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Kanoujia J, Raina N, Kishore A, Kaurav M, Tuli HS, Kumar A, Gupta M. Revealing the promising era of silk-based nanotherapeutics: a ray of hope for chronic wound healing treatment. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:6617-6641. [PMID: 39888364 DOI: 10.1007/s00210-024-03761-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 12/23/2024] [Indexed: 02/01/2025]
Abstract
Chronic wounds significantly contribute to disability and affect the mortality rate in diabetic patients. In addition, pressure ulcers, diabetic foot ulcers, arterial ulcers, and venous ulcers pose a significant health burden due to their associated morbidity and death. The complex healing process, environmental factors, and genetic factors have been identified as the rate-limiting stages of chronic wound healing. Changes in temperature, moisture content, mechanical strain, and genetics can result in slow wound healing, increased susceptibility to bacterial infections, and poor matrix remodelling. These obstacles can be addressed with natural biomaterials exhibiting antimicrobial, collagen synthesis, and granulation tissue formation properties. Recently, silk proteins have gained significant attention as a natural biomaterial owing to good biocompatibility, biodegradability, reduced immunogenicity, ease of sterilization, and promote the wound healing process. The silk components such as sericin and fibroin in combination with nano(platforms) effectively promote wound repair. This review emphasises the potential of sericin and fibroin when combined with nano(platforms) like nanoparticles, nanofibers, and nanoparticles-embedded films, membranes, gels, and nanofibers.
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Affiliation(s)
- Jovita Kanoujia
- Amity Institute of Pharmacy, Amity University Madhya Pradesh (AUMP), Gwalior, 474005, Madhya Pradesh, India
| | - Neha Raina
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, Pushp Vihar, New Delhi, 110017, India
| | - Ankita Kishore
- Amity Institute of Pharmacy, Amity University Madhya Pradesh (AUMP), Gwalior, 474005, Madhya Pradesh, India
| | - Monika Kaurav
- KIET School of Pharmacy, KIET Group of Institution, Ghaziabad, Uttar Pradesh, 201206, India
| | - Hardeep Singh Tuli
- Department of Bio-Sciences and Technology, Maharishi Markandeshwar Engineering College, Maharishi Markandeshwar (Deemed to Be University), Mullana, Ambala, 133207, India
| | - Akhilesh Kumar
- Division of Medicine, ICAR Indian Veterinary Research Institute, Izatnagar, Bareilly, UP, 243122, India
| | - Madhu Gupta
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, Pushp Vihar, New Delhi, 110017, India.
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Higuchi Y, Teo JL, Yi D, Kahn M. Safely Targeting Cancer, the Wound That Never Heals, Utilizing CBP/Beta-Catenin Antagonists. Cancers (Basel) 2025; 17:1503. [PMID: 40361430 PMCID: PMC12071182 DOI: 10.3390/cancers17091503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2025] [Revised: 04/25/2025] [Accepted: 04/25/2025] [Indexed: 05/15/2025] Open
Abstract
Stem cells, both normal somatic (SSC) and cancer stem cells (CSC) exist in minimally two states, i.e., quiescent and activated. Regulation of these two states, including their reliance on different metabolic processes, i.e., FAO and glycolysis in quiescent versus activated stem cells respectively, involves the analysis of a complex array of factors (nutrient and oxygen levels, adhesion molecules, cytokines, etc.) to initiate the epigenetic changes to either depart or enter quiescence. Quiescence is a critical feature of SSC that is required to maintain the genomic integrity of the stem cell pool, particularly in long lived complex organisms. Quiescence in CSC, whether they are derived from mutations arising in SSC, aberrant microenvironmental regulation, or via dedifferentiation of more committed progenitors, is a critical component of therapy resistance and disease latency and relapse. At the beginning of vertebrate evolution, approximately 450 million years ago, a gene duplication generated the two members of the Kat3 family, CREBBP (CBP) and EP300 (p300). Despite their very high degree of homology, these two Kat3 coactivators play critical and non-redundant roles at enhancers and super-enhancers via acetylation of H3K27, thereby controlling stem cell quiescence versus activation and the cells metabolic requirements. In this review/perspective, we discuss the unique regulatory roles of CBP and p300 and how specifically targeting the CBP/β-catenin interaction utilizing small molecule antagonists, can correct lineage infidelity and safely eliminate quiescent CSC.
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Affiliation(s)
- Yusuke Higuchi
- Beckman Research Institute, City of Hope, Duarte, CA 91010, USA;
| | - Jia-Ling Teo
- Department of Cancer Biology and Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA; (J.-L.T.); (D.Y.)
| | - Daniel Yi
- Department of Cancer Biology and Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA; (J.-L.T.); (D.Y.)
| | - Michael Kahn
- Department of Cancer Biology and Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA; (J.-L.T.); (D.Y.)
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Han R, Chen M, Peng W, Yue J, Hu J. Transcutaneous electrical acustimulation promotes wound healing in mice by modulating signaling molecules and mitochondria function. Arch Dermatol Res 2025; 317:368. [PMID: 39921686 PMCID: PMC11807081 DOI: 10.1007/s00403-024-03754-y] [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: 09/04/2024] [Revised: 12/01/2024] [Accepted: 12/20/2024] [Indexed: 02/10/2025]
Abstract
Previous research has identified a variety of factors that contribute to the development and maintenance of wounds. Concurrently, electroacupuncture has been demonstrated to facilitate wound healing. However, the effects of transcutaneous electrical acustimulation (TEA) on wound healing, as well as its relationship with key factors such as Wnt3a, TGF-β, Akt, c-Myc, VEGF-A, SP1, nitric oxide (NO), and mitochondrial function, remain largely unexplored. We hypothesize that TEA will activate the signaling factors and enhance mitochondrial functions to promote the repair of skin wounds in mice. An in vivo experimental study was conducted utilizing mouse models with skin wounds. The study comprised three groups: a TEA treatment with wound group, a skin wound model group, and a control group. Wound areas were measured by calculating the product of the length and width of each wound using calipers. Single-cell suspensions were prepared by excising the wound and the immediately surrounding tissue. These suspensions were stained with Trypan blue to assess cell viability, with specific probes to measure the rate of reactive oxygen species (ROS) positivity, and with reagents to quantify NO content. Western blotting (WB) was employed to evaluate protein levels associated with tissue changes, while quantitative polymerase chain reaction (qPCR) was used to assess RNA expression levels. Immunofluorescence staining was performed to visualize protein content and other relevant cellular structures within tissue sections. TEA exhibited anti-inflammatory properties and promoted wound healing in mice. Western blot analysis revealed that TEA enhanced the expression of proteins associated with Wnt3a, TGF-β, Akt, c-Myc, VEGF-A, and SP1 during the wound healing process. Immunofluorescence staining of tissue sections indicated that TEA upregulated the expression of COL1A1, MFN1, GRP75, GRP78, GRP75/ROS, GRP78/ROS, ISCU, and UCP1 while downregulating FIS1. Additionally, qPCR results demonstrated that TEA promoted the expression of IL-10 and miRNA205-5p while inhibiting MMP9 levels. TEA modulates various signaling molecules, influences chaperone proteins related to stress recovery responses, along with mitochondrial dynamics and metabolism.
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Affiliation(s)
- Rong Han
- Department of Biomedical Engineering (BME), City University of Hong Kong, 83 Tat Chee Avenue, Kowloon Tong, Hong Kong, China
| | - Menghua Chen
- Aussway Chinese Medicine Centre, 173 East Boundary Road, Bentleigh East, VIC, 3165, Australia
| | - Wang Peng
- Department of Biomedical Science, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon Tong, Hong Kong, China
| | - Jianbo Yue
- Division of Natural and Applied Sciences, Duke Kunshan University, Suzhou, China
| | - Jinlian Hu
- Department of Biomedical Engineering (BME), City University of Hong Kong, 83 Tat Chee Avenue, Kowloon Tong, Hong Kong, China.
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Ma X, Li M, Zhang Y, Xu T, Zhou X, Qian M, Yang Z, Han X. Akkermansia muciniphila identified as key strain to alleviate gut barrier injury through Wnt signaling pathway. eLife 2025; 12:RP92906. [PMID: 39912727 PMCID: PMC11801796 DOI: 10.7554/elife.92906] [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] [Indexed: 02/07/2025] Open
Abstract
As the largest mucosal surface, the gut has built a physical, chemical, microbial, and immune barrier to protect the body against pathogen invasion. The disturbance of gut microbiota aggravates pathogenic bacteria invasion and gut barrier injury. Fecal microbiota transplantation (FMT) is a promising treatment for microbiome-related disorders, where beneficial strain engraftment is a significant factor influencing FMT outcomes. The aim of this research was to explore the effect of FMT on antibiotic-induced microbiome-disordered (AIMD) models infected with enterotoxigenic Escherichia coli (ETEC). We used piglet, mouse, and intestinal organoid models to explore the protective effects and mechanisms of FMT on ETEC infection. The results showed that FMT regulated gut microbiota and enhanced the protection of AIMD piglets against ETEC K88 challenge, as demonstrated by reduced intestinal pathogen colonization and alleviated gut barrier injury. Akkermansia muciniphila (A. muciniphila) and Bacteroides fragilis (B. fragilis) were identified as two strains that may play key roles in FMT. We further investigated the alleviatory effects of these two strains on ETEC infection in the AIMD mice model, which revealed that A. muciniphila and B. fragilis relieved ETEC-induced intestinal inflammation by maintaining the proportion of Treg/Th17 cells and epithelial damage by moderately activating the Wnt/β-catenin signaling pathway, while the effect of A. muciniphila was better than B. fragilis. We, therefore, identified whether A. muciniphila protected against ETEC infection using basal-out and apical-out intestinal organoid models. A. muciniphila did protect the intestinal stem cells and stimulate the proliferation and differentiation of intestinal epithelium, and the protective effects of A. muciniphila were reversed by Wnt inhibitor. FMT alleviated ETEC-induced gut barrier injury and intestinal inflammation in the AIMD model. A. muciniphila was identified as a key strain in FMT to promote the proliferation and differentiation of intestinal stem cells by mediating the Wnt/β-catenin signaling pathway.
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Affiliation(s)
- Xin Ma
- Key Laboratory of Animal Nutrition and Feed Science in East China, Ministry of Agriculture, College of Animal Sciences, Zhejiang UniversityHangzhouChina
- Hainan Institute of Zhejiang University, Yongyou Industry Park, Yazhou Bay Sci-Tech CitySanyaChina
| | - Meng Li
- Key Laboratory of Animal Nutrition and Feed Science in East China, Ministry of Agriculture, College of Animal Sciences, Zhejiang UniversityHangzhouChina
- Hainan Institute of Zhejiang University, Yongyou Industry Park, Yazhou Bay Sci-Tech CitySanyaChina
| | - Yuanyuan Zhang
- Key Laboratory of Animal Nutrition and Feed Science in East China, Ministry of Agriculture, College of Animal Sciences, Zhejiang UniversityHangzhouChina
| | - Tingting Xu
- Key Laboratory of Animal Nutrition and Feed Science in East China, Ministry of Agriculture, College of Animal Sciences, Zhejiang UniversityHangzhouChina
| | - Xinchen Zhou
- Key Laboratory of Animal Nutrition and Feed Science in East China, Ministry of Agriculture, College of Animal Sciences, Zhejiang UniversityHangzhouChina
- Hainan Institute of Zhejiang University, Yongyou Industry Park, Yazhou Bay Sci-Tech CitySanyaChina
| | - Mengqi Qian
- Key Laboratory of Animal Nutrition and Feed Science in East China, Ministry of Agriculture, College of Animal Sciences, Zhejiang UniversityHangzhouChina
| | - Zhiren Yang
- Key Laboratory of Animal Nutrition and Feed Science in East China, Ministry of Agriculture, College of Animal Sciences, Zhejiang UniversityHangzhouChina
- Hainan Institute of Zhejiang University, Yongyou Industry Park, Yazhou Bay Sci-Tech CitySanyaChina
| | - Xinyan Han
- Key Laboratory of Animal Nutrition and Feed Science in East China, Ministry of Agriculture, College of Animal Sciences, Zhejiang UniversityHangzhouChina
- Hainan Institute of Zhejiang University, Yongyou Industry Park, Yazhou Bay Sci-Tech CitySanyaChina
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Dong TR, Li YJ, Jin SY, Yang FL, Xiong RX, Dai YQ, Song XZ, Guan CP. Progress on mitochondria and hair follicle development in androgenetic alopecia: relationships and therapeutic perspectives. Stem Cell Res Ther 2025; 16:44. [PMID: 39901201 PMCID: PMC11792644 DOI: 10.1186/s13287-025-04182-z] [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: 11/13/2024] [Accepted: 01/23/2025] [Indexed: 02/05/2025] Open
Abstract
Hair loss has long been a significant concern for many individuals. Recent studies have indicated that mitochondria play a more crucial role in hair loss than previously recognized. This review summarizes the connection between mitochondrial dysfunction and hair follicle development, outlines the links between diseases related to mitochondrial disorders and hair issues, and highlights the influence of mitochondrial dysfunction on androgenetic alopecia. We discuss the cellular and signaling mechanisms associated with hair loss and examine how mitochondrial dysfunction, such as insufficient energy supply, signaling irregularities, protein/gene abnormalities, and programmed cell death, can hinder the normal proliferation, differentiation, and growth of hair follicle cells. Furthermore, we discuss current treatment approaches and potential innovative therapies, including mitochondrion-targeting drugs and advanced techniques that directly target hair follicle cells, providing fresh insights into the crucial role of mitochondria in maintaining hair follicle health and managing hair disorders. Furthermore, this review explores future therapeutic strategies and proposes that mitochondrial research could lead to groundbreaking treatments for hair loss, thus providing optimism and new avenues for the treatment of individuals experiencing hair loss. This review not only underscores the central importance of mitochondria in hair health but also emphasizes the importance of advancing research and treatment in this field.
