell differentiation and has an overall anti‐inflammatory profile. Immunologically inert and skewed immune populations found in developing human skin promote wound healing, and as such may play a crucial role in the structural changes occurring during skin development.
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Affiliation(s)
- Rachel Anne Botting
- Faculty of Medical Sciences, Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Muzlifah Haniffa
- Faculty of Medical Sciences, Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK.,Wellcome Sanger Institute, Hinxton, UK.,Department of Dermatology and NIHR Newcastle Biomedical Research Centre, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
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47
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Poinas A, Perrot P, Lorant J, Nerrière O, Nguyen JM, Saiagh S, Frenard C, Leduc A, Malard O, Espitalier F, Duteille F, Chiffoleau A, Vrignaud F, Khammari A, Dréno B. CICAFAST: comparison of a biological dressing composed of fetal fibroblasts and keratinocytes on a split-thickness skin graft donor site versus a traditional dressing: a randomized controlled trial. Trials 2019; 20:612. [PMID: 31661012 PMCID: PMC6819456 DOI: 10.1186/s13063-019-3718-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Accepted: 09/13/2019] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Wound repair is one of the most complex biological processes of human life. Allogeneic cell-based engineered skin substitutes provide off-the-shelf temporary wound coverage and act as biologically active dressings, releasing growth factors, cytokines and extracellular matrix components essential for proper wound healing. However, they are susceptible to immune rejection and this is their major weakness. Thanks to their low immunogenicity and high effectiveness in regeneration, fetal skin cells represent an attractive alternative to the commonly used autologous and allogeneic skin grafts. METHODS/DESIGN We developed a new dressing comprising a collagen matrix seeded with a specific ratio of active fetal fibroblasts and keratinocytes. These produce a variety of healing growth factors and cytokines which will increase the speed of wound healing and induce an immunotolerant state, with a slight inflammatory reaction and a reduction in pain. The objective of this study is to demonstrate that the use of this biological dressing for wound healing at the split-thickness skin graft (STSG) donor site, reduces the time to healing, decreases other co-morbidities, such as pain, and improves the appearance of the scar. This investigation will be conducted as part of a randomized study comparing our new biological dressing with a conventional treatment in a single patient, thus avoiding the factors that may influence the healing of a graft donor site. DISCUSSION This clinical trial should enable the development of a new strategy for STSG donor-wound healing based on a regenerative dressing. The pain experienced in the first few days of STSG healing is well known due to the exposure of sensory nerve endings. Reducing this pain will also reduce analgesic drug intake and the duration of sick leave. Our biological dressing will meet the essential need of surgeons to "re-crop" from existing donor sites, e.g., for thermal-burn patients. By accelerating healing, improving the appearance of the scar and reducing pain, we hope to improve the conditions of treatment for skin grafts. TRIAL REGISTRATION ClinicalTrials.gov, ID: NCT03334656 . Registered on 7 November 2017.
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Affiliation(s)
- Alexandra Poinas
- Clinical Investigation Centre CIC1413, Nantes INSERM and CHU Nantes, 5, allée de l’île Gloriette, 44093 Nantes Cedex 1, France
| | - Pierre Perrot
- Plastic and Reconstructive Surgery Department, Burns Centre, Jean Monnet, CHU Nantes, 30 Boulevard Jean-Monnet, 44093 Nantes Cedex 1, France
| | - Judith Lorant
- CRCINA, INSERM, Université de Nantes, Nantes, France
| | - Olivier Nerrière
- Cell and Gene Therapy Unit, CHU Nantes, Place Alexis Ricordeau, 44093 Nantes, France
| | - Jean-Michel Nguyen
- Department of Epidemiology and Biostatistics, CHU Nantes, CRCINA, INSERM 1232, Université de Nantes, Nantes, France
| | - Soraya Saiagh
- Cell and Gene Therapy Unit, CHU Nantes, Place Alexis Ricordeau, 44093 Nantes, France
| | - Cécile Frenard
- Dermato-oncology Department, CHU Nantes, CRCINA, INSERM 1232, Université de Nantes, Place Alexis Ricordeau, 44093 Nantes, France
| | - Audrey Leduc
- Plastic and Reconstructive Surgery Department, Burns Centre, Jean Monnet, CHU Nantes, 30 Boulevard Jean-Monnet, 44093 Nantes Cedex 1, France
| | - Olivier Malard
- Department of ENT and Cervico-facial Surgery, CHU Nantes, 44093 Nantes, France
| | - Florent Espitalier
- Department of ENT and Cervico-facial Surgery, CHU Nantes, 44093 Nantes, France
| | - Franck Duteille
- Plastic and Reconstructive Surgery Department, Burns Centre, Jean Monnet, CHU Nantes, 30 Boulevard Jean-Monnet, 44093 Nantes Cedex 1, France
| | - Anne Chiffoleau
- Sponsor Department, CHU Nantes, 5 Allée de L’île Gloriette, 44093 Nantes Cedex 1, France
| | - Florence Vrignaud
- Clinical Investigation Centre CIC1413, Nantes INSERM and CHU Nantes, 5, allée de l’île Gloriette, 44093 Nantes Cedex 1, France
| | - Amir Khammari
- Clinical Investigation Centre CIC1413, Nantes INSERM and CHU Nantes, 5, allée de l’île Gloriette, 44093 Nantes Cedex 1, France
- Dermato-oncology Department, CHU Nantes, CRCINA, INSERM 1232, Université de Nantes, Place Alexis Ricordeau, 44093 Nantes, France
| | - Brigitte Dréno
- Clinical Investigation Centre CIC1413, Nantes INSERM and CHU Nantes, 5, allée de l’île Gloriette, 44093 Nantes Cedex 1, France
- Cell and Gene Therapy Unit, CHU Nantes, Place Alexis Ricordeau, 44093 Nantes, France
- Dermato-oncology Department, CHU Nantes, CRCINA, INSERM 1232, Université de Nantes, Place Alexis Ricordeau, 44093 Nantes, France
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48
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Gimenez A, Kopkin R, Chang DK, Belfort M, Reece EM. Advances in Fetal Surgery: Current and Future Relevance in Plastic Surgery. Semin Plast Surg 2019; 33:204-212. [PMID: 31384237 DOI: 10.1055/s-0039-1693431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Scarless healing has long been the holy grail for plastic surgery. While historically fetal surgery has tempted plastic surgeons with the allure of scarless correction of congenital abnormalities, the risks far outweighed the benefits and these interventions never materialized. Current advances in fetal surgery with minimally invasive fetoscopic surgery have made these early fetal interventions safer, leading to expanding applications. While the plastic surgeon's role is limited as of yet, this article provides a review of the history of fetal surgery and the advances that may become relevant to the future plastic surgeon.