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Affiliation(s)
- Ting-Ru Dong
- Department of Dermatology, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310009, China
| | - Yu-Jie Li
- Department of Dermatology, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310009, China
| | - Shi-Yu Jin
- Department of Dermatology, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310009, China
| | - Feng-Lan Yang
- Department of Dermatology, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310009, China
| | - Ren-Xue Xiong
- Department of Dermatology, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310009, China
- Department of Dermatology, Hangzhou Third People's Hospital, No 38 Xihu Rd, Hangzhou, 310009, China
| | - Ye-Qin Dai
- Department of Dermatology, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310009, China
- Department of Dermatology, Hangzhou Third People's Hospital, No 38 Xihu Rd, Hangzhou, 310009, China
| | - Xiu-Zu Song
- Department of Dermatology, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310009, China
- Department of Dermatology, Hangzhou Third People's Hospital, No 38 Xihu Rd, Hangzhou, 310009, China
| | - Cui-Ping Guan
- Department of Dermatology, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310009, China.
- Department of Dermatology, Hangzhou Third People's Hospital, No 38 Xihu Rd, Hangzhou, 310009, China.
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Li R, Wang H, Wang X, Yang Y, Zhong K, Zhang X, Li H. MSC-EVs and UCB-EVs promote skin wound healing and spatial transcriptome analysis. Sci Rep 2025; 15:4006. [PMID: 39893214 PMCID: PMC11787299 DOI: 10.1038/s41598-025-87592-6] [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: 11/13/2024] [Accepted: 01/20/2025] [Indexed: 02/04/2025] Open
Abstract
Extracellular vesicles (EVs) are important paracrine mediators derived from various cells and biological fluids, including plasma, that are capable of inducing regenerative effects by transferring bioactive molecules such as microRNAs (miRNAs). This study investigated the effect of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) isolated from umbilical cord blood and human umbilical cord plasma-derived extracellular vesicles (UCB-EVs) on wound healing and scar formation reduction. Spatial transcriptomics (ST) was used to study the effects of MSC-EVs and UCB-EVs on the heterogeneity of major cell types and wound healing pathways in mouse skin tissue. MSC-EVs and UCB-EVs were isolated using ultracentrifugation and identified using transmission electron microscopy, nanoparticle tracking analysis, and western blot. The effects of MSC-EVs and UCB-EVs on human dermal fibroblast-adult cell (HDF-a) migration and proliferation were evaluated using cell scratch assays, cell migration assays, and cell proliferation assays. In vivo, MSC-EVs and UCB-EVs were injected around full-cut wounds to evaluate their efficacy of wound healing by measuring wound closure rates and scar width and performing histological analysis. ST was performed on skin tissue samples from mice in each group after wound healing to analyze the heterogeneity of major cell types compared with the control group and investigate potential mechanisms affecting wound healing and scar formation. In vitro experiments demonstrated that MSC-EVs and UCB-EVs promoted the proliferation and migration of HDF-a cells. Local injection of MSC-EVs and UCB-EVs into the periphery of a mouse skin wound accelerated re-epithelialization, promoted wound healing, and reduced scar width. ST analysis of skin tissue from each group after wound healing revealed that MSC-EVs and UCB-EVs reduced the relative expression of marker genes in myofibroblasts, regulated wound healing, and decreased scar formation by reducing the expression of the TGF-β signaling pathway and increasing the expression of the Wnt signaling pathway. The results suggest that MSC-EVs and UCB-EVs play a significant role in the activity of cord blood plasma-derived mesenchymal stem cells and cord blood plasma. They can be considered promising new agents for promoting skin wound healing.
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Affiliation(s)
- Ruonan Li
- Key Laboratory of Animal Biochemistry and Nutrition of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Henan Agricultural University, No.15 Longzihu University Area, Zhengdong New District, Zhengzhou, 450046, China
| | - Haotian Wang
- Key Laboratory of Animal Biochemistry and Nutrition of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Henan Agricultural University, No.15 Longzihu University Area, Zhengdong New District, Zhengzhou, 450046, China
| | - Xiaolong Wang
- HenanYinfeng Biological Engineering Technology Co., LTD, No. 11 Changchun Road, Zhengzhou High tech Industrial Development Zone, Zhengzhou, 450000, China
| | - Yanbin Yang
- Key Laboratory of Animal Biochemistry and Nutrition of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Henan Agricultural University, No.15 Longzihu University Area, Zhengdong New District, Zhengzhou, 450046, China
| | - Kai Zhong
- Key Laboratory of Animal Biochemistry and Nutrition of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Henan Agricultural University, No.15 Longzihu University Area, Zhengdong New District, Zhengzhou, 450046, China.
| | - Xuemei Zhang
- HenanYinfeng Biological Engineering Technology Co., LTD, No. 11 Changchun Road, Zhengzhou High tech Industrial Development Zone, Zhengzhou, 450000, China.
| | - Heping Li
- Key Laboratory of Animal Biochemistry and Nutrition of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Henan Agricultural University, No.15 Longzihu University Area, Zhengdong New District, Zhengzhou, 450046, China.
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Zhen M, Zhu Y, Wang P, Liu X, Zhu J, Liu H, Li J, Zhao J, Shu B. HMGB1 Accelerates Wound Healing by Promoting the Differentiation of Epidermal Stem Cells via the "HMGB1-TLR4-Wnt/Notch" Axis. Adv Wound Care (New Rochelle) 2024. [PMID: 39694535 DOI: 10.1089/wound.2023.0130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2024] Open
Abstract
Objective: Impairments in the differentiation and migratory capacity of epidermal stem cells (ESCs) are pivotal factors contributing to delayed wound healing. High mobility group box1 (HMGB1) has recently emerged as a potential target for tissue repair. Therefore, we aimed to investigate the role and molecular mechanisms of HMGB1 in ESCs during the wound-healing process. Approach: Initially, we examined the expression of HMGB1 and the differentiation of ESCs in normal skin, normal wounds and chronic wounds. Then, we assessed the ESC migration and differentiation, and the key markers in the Wnt/Notch signaling pathways, after treatment of HMGB1 and inhibitor, and the knockdown of toll-like receptor 4 (TLR4), using scratch assay, qPCR, western blotting, and immunofluorescence. Finally, we conducted mice models to analyze the healing rates and quality in vivo. Results: HMGB1 was decreased across all epidermal layers, and the differentiation of ESCs was hindered in diabetic foot ulcer. In vitro, HMGB1 enhanced both the migration and differentiation of ESCs while stimulating the expression of the Wnt/Notch pathway within ESCs. However, the downregulation of TLR4 negated these effects. Finally, our in vivo experiments provided evidence that HMGB1 facilitates wound healing and epidermis differentiation via TLR4 and Wnt/Notch signaling pathways. Innovation: This study innovatively introduces HMGB1 as a novel target for skin wound healing and elucidates its mechanisms of action. Conclusions: HMGB1 accelerated wound healing by promoting the differentiation of epidermal stem cells through the "HMGB1-TLR4-Wnt/Notch" axis, which reveals a new potential mechanism and target to expedite wound healing.
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Affiliation(s)
- Miao Zhen
- Department of Burns and Wound Repair, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yongkang Zhu
- Department of Burn and Plastic Surgery, Shenzhen Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Peng Wang
- Department of Burns and Wound Repair, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiaogang Liu
- Department of Burns and Wound Repair, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Junyou Zhu
- Department of Burns and Wound Repair, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Hengdeng Liu
- Department of Burns and Wound Repair, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jingting Li
- Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jingling Zhao
- Department of Burns and Wound Repair, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Bin Shu
- Department of Burns and Wound Repair, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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Lu J, Zhang W, Zhu Y, Luo P, Tong X, Xie S, Jiang L, Guo X, Huang J, Gu M, Ding X, Xian S, Huang R, Ji S, Xia Z. Revealing the Therapeutic Potential of Stem Cells in Burn Healing: A Deeper Understanding of the Therapeutic Mechanisms of Epidermal Stem Cells and Mesenchymal Stem Cells. Stem Cells Int 2024; 2024:1914585. [PMID: 39717868 PMCID: PMC11666318 DOI: 10.1155/2024/1914585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 07/20/2024] [Accepted: 08/19/2024] [Indexed: 12/25/2024] Open
Abstract
Background: Burns are a global public health issue and a major cause of disability and death around the world. Stem cells, which are the undifferentiated cells with the potential for indefinite proliferation and multilineage differentiation, have the ability to replace injured skin and facilitate the wound repair process through paracrine mechanisms. In light of this, the present study aims to conduct a bibliometric analysis in order to identify research hotspots of stem cell-related burns and assess global research tendencies. Methods: To achieve this objective, we retrieved scientific publications on burns associated with stem cells covering the period from January 1, 1978, to October 13, 2022, from the Web of Science Core Collection (WoSCC). Bibliometric analyses, including production and collaboration analyses between countries, institutions, authors, and journals, as well as keyword and topic analyses, were conducted using the bibliometrix R package, CiteSpace, and VOSviewer. Results: A total of 1648 burns associated with stem cell documents were published and listed on WOSCC. The most contributive country, institution, journal, and author were the United States, LV Prasad Eye Institute, Burns, and Scheffer C.G. Tseng, respectively. More importantly, combined with historical direct citation network, trend topic analysis, keyword co-occurrence network, and substantial literature analysis, we eventually summarized the research hotspots and frontiers on burns associated stem cell reasearch. Conclusion: The present study obtained deep insight into the developing trends and research hotspots on burns associated with stem cells, which arouses growing concerns and implies increasing clinical implications. The mechanism and therapeutics of epidermal stem cells (ESCs) for burn wounds and the mechanism of mesenchymal stem cells (MSCs) and MSC-derived exosomes for burns wounds are two research hotspots in this field.
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Affiliation(s)
- Jianyu Lu
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Wei Zhang
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Yushu Zhu
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Pengfei Luo
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Xirui Tong
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Sujie Xie
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Luofeng Jiang
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Xinya Guo
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Jie Huang
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Minyi Gu
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Xinran Ding
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Shuyuan Xian
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Runzhi Huang
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Shizhao Ji
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Zhaofan Xia
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
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Yuan X, Meng K, Wang Y, Wang Y, Pan C, Sun H, Wang J, Li X. Unlocking the genetic secrets of Dorper sheep: insights into wool shedding and hair follicle development. Front Vet Sci 2024; 11:1489379. [PMID: 39726582 PMCID: PMC11670804 DOI: 10.3389/fvets.2024.1489379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Accepted: 11/14/2024] [Indexed: 12/28/2024] Open
Abstract
Dorper sheep is popular among farming enterprises with strong adaptability, disease resistance, and roughage tolerance, and an unique characteristic of natural shedding of wool. In a large number of observations on experimental sheep farms, it was found that the wool of some sheep still had not shed after May, thus manual shearing was required. Therefore, understanding the molecular mechanisms of normal hair follicles (HFs) development is crucial to revealing the improvement of sheep wool-related traits and mammalian skin-related traits. In this study, transcriptome analysis was performed on skin tissues of adult Dorper ewes in the shedding (S) and non-shedding (N) groups in September 2019, January 2020, and March 2020, respectively. The results identified 3,278 differentially expressed transcripts (DETs) in the three comparison groups within the S group, 720 DETs in the three comparison groups within the N group, and 1,342 DETs in the three comparison groups between the S-vs-N groups. Time-series expression analysis revealed 2 unique expression patterns in HF development, namely, elevated expression in the anagen phase (A pattern) and the telogen phase (T pattern). DETs with stage-specific expression had a significant presence in processes related to the hair cycle and skin development, and several classic signaling pathways involved in sheep HF development, such as Rap1, estrogen, PI3K-Akt, and MAPK, were detected. Combined analysis of DETs, time-series expression data, and weighted gene co-expression network analysis identified core genes and their transcripts influencing HF development, such as DBI, FZD3, KRT17, ZDHHC21, TMEM79, and HOXC13. Additionally, alternative splicing analysis predicted that the isoforms XM_004004383.4 and XM_012125926.3 of ZDHHC21 might play a crucial role in sheep HF development. This study is a valuable resource for explaining the morphology of normal growth and development of sheep HFs and the genetic foundation of mammalian skin-related traits. It also offers potential insights into factors influencing human hair advancement.
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Affiliation(s)
- Xiaochun Yuan
- College of Animal Science and Technology, Ningxia University, Yinchuan, China
| | - Ke Meng
- College of Animal Science and Technology, Ningxia University, Yinchuan, China
| | - Yayan Wang
- College of Animal Science and Technology, Ningxia University, Yinchuan, China
| | - Yifan Wang
- College of Animal Science and Technology, Ningxia University, Yinchuan, China
| | - Cuili Pan
- College of Animal Science and Technology, Ningxia University, Yinchuan, China
| | - Haoran Sun
- College of Animal Science and Technology, Ningxia University, Yinchuan, China
| | - Jankui Wang
- Beijing Key Laboratory of Animal Genetic Improvement, China Agricultural University, Beijing, China
| | - Xinhai Li
- College of Animal Science and Technology, Ningxia University, Yinchuan, China
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10
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Liu J, Liu B, Mu Q, Liu J, Li Y, Gong W, Chahaer T, Song Y, Hai E, Wang H, Zhang Y, Zhao Y. Melatonin promotes the proliferation of dermal papilla cells in cashmere goats via activation of chi-let-7d-5p/WNT2 axis. Genomics 2024; 116:110961. [PMID: 39577785 DOI: 10.1016/j.ygeno.2024.110961] [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: 07/15/2024] [Revised: 11/01/2024] [Accepted: 11/08/2024] [Indexed: 11/24/2024]
Abstract
Exogenous melatonin promotes the differentiation of secondary hair follicles in Cashmere goats, thereby improving cashmere production. MicroRNAs (miRNAs) play a crucial role in regulating post-transcriptional gene expression and influence hair follicle growth. However, the mechanism through which melatonin regulates hair follicle development via miRNA mediation remains unclear. In this study, we used RNA-seq to identify differentially expressed (DE) miRNAs during melatonin-induced growth of secondary hair follicles in inner Mongolian Cashmere goats. In total, 170 DE miRNAs were identified. Enrichment analysis revealed that the target genes of these DE miRNAs were related to biological processes such as protein modification; cytoskeletal components; and the Notch, Wnt, and MAPK signaling pathways. The miRNA-mRNA regulatory network suggested that the DE miRNA chi-let-7d-5p negatively regulates WNT2 expression. Mechanistic studies revealed that melatonin promotes the proliferation of DP cells in Cashmere goats via the chi-let-7d-5p/WNT2 axis.
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Affiliation(s)
- Junyang Liu
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot, China; Inner Mongolia Academy of Agricultural and Animal Husbandry Sciences, Hohhot, China
| | - Bin Liu
- Inner Mongolia Academy of Agricultural and Animal Husbandry Sciences, Hohhot, China
| | - Qing Mu
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot, China; Inner Mongolia Key Laboratory of Sheep & Goat Genetics Breeding and Reproduction, College of Animal Science, Inner Mongolia Agricultural University, Hohhot, China
| | - Jiasen Liu
- Inner Mongolia Academy of Agricultural and Animal Husbandry Sciences, Hohhot, China
| | - Yunhua Li
- Inner Mongolia Academy of Agricultural and Animal Husbandry Sciences, Hohhot, China
| | - Wendian Gong
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot, China
| | - Tergel Chahaer
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot, China; Inner Mongolia Key Laboratory of Sheep & Goat Genetics Breeding and Reproduction, College of Animal Science, Inner Mongolia Agricultural University, Hohhot, China
| | - Yukun Song
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot, China; Inner Mongolia Key Laboratory of Sheep & Goat Genetics Breeding and Reproduction, College of Animal Science, Inner Mongolia Agricultural University, Hohhot, China
| | - Erhan Hai
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot, China; Inner Mongolia Key Laboratory of Sheep & Goat Genetics Breeding and Reproduction, College of Animal Science, Inner Mongolia Agricultural University, Hohhot, China
| | - Haoyuan Wang
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot, China; Inner Mongolia Key Laboratory of Sheep & Goat Genetics Breeding and Reproduction, College of Animal Science, Inner Mongolia Agricultural University, Hohhot, China
| | - Yanjun Zhang
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot, China; Inner Mongolia Key Laboratory of Sheep & Goat Genetics Breeding and Reproduction, College of Animal Science, Inner Mongolia Agricultural University, Hohhot, China
| | - Yanhong Zhao
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot, China; Inner Mongolia Key Laboratory of Sheep & Goat Genetics Breeding and Reproduction, College of Animal Science, Inner Mongolia Agricultural University, Hohhot, China.
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11
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Zhou T, Zhang C, Wang X, Lin J, Yu J, Liang Y, Guo H, Yang M, Shen X, Li J, Shi R, Wang Y, Yang J, Shu Z. Research on traditional Chinese medicine as an effective drug for promoting wound healing. JOURNAL OF ETHNOPHARMACOLOGY 2024; 332:118358. [PMID: 38763370 DOI: 10.1016/j.jep.2024.118358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Revised: 04/26/2024] [Accepted: 05/16/2024] [Indexed: 05/21/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The incidence of skin trauma is high and the repair process is complex, often leading to poor healing and other issues, which can result in significant economic and social burdens. Traditional Chinese medicine (TCM) is a valuable resource with proven effectiveness and safety in wound repair, widely utilized in clinical practice. A systematic analysis of wound healing with a focus on TCM research progress holds both academic and clinical importance. AIM OF THE REVIEW This article reviews the research progress of TCM in promoting wound healing, and provides basic data for the development of innovative drugs that promote wound healing. MATERIALS AND METHODS This article provides a review of the literature from the past decade and conducts a thorough analysis of various databases that contain reports on the use of TCM for wound repair. The data for this systematic research was gathered from electronic databases including CNKI, SciFinder, and PubMed. The study explores and summarizes the research findings and patterns by creating relevant charts. RESULTS This study reviewed the mechanism of wound healing, experimental TCM methods to promote wound healing, the theory and mode of action of TCM to promote wound healing, the active ingredients of TCM that promote wound healing, the efficacy of TCM formulae to promote wound healing, and the potential toxicity of TCM and its antidotes. This study enriched the theory of TCM in promoting wound healing. CONCLUSION Skin wound healing is a complex process that can be influenced by various internal and external factors. This article offers a theoretical foundation for exploring and utilizing TCM resources that enhance wound repair. By analyzing a range of TCM that promote wound healing, the article highlights the clinical importance and future potential of these medicines in promoting wound healing.
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Affiliation(s)
- Tong Zhou
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Department of Biology, Faculty of Arts and Sciences, Beijing Normal University, Zhuhai, 519087, PR China
| | - Chongyang Zhang
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Department of Biology, Faculty of Arts and Sciences, Beijing Normal University, Zhuhai, 519087, PR China
| | - Xiao Wang
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Department of Biology, Faculty of Arts and Sciences, Beijing Normal University, Zhuhai, 519087, PR China
| | - Jiazi Lin
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Department of Biology, Faculty of Arts and Sciences, Beijing Normal University, Zhuhai, 519087, PR China
| | - Jiamin Yu
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Department of Biology, Faculty of Arts and Sciences, Beijing Normal University, Zhuhai, 519087, PR China
| | - Yefang Liang
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Department of Biology, Faculty of Arts and Sciences, Beijing Normal University, Zhuhai, 519087, PR China
| | - Huilin Guo
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Department of Biology, Faculty of Arts and Sciences, Beijing Normal University, Zhuhai, 519087, PR China
| | - Mengru Yang
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Department of Biology, Faculty of Arts and Sciences, Beijing Normal University, Zhuhai, 519087, PR China
| | - Xuejuan Shen
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Department of Biology, Faculty of Arts and Sciences, Beijing Normal University, Zhuhai, 519087, PR China
| | - Jianhua Li
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Department of Biology, Faculty of Arts and Sciences, Beijing Normal University, Zhuhai, 519087, PR China
| | - Ruixiang Shi
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Department of Biology, Faculty of Arts and Sciences, Beijing Normal University, Zhuhai, 519087, PR China
| | - Yi Wang
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China.
| | - Ji Yang
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China.
| | - Zunpeng Shu
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Department of Biology, Faculty of Arts and Sciences, Beijing Normal University, Zhuhai, 519087, PR China.
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12
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Lui PP, Xu JZ, Aziz H, Sen M, Ali N. Jagged-1+ skin Tregs modulate cutaneous wound healing. Sci Rep 2024; 14:20999. [PMID: 39251686 PMCID: PMC11385218 DOI: 10.1038/s41598-024-71512-1] [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: 06/10/2024] [Accepted: 08/28/2024] [Indexed: 09/11/2024] Open
Abstract
Skin-resident regulatory T cells (Tregs) play an irreplaceable role in orchestrating cutaneous immune homeostasis and repair, including the promotion of hair regeneration via the Notch signaling ligand Jagged-1 (Jag1). While skin Tregs are indispensable for facilitating tissue repair post-wounding, it remains unknown if Jag1-expressing skin Tregs impact wound healing. Using a tamoxifen inducible Foxp3creERT2Jag1fl/fl model, we show that loss of functional Jag1 in Tregs significantly delays the rate of full-thickness wound closure. Unlike in hair regeneration, skin Tregs do not utilize Jag1 to impact epithelial stem cells during wound healing. Instead, mice with Treg-specific Jag1 ablation exhibit a significant reduction in Ly6G + neutrophil accumulation at the wound site. However, during both homeostasis and wound healing, the loss of Jag1 in Tregs does not impact the overall abundance or activation profile of immune cell targets in the skin, such as CD4+ and CD8+ T cells, or pro-inflammatory macrophages. This collectively suggests that skin Tregs may utilize Jag1-Notch signalling to co-ordinate innate cell recruitment under conditions of injury but not homeostasis. Overall, our study demonstrates the importance of Jag1 expression in Tregs to facilitate adequate wound repair in the skin.
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Affiliation(s)
- Prudence PokWai Lui
- Peter Gorer Department of Immunobiology, King's College London, London, SE1 9RT, UK
- Centre for Gene Therapy and Regenerative Medicine, King's College London, London, SE1 9RT, UK
| | - Jessie Z Xu
- Peter Gorer Department of Immunobiology, King's College London, London, SE1 9RT, UK
- Centre for Gene Therapy and Regenerative Medicine, King's College London, London, SE1 9RT, UK
| | - Hafsah Aziz
- Peter Gorer Department of Immunobiology, King's College London, London, SE1 9RT, UK
- Centre for Gene Therapy and Regenerative Medicine, King's College London, London, SE1 9RT, UK
| | - Monica Sen
- Peter Gorer Department of Immunobiology, King's College London, London, SE1 9RT, UK
- Centre for Gene Therapy and Regenerative Medicine, King's College London, London, SE1 9RT, UK
| | - Niwa Ali
- Peter Gorer Department of Immunobiology, King's College London, London, SE1 9RT, UK.
- Centre for Gene Therapy and Regenerative Medicine, King's College London, London, SE1 9RT, UK.