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Affiliation(s)
- Alejandro Gimenez
- Division of Plastic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas
| | - Rachel Kopkin
- School of Medicine, Health Sciences Center, Louisiana State University, New Orleans, Louisiana.,Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas
| | - Daniel K Chang
- Division of Plastic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas
| | - Michael Belfort
- Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas
| | - Edward M Reece
- Division of Plastic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas
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Korntner S, Lehner C, Gehwolf R, Wagner A, Grütz M, Kunkel N, Tempfer H, Traweger A. Limiting angiogenesis to modulate scar formation. Adv Drug Deliv Rev 2019; 146:170-189. [PMID: 29501628 DOI: 10.1016/j.addr.2018.02.010] [Citation(s) in RCA: 91] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2017] [Revised: 01/22/2018] [Accepted: 02/26/2018] [Indexed: 02/06/2023]
Abstract
Angiogenesis, the process of new blood vessel formation from existing blood vessels, is a key aspect of virtually every repair process. During wound healing an extensive, but immature and leaky vascular plexus forms which is subsequently reduced by regression of non-functional vessels. More recent studies indicate that uncontrolled vessel growth or impaired vessel regression as a consequence of an excessive inflammatory response can impair wound healing, resulting in scarring and dysfunction. However, in order to elucidate targetable factors to promote functional tissue regeneration we need to understand the molecular and cellular underpinnings of physiological angiogenesis, ranging from induction to resolution of blood vessels. Especially for avascular tissues (e.g. cornea, tendon, ligament, cartilage, etc.), limiting rather than boosting vessel growth during wound repair potentially is beneficial to restore full tissue function and may result in favourable long-term healing outcomes.
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50
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Strnadova K, Sandera V, Dvorankova B, Kodet O, Duskova M, Smetana K, Lacina L. Skin aging: the dermal perspective. Clin Dermatol 2019; 37:326-335. [PMID: 31345320 DOI: 10.1016/j.clindermatol.2019.04.005] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The world population of adults aged 60 years or more is increasing globally, and this development can impact skin disease morbidity and mortality, as well as being reflected in the health care system organization. There is substantial evidence that the burden from a remarkable number of skin nonmalignant and malignant conditions is greater in the elderly. Dermatologic research and clinical education in dermatology should focus on both challenges and opportunities created by aging. Skin aging due to intrinsic and extrinsic factors can alter significantly epidermal and dermal structure and functions. Dermal aging can be linked to a great number of complications in routine dermatologic conditions, with slow healing as an example of a severe complication in the elderly. This may be attributed to aged dermal fibroblasts modifying the tissue microenvironment via a shift in their soluble factors and extracellular matrix repertoire. This senescence-associated secretory phenotype can explain the particular proclivity of aged skin to develop malignancies.
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Affiliation(s)
- Karolina Strnadova
- Institute of Anatomy, First Faculty of Medicine, Charles University, Prague, Czech Republic; BIOCEV, First Faculty of Medicine, Charles University, Vestec, Czech Republic
| | - Vojtech Sandera
- Department of Plastic Surgery, Third Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Barbora Dvorankova
- Institute of Anatomy, First Faculty of Medicine, Charles University, Prague, Czech Republic; BIOCEV, First Faculty of Medicine, Charles University, Vestec, Czech Republic
| | - Ondrej Kodet
- Institute of Anatomy, First Faculty of Medicine, Charles University, Prague, Czech Republic; BIOCEV, First Faculty of Medicine, Charles University, Vestec, Czech Republic; Department of Dermatovenereology, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Marketa Duskova
- Department of Plastic Surgery, Third Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Karel Smetana
- Institute of Anatomy, First Faculty of Medicine, Charles University, Prague, Czech Republic; BIOCEV, First Faculty of Medicine, Charles University, Vestec, Czech Republic
| | - Lukas Lacina
- Institute of Anatomy, First Faculty of Medicine, Charles University, Prague, Czech Republic; BIOCEV, First Faculty of Medicine, Charles University, Vestec, Czech Republic; Department of Dermatovenereology, First Faculty of Medicine, Charles University, Prague, Czech Republic.
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