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Wiart C, Tan PL, Rajagopal M, Chew YL, Leong MY, Tan LF, Yap VL. Review of Malaysian medicinal plants with potential wound healing activity. BMC Complement Med Ther 2024; 24:268. [PMID: 38997637 PMCID: PMC11245834 DOI: 10.1186/s12906-024-04548-5] [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: 07/06/2023] [Accepted: 06/11/2024] [Indexed: 07/14/2024] Open
Abstract
Wound is defined as the damage to biological tissues including skin, mucous membranes and organ tissues. The acute wound heals in less than 4 weeks without complications, while a chronic wound takes longer than 6 weeks to heal. Wound healing occurs in 4 phases, namely, coagulation, inflammatory, proliferative and remodeling phases. Triclosan and benzalkonium chloride are commonly used as skin disinfectants in wound healing. However, they cause allergic contact dermatitis and antibiotic resistance. Medicinal plants are widely studied due to the limited availability of wound healing agents. The present review included six commonly available medicinal plants in Malaysia such as Aloe barbadensis Miller, Carica papaya Linn., Centella asiatica Linn., Cymbopogon nardus Linn., Ficus benghalensis Linn. and Hibiscus rosa sinensis Linn. Various search engines and databases were used to obtain the scientific findings, including Google Scholar, ScienceDirect, PubMed Central and Research Gate. The review discussed the possible mechanism of action of medicinal plants and their active constituents in the wound healing process. In addition, their application in nanotechnology and wound dressings was also discussed in detail.
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Affiliation(s)
- Christophe Wiart
- Institute for Tropical Biology & Conservation, Universiti Malaysia Sabah, Kota Kinabalu, Sabah, Malaysia.
| | - Puay Luan Tan
- Faculty of Pharmaceutical Sciences, UCSI University, Cheras, Wilayah Persekutuan Kuala, Lumpur, Malaysia.
| | - Mogana Rajagopal
- Faculty of Pharmaceutical Sciences, UCSI University, Cheras, Wilayah Persekutuan Kuala, Lumpur, Malaysia.
| | - Yik-Ling Chew
- Faculty of Pharmaceutical Sciences, UCSI University, Cheras, Wilayah Persekutuan Kuala, Lumpur, Malaysia
| | - Mun Yee Leong
- Faculty of Pharmaceutical Sciences, UCSI University, Cheras, Wilayah Persekutuan Kuala, Lumpur, Malaysia
| | - Lee Fang Tan
- Faculty of Pharmaceutical Sciences, UCSI University, Cheras, Wilayah Persekutuan Kuala, Lumpur, Malaysia
| | - Vi Lien Yap
- Faculty of Pharmaceutical Sciences, UCSI University, Cheras, Wilayah Persekutuan Kuala, Lumpur, Malaysia
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14
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Condorelli AG, Nobili R, Muglia A, Scarpelli G, Marzuolo E, De Stefanis C, Rota R, Diociaiuti A, Alaggio R, Castiglia D, Odorisio T, El Hachem M, Zambruno G. Gamma-Secretase Inhibitors Downregulate the Profibrotic NOTCH Signaling Pathway in Recessive Dystrophic Epidermolysis Bullosa. J Invest Dermatol 2024; 144:1522-1533.e10. [PMID: 38237731 DOI: 10.1016/j.jid.2023.10.045] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 09/29/2023] [Accepted: 10/12/2023] [Indexed: 03/03/2024]
Abstract
Recessive dystrophic epidermolysis bullosa (RDEB) is a rare skin fragility disorder caused by mutations in COL7A1. RDEB is hallmarked by trauma-induced unremitting blistering, chronic wounds with inflammation, and progressive fibrosis, leading to severe disease complications. There is currently no cure for RDEB-associated fibrosis. Our previous studies and increasing evidence highlighted the profibrotic role of NOTCH pathway in different skin disorders, including RDEB. In this study, we further investigated the role of NOTCH signaling in RDEB pathogenesis and explored the effects of its inhibition by γ-secretase inhibitors DAPT and PF-03084014 (nirogacestat). Our analyses demonstrated that JAG1 and cleaved NOTCH1 are upregulated in primary RDEB fibroblasts (ie, RDEB-derived fibroblasts) compared with controls, and their protein levels are further increased by TGF-β1 stimulation. Functional assays unveiled the involvement of JAG1/NOTCH1 axis in RDEB fibrosis and demonstrated that its blockade counteracts a variety of fibrotic traits. In particular, RDEB-derived fibroblasts treated with PF-03084014 showed (i) a significant reduction of contractility, (ii) a diminished secretion of TGF-β1 and collagens, and (iii) the downregulation of several fibrotic proteins. Although less marked than PF-03084014-treated cells, RDEB-derived fibroblasts exhibited a reduction of fibrotic traits also upon DAPT treatment. This study provides potential therapeutic strategies to antagonize RDEB fibrosis onset and progression.
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Affiliation(s)
- Angelo Giuseppe Condorelli
- Genodermatosis Unit, Translational Pediatrics and Clinical Genetics Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
| | - Rebecca Nobili
- Genodermatosis Unit, Translational Pediatrics and Clinical Genetics Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Anita Muglia
- Genodermatosis Unit, Translational Pediatrics and Clinical Genetics Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Giorgia Scarpelli
- Genodermatosis Unit, Translational Pediatrics and Clinical Genetics Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Elisa Marzuolo
- Genodermatosis Unit, Translational Pediatrics and Clinical Genetics Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | | | - Rossella Rota
- Department of Hematology and Oncology, Cell and Gene Therapy Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Andrea Diociaiuti
- Genodermatosis Unit, Translational Pediatrics and Clinical Genetics Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy; Dermatology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Rita Alaggio
- Pathology Unit and Predictive Molecular Pathology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy; Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "La Sapienza", Rome, Italy
| | - Daniele Castiglia
- Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata-IRCCS, Rome, Italy
| | - Teresa Odorisio
- Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata-IRCCS, Rome, Italy
| | - May El Hachem
- Genodermatosis Unit, Translational Pediatrics and Clinical Genetics Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy; Dermatology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Giovanna Zambruno
- Genodermatosis Unit, Translational Pediatrics and Clinical Genetics Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
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15
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Xu LM, Yu XX, Zhang N, Chen YS. Exosomes from umbilical cord mesenchymal stromal cells promote the collagen production of fibroblasts from pelvic organ prolapse. World J Stem Cells 2024; 16:708-727. [PMID: 38948096 PMCID: PMC11212552 DOI: 10.4252/wjsc.v16.i6.708] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 03/23/2024] [Accepted: 04/22/2024] [Indexed: 06/25/2024] Open
Abstract
BACKGROUND Pelvic organ prolapse (POP) involves pelvic organ herniation into the vagina due to pelvic floor tissue laxity, and vaginal structure is an essential factor. In POP, the vaginal walls exhibit abnormal collagen distribution and decreased fibroblast levels and functions. The intricate etiology of POP and the prohibition of transvaginal meshes in pelvic reconstruction surgery present challenges in targeted therapy development. Human umbilical cord mesenchymal stromal cells (hucMSCs) present limitations, but their exosomes (hucMSC-Exo) are promising therapeutic tools for promoting fibroblast proliferation and extracellular matrix remodeling. AIM To investigate the effects of hucMSC-Exo on the functions of primary vaginal fibroblasts and to elucidate the underlying mechanism involved. METHODS Human vaginal wall collagen content was assessed by Masson's trichrome and Sirius blue staining. Gene expression differences in fibroblasts from patients with and without POP were assessed via RNA sequencing (RNA-seq). The effects of hucMSC-Exo on fibroblasts were determined via functional experiments in vitro. RNA-seq data from fibroblasts exposed to hucMSC-Exo and microRNA (miRNA) sequencing data from hucMSC-Exo were jointly analyzed to identify effective molecules. RESULTS In POP, the vaginal wall exhibited abnormal collagen distribution and reduced fibroblast 1 quality and quantity. Treatment with 4 or 6 μg/mL hucMSC-Exo suppressed inflammation in POP group fibroblasts, stimulated primary fibroblast growth, and elevated collagen I (Col1) production in vitro. High-throughput RNA-seq of fibroblasts treated with hucMSC-Exo and miRNA sequencing of hucMSC-Exo revealed that abundant exosomal miRNAs downregulated matrix metalloproteinase 11 (MMP11) expression. CONCLUSION HucMSC-Exo normalized the growth and function of primary fibroblasts from patients with POP by promoting cell growth and Col1 expression in vitro. Abundant miRNAs in hucMSC-Exo targeted and downregulated MMP11 expression. HucMSC-Exo-based therapy may be ideal for safely and effectively treating POP.
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Affiliation(s)
- Lei-Mei Xu
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China
- Department of Gynecology, Shanghai Key Laboratory of Female Reproductive Endocrine-related Diseases, Shanghai 200011, China
| | - Xin-Xin Yu
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China
| | - Ning Zhang
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China
| | - Yi-Song Chen
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China.
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16
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Xu LM, Yu XX, Zhang N, Chen YS. Exosomes from umbilical cord mesenchymal stromal cells promote the collagen production of fibroblasts from pelvic organ prolapse. World J Stem Cells 2024; 16:707-726. [DOI: 10.4252/wjsc.v16.i6.707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 03/23/2024] [Accepted: 04/22/2024] [Indexed: 06/25/2024] Open
Abstract
BACKGROUND Pelvic organ prolapse (POP) involves pelvic organ herniation into the vagina due to pelvic floor tissue laxity, and vaginal structure is an essential factor. In POP, the vaginal walls exhibit abnormal collagen distribution and decreased fibroblast levels and functions. The intricate etiology of POP and the prohibition of transvaginal meshes in pelvic reconstruction surgery present challenges in targeted therapy development. Human umbilical cord mesenchymal stromal cells (hucMSCs) present limitations, but their exosomes (hucMSC-Exo) are promising therapeutic tools for promoting fibroblast proliferation and extracellular matrix remodeling.
AIM To investigate the effects of hucMSC-Exo on the functions of primary vaginal fibroblasts and to elucidate the underlying mechanism involved.
METHODS Human vaginal wall collagen content was assessed by Masson’s trichrome and Sirius blue staining. Gene expression differences in fibroblasts from patients with and without POP were assessed via RNA sequencing (RNA-seq). The effects of hucMSC-Exo on fibroblasts were determined via functional experiments in vitro. RNA-seq data from fibroblasts exposed to hucMSC-Exo and microRNA (miRNA) sequencing data from hucMSC-Exo were jointly analyzed to identify effective molecules.
RESULTS In POP, the vaginal wall exhibited abnormal collagen distribution and reduced fibroblast 1 quality and quantity. Treatment with 4 or 6 μg/mL hucMSC-Exo suppressed inflammation in POP group fibroblasts, stimulated primary fibroblast growth, and elevated collagen I (Col1) production in vitro. High-throughput RNA-seq of fibroblasts treated with hucMSC-Exo and miRNA sequencing of hucMSC-Exo revealed that abundant exosomal miRNAs downregulated matrix metalloproteinase 11 (MMP11) expression.
CONCLUSION HucMSC-Exo normalized the growth and function of primary fibroblasts from patients with POP by promoting cell growth and Col1 expression in vitro. Abundant miRNAs in hucMSC-Exo targeted and downregulated MMP11 expression. HucMSC-Exo-based therapy may be ideal for safely and effectively treating POP.
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Affiliation(s)
- Lei-Mei Xu
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China
- Department of Gynecology, Shanghai Key Laboratory of Female Reproductive Endocrine-related Diseases, Shanghai 200011, China
| | - Xin-Xin Yu
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China
| | - Ning Zhang
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China
| | - Yi-Song Chen
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China
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17
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Keng JW, Lee SK, Sang SH, Liew KB, Teo SS, Mossadeq WMSM, Chow SC, Akowuah GA, Lee SK, Mai CW, Chew YL. Cassia alata and Its Phytochemicals: A Promising Natural Strategy in Wound Recovery. SCI 2024; 6:34. [DOI: 10.3390/sci6020034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2025] Open
Abstract
Cassia alata, a traditional herb with a global presence, is renowned for its anti-inflammatory, antibacterial, and antifungal properties, making it a go-to remedy for skin ailments. While it has demonstrated wound healing capabilities in both in vitro and in vivo studies, the precise mechanisms remain elusive. This review aims to highlight its key phytochemicals, their effects, and the mechanism of action. The compounds that have been reviewed and discussed include kaempferol, apigenin, quercetin, rhein, and rutin. These polyphenols play important roles in normal and impaired wound healing processes, encompassing hemostasis, inflammation, proliferation, and tissue remodeling.
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Affiliation(s)
- Jing-Wen Keng
- Faculty of Pharmaceutical Sciences, UCSI University, Kuala Lumpur 56000, Malaysia
| | - Sue-Kei Lee
- Faculty of Pharmaceutical Sciences, UCSI University, Kuala Lumpur 56000, Malaysia
| | - Sze-Huey Sang
- Faculty of Pharmaceutical Sciences, UCSI University, Kuala Lumpur 56000, Malaysia
| | - Kai-Bin Liew
- Faculty of Pharmacy, University of Cyberjaya, Persiaran Bestari, Cyber 11, Cyberjaya 63000, Malaysia
| | - Swee-Sen Teo
- Faculty of Applied Sciences, UCSI University, Kuala Lumpur 56000, Malaysia
| | | | - Sek-Chuen Chow
- School of Science, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway 46150, Malaysia
| | - Gabriel Akyirem Akowuah
- School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway 46150, Malaysia
| | - Siew-Keah Lee
- M. Kandiah Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Jalan Sungai Long, Bandar Sungai Long, Kajang 43000, Malaysia
| | - Chun-Wai Mai
- Faculty of Pharmaceutical Sciences, UCSI University, Kuala Lumpur 56000, Malaysia
| | - Yik-Ling Chew
- Faculty of Pharmaceutical Sciences, UCSI University, Kuala Lumpur 56000, Malaysia
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Feng J, Zhang Q, Pu F, Zhu Z, Lu K, Lu WW, Tong L, Yu H, Chen D. Signalling interaction between β-catenin and other signalling molecules during osteoarthritis development. Cell Prolif 2024; 57:e13600. [PMID: 38199244 PMCID: PMC11150147 DOI: 10.1111/cpr.13600] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 11/29/2023] [Accepted: 12/29/2023] [Indexed: 01/12/2024] Open
Abstract
Osteoarthritis (OA) is the most prevalent disorder of synovial joint affecting multiple joints. In the past decade, we have witnessed conceptual switch of OA pathogenesis from a 'wear and tear' disease to a disease affecting entire joint. Extensive studies have been conducted to understand the underlying mechanisms of OA using genetic mouse models and ex vivo joint tissues derived from individuals with OA. These studies revealed that multiple signalling pathways are involved in OA development, including the canonical Wnt/β-catenin signalling and its interaction with other signalling pathways, such as transforming growth factor β (TGF-β), bone morphogenic protein (BMP), Indian Hedgehog (Ihh), nuclear factor κB (NF-κB), fibroblast growth factor (FGF), and Notch. The identification of signalling interaction and underlying mechanisms are currently underway and the specific molecule(s) and key signalling pathway(s) playing a decisive role in OA development need to be evaluated. This review will focus on recent progresses in understanding of the critical role of Wnt/β-catenin signalling in OA pathogenesis and interaction of β-catenin with other pathways, such as TGF-β, BMP, Notch, Ihh, NF-κB, and FGF. Understanding of these novel insights into the interaction of β-catenin with other pathways and its integration into a complex gene regulatory network during OA development will help us identify the key signalling pathway of OA pathogenesis leading to the discovery of novel therapeutic strategies for OA intervention.
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Affiliation(s)
- Jing Feng
- Department of Orthopedics, Traditional Chinese and Western Medicine Hospital of WuhanTongji Medical College, Huazhong University of Science and TechnologyWuhanHubeiChina
- Department of OrthopedicsWuhan No. 1 HospitalWuhanHubeiChina
| | - Qing Zhang
- Department of EmergencyRenmin Hospital, Wuhan UniversityWuhanHubeiChina
| | - Feifei Pu
- Department of Orthopedics, Traditional Chinese and Western Medicine Hospital of WuhanTongji Medical College, Huazhong University of Science and TechnologyWuhanHubeiChina
- Department of OrthopedicsWuhan No. 1 HospitalWuhanHubeiChina
| | - Zhenglin Zhu
- Department of Orthopedic Surgerythe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
| | - Ke Lu
- Faculty of Pharmaceutical SciencesShenzhen Institute of Advanced TechnologyShenzhenChina
- Research Center for Computer‐aided Drug DiscoveryShenzhen Institute of Advanced Technology, Chinese Academy of SciencesShenzhenChina
| | - William W. Lu
- Faculty of Pharmaceutical SciencesShenzhen Institute of Advanced TechnologyShenzhenChina
| | - Liping Tong
- Research Center for Computer‐aided Drug DiscoveryShenzhen Institute of Advanced Technology, Chinese Academy of SciencesShenzhenChina
| | - Huan Yu
- Department of Orthopedics, Traditional Chinese and Western Medicine Hospital of WuhanTongji Medical College, Huazhong University of Science and TechnologyWuhanHubeiChina
- Department of OrthopedicsWuhan No. 1 HospitalWuhanHubeiChina
| | - Di Chen
- Faculty of Pharmaceutical SciencesShenzhen Institute of Advanced TechnologyShenzhenChina
- Research Center for Computer‐aided Drug DiscoveryShenzhen Institute of Advanced Technology, Chinese Academy of SciencesShenzhenChina
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19
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Novak S, Tanigawa H, Singh V, Root SH, Schmidt TA, Hankenson KD, Kalajzic I. Endothelial to mesenchymal Notch signaling regulates skeletal repair. JCI Insight 2024; 9:e181073. [PMID: 38781018 PMCID: PMC11383173 DOI: 10.1172/jci.insight.181073] [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: 03/12/2024] [Accepted: 05/15/2024] [Indexed: 05/25/2024] Open
Abstract
We present a transcriptomic analysis that provides a better understanding of regulatory mechanisms within the healthy and injured periosteum. The focus of this work is on characterizing early events controlling bone healing during formation of periosteal callus on day 3 after fracture. Building on our previous findings showing that induced Notch1 signaling in osteoprogenitors leads to better healing, we compared samples in which the Notch 1 intracellular domain is overexpressed by periosteal stem/progenitor cells, with control intact and fractured periosteum. Molecular mechanisms and changes in skeletal stem/progenitor cells (SSPCs) and other cell populations within the callus, including hematopoietic lineages, were determined. Notably, Notch ligands were differentially expressed in endothelial and mesenchymal populations, with Dll4 restricted to endothelial cells, whereas Jag1 was expressed by mesenchymal populations. Targeted deletion of Dll4 in endothelial cells using Cdh5CreER resulted in negative effects on early fracture healing, while deletion in SSPCs using α-smooth muscle actin-CreER did not impact bone healing. Translating these observations into a clinically relevant model of bone healing revealed the beneficial effects of delivering Notch ligands alongside the osteogenic inducer, BMP2. These findings provide insights into the regulatory mechanisms within the healthy and injured periosteum, paving the way for novel translational approaches to bone healing.
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Affiliation(s)
- Sanja Novak
- Center for Regenerative Medicine and Skeletal Development, School of Dental Medicine, UConn Health, Farmington, Connecticut, USA
| | - Hitoshi Tanigawa
- Center for Regenerative Medicine and Skeletal Development, School of Dental Medicine, UConn Health, Farmington, Connecticut, USA
| | - Vijender Singh
- Institute for Systems Genomics, Computational Biology Core, UConn, Storrs, Connecticut, USA
| | - Sierra H Root
- Center for Regenerative Medicine and Skeletal Development, School of Dental Medicine, UConn Health, Farmington, Connecticut, USA
| | - Tannin A Schmidt
- Biomedical Engineering Department, School of Dental Medicine, UConn Health, Farmington, Connecticut, USA
| | - Kurt D Hankenson
- Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Ivo Kalajzic
- Center for Regenerative Medicine and Skeletal Development, School of Dental Medicine, UConn Health, Farmington, Connecticut, USA
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20
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Yu C, Yu S, Liu Z, Xu L, Zhang Z, Wan J, Ji P, Zhang P, Fu Y, Le Y, Hou R. Morroniside promotes skin wound re-epithelialization by facilitating epidermal stem cell proliferation through GLP-1R-mediated upregulation of β-catenin expression. Acta Biochim Biophys Sin (Shanghai) 2024; 56:1072-1084. [PMID: 38779766 PMCID: PMC11322873 DOI: 10.3724/abbs.2024070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Accepted: 02/06/2024] [Indexed: 05/25/2024] Open
Abstract
Epidermal stem cells (EpSCs) play a vital role in skin wound healing through re-epithelialization. Identifying chemicals that can promote EpSC proliferation is helpful for treating skin wounds. This study investigates the effect of morroniside on cutaneous wound healing in mice and explores the underlying mechanisms. Application of 10‒50 μg/mL of morroniside to the skin wound promotes wound healing in mice. In vitro studies demonstrate that morroniside stimulates the proliferation of mouse and human EpSCs in a time- and dose-dependent manner. Mechanistic studies reveal that morroniside promotes the proliferation of EpSCs by facilitating the cell cycle transition from the G1 to S phase. Morroniside increases the expression of β-catenin via the glucagon-like peptide-1 receptor (GLP-1R)-mediated PKA, PKA/PI3K/AKT and PKA/ERK signaling pathways, resulting in an increase in cyclin D1 and cyclin E1 expression, either directly or by upregulating c-Myc expression. This process ultimately leads to EpSC proliferation. Administration of morroniside to mouse skin wounds increases the phosphorylation of AKT and ERK, the expressions of β-catenin, c-Myc, cyclin D1, and cyclin E1, as well as the proliferation of EpSCs, in periwound skin tissue, and accelerates wound re-epithelialization. These effects of morroniside are mediated by the GLP-1R. Overall, these results indicate that morroniside promotes skin wound healing by stimulating the proliferation of EpSCs via increasing β-catenin expression and subsequently upregulating c-Myc, cyclin D1, and cyclin E1 expressions through GLP-1R signaling pathways. Morroniside has clinical potential for treating skin wounds.
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Affiliation(s)
- Chenghao Yu
- Suzhou Ruihua Orthopedic HospitalSuzhou Medical College of Soochow UniversitySuzhou215104China
- Department of Hand SurgerySuzhou Ruihua Orthopedic HospitalSuzhou215104China
| | - Siyuan Yu
- Department of Hand SurgerySuzhou Ruihua Orthopedic HospitalSuzhou215104China
- Yangzhou University Medical CollegeYangzhou225009China
| | - Zuohua Liu
- Suzhou Ruihua Orthopedic HospitalSuzhou Medical College of Soochow UniversitySuzhou215104China
- Department of Hand SurgerySuzhou Ruihua Orthopedic HospitalSuzhou215104China
| | - Lei Xu
- Suzhou Ruihua Orthopedic HospitalSuzhou Medical College of Soochow UniversitySuzhou215104China
- Department of Hand SurgerySuzhou Ruihua Orthopedic HospitalSuzhou215104China
| | - Zhiqiang Zhang
- Suzhou Ruihua Orthopedic HospitalSuzhou Medical College of Soochow UniversitySuzhou215104China
- Department of Hand SurgerySuzhou Ruihua Orthopedic HospitalSuzhou215104China
| | - Jiaming Wan
- Department of Hand SurgerySuzhou Ruihua Orthopedic HospitalSuzhou215104China
- Yangzhou University Medical CollegeYangzhou225009China
| | - Pengxiang Ji
- Department of Hand SurgerySuzhou Ruihua Orthopedic HospitalSuzhou215104China
| | - Ping Zhang
- Department of Hand SurgerySuzhou Ruihua Orthopedic HospitalSuzhou215104China
| | - Yi Fu
- Department of Human AnatomyHistology and EmbryologySchool of Biology and Basic Medical SciencesSuzhou Medical College of Soochow UniversitySuzhou215123China
| | - Yingying Le
- Shanghai Institute of Nutrition and HealthUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghai200031China
| | - Ruixing Hou
- Suzhou Ruihua Orthopedic HospitalSuzhou Medical College of Soochow UniversitySuzhou215104China
- Department of Hand SurgerySuzhou Ruihua Orthopedic HospitalSuzhou215104China
- Yangzhou University Medical CollegeYangzhou225009China
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21
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Aouabdi S, Nedjadi T, Alsiary R, Mouffouk F, Ansari HR. Transcriptomics Demonstrates Significant Biological Effect of Growing Stem Cells on RGD-Cotton Scaffold. Tissue Eng Part A 2024. [PMID: 38666698 DOI: 10.1089/ten.tea.2023.0333] [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: 05/07/2024] Open
Abstract
Stem cell therapy provides a viable alternative treatment for degenerated or damaged tissue. Stem cells have been used either alone or in conjunction with an artificial scaffold. The latter provides a structural advantage by enabling the cells to thrive in three-dimensional (3D) settings, closely resembling the natural in vivo environments. Previously, we disclosed the development of a 3D scaffold made from cotton, which was conjugated with arginyl-glycyl-aspartic acid (RGD), to facilitate the growth and proliferation of mesenchymal stem cells (MSCs). This scaffold allowed the MSCs to adhere and proliferate without compromising their viability or their stem cell markers. A comprehensive analysis investigation of the molecular changes occurring in MSCs adhering to the cotton fibers will contribute to the advancement of therapy. The objective of this study is to analyze the molecular processes occurring in the growth of MSCs on a cotton-RGD conjugated-based scaffold by examining their gene expression profiles. To achieve this, we conducted an experiment where MSCs were seeded with and without the scaffold for a duration of 48 h. Subsequently, cells were collected for RNA extraction, cDNA synthesis, and whole-transcriptomic analysis performed on both populations. Our analysis revealed several upregulated and downregulated differently expressed genes in the MSCs adhering to the scaffold compared with the control cells. Through gene ontology analysis, we were able to identify enriched biological processes, molecular functions, pathways, and protein-protein interactions in these differentially expressed genes. Our data suggest that the scaffold may have the potential to enhance osteogenesis in the MSCs. Furthermore, our results indicate that the scaffold does not induce oxidative stress, inflammation, or aging in the MSCs. These findings provide valuable insights for the application of MSCs in tissue engineering and regenerative medicine.
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Affiliation(s)
- Sihem Aouabdi
- King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
- King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
| | - Taoufik Nedjadi
- King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
- King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
| | - Rawiah Alsiary
- King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
- King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
| | - Fouzi Mouffouk
- Department of Chemistry, Kuwait University, Kuwait, Kuwait
| | - Hifzur Rahman Ansari
- King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
- King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
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22
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Gumede DB, Abrahamse H, Houreld NN. Targeting Wnt/β-catenin signaling and its interplay with TGF-β and Notch signaling pathways for the treatment of chronic wounds. Cell Commun Signal 2024; 22:244. [PMID: 38671406 PMCID: PMC11046856 DOI: 10.1186/s12964-024-01623-9] [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: 02/29/2024] [Accepted: 04/20/2024] [Indexed: 04/28/2024] Open
Abstract
Wound healing is a tightly regulated process that ensures tissue repair and normal function following injury. It is modulated by activation of pathways such as the transforming growth factor-beta (TGF-β), Notch, and Wnt/β-catenin signaling pathways. Dysregulation of this process causes poor wound healing, which leads to tissue fibrosis and ulcerative wounds. The Wnt/β-catenin pathway is involved in all phases of wound healing, primarily in the proliferative phase for formation of granulation tissue. This review focuses on the role of the Wnt/β-catenin signaling pathway in wound healing, and its transcriptional regulation of target genes. The crosstalk between Wnt/β-catenin, Notch, and the TGF-β signaling pathways, as well as the deregulation of Wnt/β-catenin signaling in chronic wounds are also considered, with a special focus on diabetic ulcers. Lastly, we discuss current and prospective therapies for chronic wounds, with a primary focus on strategies that target the Wnt/β-catenin signaling pathway such as photobiomodulation for healing diabetic ulcers.
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Affiliation(s)
- Dimakatso B Gumede
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, P.O. Box 17011, Doornfontein, 2028, South Africa
| | - Heidi Abrahamse
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, P.O. Box 17011, Doornfontein, 2028, South Africa
| | - Nicolette N Houreld
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, P.O. Box 17011, Doornfontein, 2028, South Africa.
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23
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Tao X, Pan X, Xue M, Zhao G, Rui Y. Thymosin β4 improves the survival of cutaneous flaps of rats and activates the Wnt/β-catenin pathway. Arch Med Sci 2024; 20:708-712. [PMID: 38757041 PMCID: PMC11094814 DOI: 10.5114/aoms/186188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Accepted: 03/17/2024] [Indexed: 05/18/2024] Open
Affiliation(s)
- Xianyao Tao
- Department of Hand Surgery, Wuxi Ninth People' s Hospital affiliated to Soochow University, Wuxi, China
| | - Xiaoyun Pan
- Department of Hand Surgery, Wuxi Ninth People' s Hospital affiliated to Soochow University, Wuxi, China
| | - Mingyu Xue
- Department of Hand Surgery, Wuxi Ninth People' s Hospital affiliated to Soochow University, Wuxi, China
| | - Gang Zhao
- Department of Hand Surgery, Wuxi Ninth People' s Hospital affiliated to Soochow University, Wuxi, China
| | - Yongjun Rui
- Department of Hand Surgery, Wuxi Ninth People' s Hospital affiliated to Soochow University, Wuxi, China
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24
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Outskouni Z, Christodoulou C, Goutas A, Kyriazis ID, Paraskevopoulou A, Laliotis GP, Matsakidou A, Gogas A, Trachana V. Cryptomphalus aspersa Egg Extract Protects against Human Stem Cell Stress-Induced Premature Senescence. Int J Mol Sci 2024; 25:3715. [PMID: 38612526 PMCID: PMC11011511 DOI: 10.3390/ijms25073715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Revised: 03/23/2024] [Accepted: 03/25/2024] [Indexed: 04/14/2024] Open
Abstract
Cellular senescence is a tightly regulated pathophysiologic process and is caused by replicative exhaustion or external stressors. Since naturally derived bioactive compounds with anti-ageing properties have recently captured scientific interest, we analysed the anti-ageing and antioxidant efficacy of Cryptomphalus aspersa egg extract (CAEE). Its effects on stemness, wound-healing properties, antioxidant defense mechanisms, and DNA damage repair ability of Human Wharton's jelly mesenchymal stem cells (WJ-MSCs) were analysed. Our results revealed that CAEE fortifies WJ-MSCs stemness, which possibly ameliorates their wound-healing ability. Additionally, we show that CAEE possesses a strong antioxidant capacity as demonstrated by the elevation of the levels of the basic antioxidant molecule, GSH, and the induction of the NRF2, a major antioxidant regulator. In addition, CAEE alleviated cells' oxidative stress and therefore prevented stress-induced premature senescence (SIPS). Furthermore, we demonstrated that the prevention of SIPS could be mediated via the extract's ability to induce autophagy, as indicated by the elevation of the protein levels of all basic autophagic molecules and the increase in formation of autophagolysosomes in CAEE-treated WJ-MSCs. Moreover, CAEE-treated cells exhibited decreased Caveolin-1 levels. We propose that Cryptomphalus aspersa egg extract comprises bioactive compounds that can demonstrate strong antioxidant/anti-ageing effects by regulating the Caveolin-1-autophagy-senescence molecular axis.
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Affiliation(s)
- Zozo Outskouni
- Department of Biology, Faculty of Medicine, University of Thessaly, 41500 Larisa, Greece; (Z.O.); (C.C.); (A.G.); (I.D.K.)
| | - Christina Christodoulou
- Department of Biology, Faculty of Medicine, University of Thessaly, 41500 Larisa, Greece; (Z.O.); (C.C.); (A.G.); (I.D.K.)
| | - Andreas Goutas
- Department of Biology, Faculty of Medicine, University of Thessaly, 41500 Larisa, Greece; (Z.O.); (C.C.); (A.G.); (I.D.K.)
- Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece
| | - Ioannis D. Kyriazis
- Department of Biology, Faculty of Medicine, University of Thessaly, 41500 Larisa, Greece; (Z.O.); (C.C.); (A.G.); (I.D.K.)
| | - Adamantini Paraskevopoulou
- Laboratory of Food Chemistry & Technology, School of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (A.P.); (A.M.)
| | - George P. Laliotis
- Laboratory of Animal Breeding and Husbandry, Department of Animal Science, Agricultural University of Athens, 75 Iera Odos, 11855 Athens, Greece;
| | - Anthia Matsakidou
- Laboratory of Food Chemistry & Technology, School of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (A.P.); (A.M.)
| | | | - Varvara Trachana
- Department of Biology, Faculty of Medicine, University of Thessaly, 41500 Larisa, Greece; (Z.O.); (C.C.); (A.G.); (I.D.K.)
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25
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Ascanelli C, Dahir R, Wilson CH. Manipulating Myc for reparative regeneration. Front Cell Dev Biol 2024; 12:1357589. [PMID: 38577503 PMCID: PMC10991803 DOI: 10.3389/fcell.2024.1357589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 02/15/2024] [Indexed: 04/06/2024] Open
Abstract
The Myc family of proto-oncogenes is a key node for the signal transduction of external pro-proliferative signals to the cellular processes required for development, tissue homoeostasis maintenance, and regeneration across evolution. The tight regulation of Myc synthesis and activity is essential for restricting its oncogenic potential. In this review, we highlight the central role that Myc plays in regeneration across the animal kingdom (from Cnidaria to echinoderms to Chordata) and how Myc could be employed to unlock the regenerative potential of non-regenerative tissues in humans for therapeutic purposes. Mastering the fine balance of harnessing the ability of Myc to promote transcription without triggering oncogenesis may open the door to many exciting opportunities for therapeutic development across a wide array of diseases.
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Affiliation(s)
| | | | - Catherine H. Wilson
- Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
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26
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Shyu YC, Huang TS, Chiu HS, Sumazin P, Lin XY, Liao PC, Liou CC, Hsu FC, Lin JS, Hsu CC, Hsu PH, Sun CC, Chen CT. Deciphering Early-Stage Molecular Mechanisms of Negative Pressure Wound Therapy in a Murine Model. Int J Mol Sci 2024; 25:2373. [PMID: 38397048 PMCID: PMC10888958 DOI: 10.3390/ijms25042373] [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: 01/23/2024] [Revised: 02/13/2024] [Accepted: 02/15/2024] [Indexed: 02/25/2024] Open
Abstract
Negative Pressure Wound Therapy (NPWT) is a commonly employed clinical strategy for wound healing, yet its early-stage mechanisms remain poorly understood. To address this knowledge gap and overcome the limitations of human trials, we establish an NPWT C57BL/6JNarl mouse model to investigate the molecular mechanisms involved in NPWT. In this study, we investigate the intricate molecular mechanisms through which NPWT expedites wound healing. Our focus is on NPWT's modulation of inflammatory immune responses and the concurrent orchestration of multiple signal transduction pathways, resulting in shortened coagulation time and reduced inflammation. Notably, we observe a significant rise in dickkopf-related protein 1 (DKK-1) concentration during NPWT, promoting the differentiation of Hair Follicle Stem Cells (HFSCs) into epidermal cells, expediting wound closure. Under negative pressure, macrophages express and release DKK-1 cytokines, crucial for stimulating HFSC differentiation, as validated in animal experiments and in vitro studies. Our findings illuminate the inflammatory dynamics under NPWT, revealing potential signal transduction pathways. The proposed framework, involving early hemostasis, balanced inflammation, and macrophage-mediated DKK-1 induction, provides a novel perspective on enhancing wound healing during NPWT. Furthermore, these insights lay the groundwork for future pharmacological advancements in managing extensive wounds, opening avenues for targeted therapeutic interventions in wound care.
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Affiliation(s)
- Yu-Chiau Shyu
- Community Medicine Research Center, Chang Gung Memorial Hospital, Keelung Branch, Keelung 204, Taiwan; (X.-Y.L.); (P.-C.L.); (C.-C.L.); (F.-C.H.); (J.-S.L.)
- Department of Nursing, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan
| | - Ting-Shuo Huang
- Department of General Surgery, Jen Ai Hospital, Taichung 400, Taiwan;
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Hua-Sheng Chiu
- Department of Pediatrics, Baylor College of Medicine, Texas Children’s Hospital Cancer Center, Houston, TX 77030, USA; (H.-S.C.); (P.S.)
| | - Pavel Sumazin
- Department of Pediatrics, Baylor College of Medicine, Texas Children’s Hospital Cancer Center, Houston, TX 77030, USA; (H.-S.C.); (P.S.)
| | - Xin-Yu Lin
- Community Medicine Research Center, Chang Gung Memorial Hospital, Keelung Branch, Keelung 204, Taiwan; (X.-Y.L.); (P.-C.L.); (C.-C.L.); (F.-C.H.); (J.-S.L.)
| | - Po-Cheng Liao
- Community Medicine Research Center, Chang Gung Memorial Hospital, Keelung Branch, Keelung 204, Taiwan; (X.-Y.L.); (P.-C.L.); (C.-C.L.); (F.-C.H.); (J.-S.L.)
| | - Cai-Cin Liou
- Community Medicine Research Center, Chang Gung Memorial Hospital, Keelung Branch, Keelung 204, Taiwan; (X.-Y.L.); (P.-C.L.); (C.-C.L.); (F.-C.H.); (J.-S.L.)
| | - Fang-Chia Hsu
- Community Medicine Research Center, Chang Gung Memorial Hospital, Keelung Branch, Keelung 204, Taiwan; (X.-Y.L.); (P.-C.L.); (C.-C.L.); (F.-C.H.); (J.-S.L.)
| | - Jyuan-Siou Lin
- Community Medicine Research Center, Chang Gung Memorial Hospital, Keelung Branch, Keelung 204, Taiwan; (X.-Y.L.); (P.-C.L.); (C.-C.L.); (F.-C.H.); (J.-S.L.)
| | - Chih-Chin Hsu
- Department of Medicine, School of Medicine, Chang Gung University, Taoyuan 333, Taiwan;
- Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital, Keelung Branch, Keelung 204, Taiwan
| | - Pang-Hung Hsu
- Department of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung 202, Taiwan;
| | - Chi-Chin Sun
- Department of Ophthalmology, Chang Gung Memorial Hospital, Keelung Branch, Keelung 204, Taiwan;
| | - Chien-Tzung Chen
- Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan 333, Taiwan
- Craniofacial Research Center, Chang Gung University, Taoyuan 333, Taiwan
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27
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Shi Y, Wang S, Liu D, Wang Z, Zhu Y, Li J, Xu K, Li F, Wen H, Yang R. Exosomal miR-4645-5p from hypoxic bone marrow mesenchymal stem cells facilitates diabetic wound healing by restoring keratinocyte autophagy. BURNS & TRAUMA 2024; 12:tkad058. [PMID: 38250706 PMCID: PMC10796268 DOI: 10.1093/burnst/tkad058] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 11/16/2023] [Accepted: 11/17/2023] [Indexed: 01/23/2024]
Abstract
BACKGROUND Refractory diabetic wounds are a common occurrence in patients with diabetes and epidermis-specific macroautophagy/autophagy impairment has been implicated in their pathogenesis. Therefore, identifying and developing treatment strategies capable of normalizing epidermis-specific macroautophagy/autophagy could facilitate diabetic wound healing. The study aims to investigate the potential of bone marrow mesenchymal stem cell-derived exosomes (BMSC-exos) from hypoxic conditions as a treatment to normalize epidermis-specific autophagy for diabetic wound healing. METHODS We compared the effects of bone marrow mesenchymal stem cell (BMSC)-sourced exosomes (BMSC-Exos) from hypoxic conditions to those of BMSC in normoxic conditions (noBMSC-Exos). Our studies involved morphometric assessment of the exosomes, identification of the microRNA (miRNA) responsible for the effects, evaluation of keratinocyte functions and examination of effects of the exosomes on several molecules involved in the autophagy pathway such as microtubule-associated protein 1 light chain 3 beta, beclin 1, sequestosome 1, autophagy-related 5 and autophagy-related 5. The experiments used human BMSCs from the American Type Culture Collection, an in vivo mouse model of diabetes (db/db) to assess wound healing, as well as the human keratinocyte HaCaT cell line. In the methodology, the authors utilized an array of approaches that included electron microscopy, small interfering RNA (siRNA) studies, RNA in situ hybridization, quantitative real-time reverse transcription PCR (qRT-PCR), the isolation, sequencing and differential expression of miRNAs, as well as the use of miR-4645-5p-specific knockdown with an inhibitor. RESULTS Hypoxia affected the release of exosomes from hypoxic BMSCs (hy-BMSCs) and influenced the size and morphology of the exosomes. Moreover, hyBMSC-Exo treatment markedly improved keratinocyte function, including keratinocyte autophagy, proliferation and migration. miRNA microarray and bioinformatics analysis showed that the target genes of the differentially expressed miRNAs were mainly enriched in 'autophagy' and 'process utilizing autophagic mechanism' in the 'biological process' category and miR-4645-5p as a major contributor to the pro-autophagy effect of hyBMSC-Exos. Moreover, mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2) was identified as a potential target of exosomal miR-4645-5p; this was confirmed using a dual luciferase assay. Exosomal miR-4645-5p mediates the inactivation of the MAPKAPK2-induced AKT kinase group (comprising AKT1, AKT2, and AKT3), which in turn suppresses AKT-mTORC1 signaling, thereby facilitating miR-4645-5p-mediated autophagy. CONCLUSIONS Overall, the results of this study showed that hyBMSC-Exo-mediated transfer of miR-4645-5p inactivated MAPKAPK2-induced AKT-mTORC1 signaling in keratinocytes, which activated keratinocyte autophagy, proliferation and migration, resulting in diabetic wound healing in mice. Collectively, the findings could aid in the development of a novel therapeutic strategy for diabetic wounds.
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Affiliation(s)
- Yan Shi
- Department of Plastic, Medical Center of Burn Plastic and Wound Repair, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Yongwaizheng Road, Donghu District, Nanchang, Jiangxi, 330006, China
| | - Shang Wang
- Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University, Medical College Road, Yuzhong District, Chongqing, 400016, China
| | - Dewu Liu
- Medical Center of Burn Plastic and Wound Repair, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Yongwaizheng Road, Donghu District, Nanchang, Jiangxi, 330006, China
| | - Zhengguang Wang
- Department of Orthopaedics, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing, 100191 China
| | - Yihan Zhu
- Department of Plastic and Aesthetic Surgery, Jiangxi Maternal and Child Health Hospital, Bayidadao Road, Donghu District, Nanchang 330006, China
| | - Jun Li
- HaploX Biotechnology Co., Ltd., Songpingshan Road, Nanshan District, Shenzhen 518057, Guangdong China
| | - Kui Xu
- Key Laboratory of Xin’an Medicine, Ministry of Education, Anhui University of Chinese Medicine,Qianjiang Road, Yaohai District, Hefei 230038, Anhui, P. R. China
| | - Furong Li
- Translational Medicine Collaborative Innovation Center, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affifiliated Hospital, Southern University of Science and Technology), Dongmenbei Road, Luohu District, Shenzhen 518020, Guangdong, China
| | - Huicai Wen
- Department of Plastic, Medical Center of Burn Plastic and Wound Repair, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Yongwaizheng Road, Donghu District, Nanchang, Jiangxi, 330006, China
| | - Ronghua Yang
- Department of Burn and Plastic Surgery, Guangzhou First People's Hospital, South China University of Technology, Panfu Road, Yuexiu District, Guangzhou, Guangdong, 510180, China
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Bai R, Guo Y, Liu W, Song Y, Yu Z, Ma X. The Roles of WNT Signaling Pathways in Skin Development and Mechanical-Stretch-Induced Skin Regeneration. Biomolecules 2023; 13:1702. [PMID: 38136575 PMCID: PMC10741662 DOI: 10.3390/biom13121702] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 11/10/2023] [Accepted: 11/14/2023] [Indexed: 12/24/2023] Open
Abstract
The WNT signaling pathway plays a critical role in a variety of biological processes, including development, adult tissue homeostasis maintenance, and stem cell regulation. Variations in skin conditions can influence the expression of the WNT signaling pathway. In light of the above, a deeper understanding of the specific mechanisms of the WNT signaling pathway in different physiological and pathological states of the skin holds the potential to significantly advance clinical treatments of skin-related diseases. In this review, we present a comprehensive analysis of the molecular and cellular mechanisms of the WNT signaling pathway in skin development, wound healing, and mechanical stretching. Our review sheds new light on the crucial role of the WNT signaling pathway in the regulation of skin physiology and pathology.
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Affiliation(s)
- Ruoxue Bai
- Department of Plastic Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
| | - Yaotao Guo
- Department of Plastic Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
- Department of The Cadet Team 6, School of Basic Medicine, Fourth Military Medical University, Xi’an 710032, China
| | - Wei Liu
- Department of Plastic Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
| | - Yajuan Song
- Department of Plastic Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
| | - Zhou Yu
- Department of Plastic Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
| | - Xianjie Ma
- Department of Plastic Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
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29
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Yoon M, Kim E, Seo SH, Kim GU, Choi KY. KY19382 Accelerates Cutaneous Wound Healing via Activation of the Wnt/β-Catenin Signaling Pathway. Int J Mol Sci 2023; 24:11742. [PMID: 37511501 PMCID: PMC10380997 DOI: 10.3390/ijms241411742] [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: 06/20/2023] [Revised: 07/17/2023] [Accepted: 07/19/2023] [Indexed: 07/30/2023] Open
Abstract
The Wnt/β-catenin signaling pathway plays important roles in the multi-phases of wound healing: homeostasis, inflammation, proliferative, and remodeling phases. However, there are no clinically available therapeutic agents targeting the Wnt/β-catenin pathway. In this study, we tested the effect of 5, 6-dichloroindirubin-3'-methoxime (KY19382), a small molecule that activates the Wnt/β-catenin pathway via interference with the function of the negative feedback regulator CXXC5, on cutaneous wound healing. KY19382 significantly enhanced cell migration of human keratinocytes and dermal fibroblasts with increased levels of β-catenin, phalloidin, Keratin 14, proliferating cell nuclear antigen (PCNA), Collagen I, and alpha-smooth muscle actin (α-SMA) by activating the Wnt/β-catenin signaling pathway without causing significant cytotoxicity. In addition, levels of Collagen I, Keratin 14, PCNA, and stem cell markers were significantly increased by KY19382 in a cutaneous murine wound healing model. Moreover, KY19382 treatment accelerated re-epithelialization and neo-epidermis formation with collagen deposition and stem cell activation at an early stage of cutaneous wound healing. Overall, KY19382 accelerates wound healing via activating the Wnt/β-catenin pathway, and may have the potential to be used for the development of a new wound healing agent.
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Affiliation(s)
- Minguen Yoon
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea
| | - Eunhwan Kim
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea
| | - Seol Hwa Seo
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea
| | - Geon-Uk Kim
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea
| | - Kang-Yell Choi
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea
- CK Regeon Inc., Seoul 03722, Republic of Korea
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30
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Tyler AL, Spruce C, Kursawe R, Haber A, Ball RL, Pitman WA, Fine AD, Raghupathy N, Walker M, Philip VM, Baker CL, Mahoney JM, Churchill GA, Trowbridge JJ, Stitzel ML, Paigen K, Petkov PM, Carter GW. Variation in histone configurations correlates with gene expression across nine inbred strains of mice. Genome Res 2023; 33:857-871. [PMID: 37217254 PMCID: PMC10519406 DOI: 10.1101/gr.277467.122] [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: 11/02/2022] [Accepted: 05/19/2023] [Indexed: 05/24/2023]
Abstract
The Diversity Outbred (DO) mice and their inbred founders are widely used models of human disease. However, although the genetic diversity of these mice has been well documented, their epigenetic diversity has not. Epigenetic modifications, such as histone modifications and DNA methylation, are important regulators of gene expression and, as such, are a critical mechanistic link between genotype and phenotype. Therefore, creating a map of epigenetic modifications in the DO mice and their founders is an important step toward understanding mechanisms of gene regulation and the link to disease in this widely used resource. To this end, we performed a strain survey of epigenetic modifications in hepatocytes of the DO founders. We surveyed four histone modifications (H3K4me1, H3K4me3, H3K27me3, and H3K27ac), as well as DNA methylation. We used ChromHMM to identify 14 chromatin states, each of which represents a distinct combination of the four histone modifications. We found that the epigenetic landscape is highly variable across the DO founders and is associated with variation in gene expression across strains. We found that epigenetic state imputed into a population of DO mice recapitulated the association with gene expression seen in the founders, suggesting that both histone modifications and DNA methylation are highly heritable mechanisms of gene expression regulation. We illustrate how DO gene expression can be aligned with inbred epigenetic states to identify putative cis-regulatory regions. Finally, we provide a data resource that documents strain-specific variation in the chromatin state and DNA methylation in hepatocytes across nine widely used strains of laboratory mice.
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Affiliation(s)
- Anna L Tyler
- The Jackson Laboratory for Mammalian Genetics, Bar Harbor, Maine 04609, USA
| | - Catrina Spruce
- The Jackson Laboratory for Mammalian Genetics, Bar Harbor, Maine 04609, USA
| | - Romy Kursawe
- The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06032, USA
| | - Annat Haber
- The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06032, USA
| | - Robyn L Ball
- The Jackson Laboratory for Mammalian Genetics, Bar Harbor, Maine 04609, USA
| | - Wendy A Pitman
- The Jackson Laboratory for Mammalian Genetics, Bar Harbor, Maine 04609, USA
| | - Alexander D Fine
- The Jackson Laboratory for Mammalian Genetics, Bar Harbor, Maine 04609, USA
| | | | - Michael Walker
- The Jackson Laboratory for Mammalian Genetics, Bar Harbor, Maine 04609, USA
| | - Vivek M Philip
- The Jackson Laboratory for Mammalian Genetics, Bar Harbor, Maine 04609, USA
| | | | - J Matthew Mahoney
- The Jackson Laboratory for Mammalian Genetics, Bar Harbor, Maine 04609, USA
| | - Gary A Churchill
- The Jackson Laboratory for Mammalian Genetics, Bar Harbor, Maine 04609, USA
| | | | - Michael L Stitzel
- The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06032, USA
| | - Kenneth Paigen
- The Jackson Laboratory for Mammalian Genetics, Bar Harbor, Maine 04609, USA
| | - Petko M Petkov
- The Jackson Laboratory for Mammalian Genetics, Bar Harbor, Maine 04609, USA;
| | - Gregory W Carter
- The Jackson Laboratory for Mammalian Genetics, Bar Harbor, Maine 04609, USA
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31
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Xu L, Sima Y, Xiao C, Chen Y. Exosomes derived from mesenchymal stromal cells: a promising treatment for pelvic floor dysfunction. Hum Cell 2023; 36:937-949. [PMID: 36940057 DOI: 10.1007/s13577-023-00887-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 02/25/2023] [Indexed: 03/21/2023]
Abstract
Pelvic floor dysfunction (PFDs), which include pelvic organ prolapse (POP), stress urinary incontinence (SUI) and anal incontinence (AI), are common degenerative diseases in women that have dramatic effects on quality of life. The pathology of PFDs is based on impaired pelvic connective tissue supportive strength due to an imbalance in extracellular matrix (ECM) metabolism, the loss of a variety of cell types, such as fibroblasts, muscle cells, peripheral nerve cells, and oxidative stress and inflammation in the pelvic environment. Fortunately, exosomes, which are one of the major secretions of mesenchymal stromal cells (MSCs), are involved in intercellular communication and the modulation of molecular activities in recipient cells via their contents, which are bioactive proteins and genetic factors such as mRNAs and miRNAs. These components modify fibroblast activation and secretion, facilitate ECM modelling, and promote cell proliferation to enhance pelvic tissue regeneration. In this review, we focus on the molecular mechanisms and future directions of exosomes derived from MSCs that are of great value in the treatment of PFD.
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Affiliation(s)
- Leimei Xu
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, 128 ShenYang Road, Shanghai, 200011, People's Republic of China.,Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Shanghai, China
| | - Yizhen Sima
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, 128 ShenYang Road, Shanghai, 200011, People's Republic of China.,Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Shanghai, China
| | - Chengzhen Xiao
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, 128 ShenYang Road, Shanghai, 200011, People's Republic of China
| | - Yisong Chen
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, 128 ShenYang Road, Shanghai, 200011, People's Republic of China. .,Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Shanghai, China.
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32
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Comparisons between Plant and Animal Stem Cells Regarding Regeneration Potential and Application. Int J Mol Sci 2023; 24:ijms24054392. [PMID: 36901821 PMCID: PMC10002278 DOI: 10.3390/ijms24054392] [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: 12/23/2022] [Revised: 02/16/2023] [Accepted: 02/21/2023] [Indexed: 02/25/2023] Open
Abstract
Regeneration refers to the process by which organisms repair and replace lost tissues and organs. Regeneration is widespread in plants and animals; however, the regeneration capabilities of different species vary greatly. Stem cells form the basis for animal and plant regeneration. The essential developmental processes of animals and plants involve totipotent stem cells (fertilized eggs), which develop into pluripotent stem cells and unipotent stem cells. Stem cells and their metabolites are widely used in agriculture, animal husbandry, environmental protection, and regenerative medicine. In this review, we discuss the similarities and differences in animal and plant tissue regeneration, as well as the signaling pathways and key genes involved in the regulation of regeneration, to provide ideas for practical applications in agriculture and human organ regeneration and to expand the application of regeneration technology in the future.
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Chang J, Sun Y, Meng X, Zeng F, Wang X. EGFL7 affects the migration of epidermal stem cells in refractory diabetic wounds by regulating Notch signaling pathway. Regen Med 2023; 18:137-153. [PMID: 36530156 DOI: 10.2217/rme-2022-0123] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Aim: This study aimed to explore the role of EGFL7 in the healing process of refractory diabetic wounds. Methods: Epidermal stem cells (ESCs) were isolated from healthy mice and diabetic mice, identified by immunofluorescence, transfected with EGFL7 overexpression and silencing lentiviral vectors, and treated with Notch pathway inhibitor (DAPT). Results: SiEGFL7 significantly inhibited the proliferation, invasion and migration of ESCs of healthy mice. DAPT prominently inhibited the expressions of Notch1, Notch2, Hes1 and Jag1 in ESCs of healthy mice induced by overexpressed EGFL7. Overexpressed EGFL7 promoted wound healing in diabetic mice with refractory wounds. Conclusion: EGFL7 affects the proliferation and migration of ESCs in refractory diabetic wounds by regulating the Notch signaling pathway.
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Affiliation(s)
- Jinyuan Chang
- Department of Burn and Plastic Surgery, The Second Xiangya Hospital of Central South University, No. 139, Shaoshan South Road, Furong District, Changsha, Hunan, 410011, China
| | - Yang Sun
- Department of Burn and Plastic Surgery, The Second Xiangya Hospital of Central South University, No. 139, Shaoshan South Road, Furong District, Changsha, Hunan, 410011, China
| | - Xianxi Meng
- Department of Burn and Plastic Surgery, The Second Xiangya Hospital of Central South University, No. 139, Shaoshan South Road, Furong District, Changsha, Hunan, 410011, China
| | - Fanglin Zeng
- Department of Burn and Plastic Surgery, The Second Xiangya Hospital of Central South University, No. 139, Shaoshan South Road, Furong District, Changsha, Hunan, 410011, China
| | - Xiancheng Wang
- Department of Burn and Plastic Surgery, The Second Xiangya Hospital of Central South University, No. 139, Shaoshan South Road, Furong District, Changsha, Hunan, 410011, China
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Euodia daniellii Hemsl. Extract and Its Active Component Hesperidin Accelerate Cutaneous Wound Healing via Activation of Wnt/β-Catenin Signaling Pathway. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27207134. [PMID: 36296727 PMCID: PMC9608813 DOI: 10.3390/molecules27207134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 10/06/2022] [Accepted: 10/20/2022] [Indexed: 11/06/2022]
Abstract
The activation of the Wnt/β-catenin signaling pathway plays a key role in the wound-healing process through tissue regeneration. The extract of Euodia daniellii Hemsl. (E. daniellii), a member of the Rutaceae family, activates the Wnt/β-catenin signaling pathway. However, the function of E. daniellii in wound healing has not yet been elucidated. We performed a migration assay to determine the wound-healing effect of E. daniellii extract in vitro using human keratinocytes and dermal fibroblast. In addition, a mouse acute wound model was used to investigate the cutaneous wound-healing effect of E. daniellii extract in vivo and confirm the potential mechanism. E. daniellii extract enhanced the migration of human keratinocytes and dermal fibroblasts via the activation of the Wnt/β-catenin pathway. Moreover, the E. daniellii extract increased the levels of keratin 14, PCNA, collagen I, and α-SMA, with nuclei accumulation of β-catenin in vitro. E. daniellii extract also efficiently accelerated re-epithelialization and stimulated wound healing in vivo. Furthermore, we confirmed that hesperidin, one of the components of E. daniellii, efficiently accelerated the migration of human keratinocytes and dermal fibroblasts, as well as wound healing in vivo via the activation of the Wnt/β-catenin pathway. Overall, E. daniellii extract and its active component, hesperidin, have potential to be used as therapeutic agents for wound healing.
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Predes D, Maia LA, Matias I, Araujo HPM, Soares C, Barros-Aragão FGQ, Oliveira LFS, Reis RR, Amado NG, Simas ABC, Mendes FA, Gomes FCA, Figueiredo CP, Abreu JG. The Flavonol Quercitrin Hinders GSK3 Activity and Potentiates the Wnt/β-Catenin Signaling Pathway. Int J Mol Sci 2022; 23:ijms232012078. [PMID: 36292931 PMCID: PMC9602613 DOI: 10.3390/ijms232012078] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/09/2022] [Accepted: 09/10/2022] [Indexed: 11/23/2022] Open
Abstract
The Wnt/β-catenin signaling pathway dictates cell proliferation and differentiation during embryonic development and tissue homeostasis. Its deregulation is associated with many pathological conditions, including neurodegenerative disease, frequently downregulated. The lack of efficient treatment for these diseases, including Alzheimer’s disease (AD), makes Wnt signaling an attractive target for therapies. Interestingly, novel Wnt signaling activating compounds are less frequently described than inhibitors, turning the quest for novel positive modulators even more appealing. In that sense, natural compounds are an outstanding source of potential drug leads. Here, we combine different experimental models, cell-based approaches, neuronal culture assays, and rodent behavior tests with Xenopus laevis phenotypic analysis to characterize quercitrin, a natural compound, as a novel Wnt signaling potentiator. We find that quercitrin potentiates the signaling in a concentration-dependent manner and increases the occurrence of the Xenopus secondary axis phenotype mediated by Xwnt8 injection. Using a GSK3 biosensor, we describe that quercitrin impairs GSK3 activity and increases phosphorylated GSK3β S9 levels. Treatment with XAV939, an inhibitor downstream of GSK3, impairs the quercitrin-mediated effect. Next, we show that quercitrin potentiates the Wnt3a-synaptogenic effect in hippocampal neurons in culture, which is blocked by XAV939. Quercitrin treatment also rescues the hippocampal synapse loss induced by intracerebroventricular injection of amyloid-β oligomers (AβO) in mice. Finally, quercitrin rescues AβO-mediated memory impairment, which is prevented by XAV939. Thus, our study uncovers a novel function for quercitrin as a Wnt/β-catenin signaling potentiator, describes its mechanism of action, and opens new avenues for AD treatments.
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Affiliation(s)
- Danilo Predes
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Lorena A. Maia
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Isadora Matias
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | | | - Carolina Soares
- Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-901, Brazil
| | | | - Luiz F. S. Oliveira
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Renata R. Reis
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Nathalia G. Amado
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Alessandro B. C. Simas
- Instituto de Pesquisas de Produtos Naturais Walter Mors, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-901, Brazil
| | - Fabio A. Mendes
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Flávia C. A. Gomes
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Claudia P. Figueiredo
- Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-901, Brazil
| | - Jose G. Abreu
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
- Correspondence: ; Tel.: +55-21-3938-6486
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36
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Royzman D, Peckert-Maier K, Stich L, König C, Wild AB, Tauchi M, Ostalecki C, Kiesewetter F, Seyferth S, Lee G, Eming SA, Fuchs M, Kunz M, Stürmer EK, Peters EMJ, Berking C, Zinser E, Steinkasserer A. Soluble CD83 improves and accelerates wound healing by the induction of pro-resolving macrophages. Front Immunol 2022; 13:1012647. [PMID: 36248909 PMCID: PMC9564224 DOI: 10.3389/fimmu.2022.1012647] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 09/13/2022] [Indexed: 11/22/2022] Open
Abstract
To facilitate the recovery process of chronic and hard-to-heal wounds novel pro-resolving treatment options are urgently needed. We investigated the pro-regenerative properties of soluble CD83 (sCD83) on cutaneous wound healing, where sCD83 accelerated wound healing not only after systemic but also after topical application, which is of high therapeutic interest. Cytokine profile analyses revealed an initial upregulation of inflammatory mediators such as TNFα and IL-1β, followed by a switch towards pro-resolving factors, including YM-1 and IL-10, both expressed by tissue repair macrophages. These cells are known to mediate resolution of inflammation and stimulate wound healing processes by secretion of growth factors such as epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF), which promote vascularization as well as fibroblast and keratinocyte differentiation. In conclusion, we have found strong wound healing capacities of sCD83 beyond the previously described role in transplantation and autoimmunity. This makes sCD83 a promising candidate for the treatment of chronic- and hard-to-heal wounds.
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Affiliation(s)
- Dmytro Royzman
- Department of Immune Modulation, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
- *Correspondence: Dmytro Royzman, ; Alexander Steinkasserer,
| | - Katrin Peckert-Maier
- Department of Immune Modulation, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Lena Stich
- Department of Immune Modulation, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Christina König
- Department of Immune Modulation, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Andreas B. Wild
- Department of Immune Modulation, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Miyuki Tauchi
- Department of Internal Medicine 2, University Hospital Erlangen, FAU, Erlangen, Germany
| | - Christian Ostalecki
- Department of Dermatology, University Hospital Erlangen, FAU, Erlangen, Germany
| | | | - Stefan Seyferth
- Division of Pharmaceutics, Department of Chemistry and Pharmacy, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Geoffrey Lee
- Division of Pharmaceutics, Department of Chemistry and Pharmacy, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Sabine A. Eming
- Department of Dermatology, University Hospital Cologne, Center for Molecular Medicine Cologne (CMMC), Cologne Excellence Cluster Cluster of Excellence for Aging Research (CECAD), University of Cologne, Cologne, Germany
| | - Maximilian Fuchs
- Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hannover, Germany
| | - Meik Kunz
- Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hannover, Germany
- Department of Medical Informatics, Friedrich-Alexander University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Germany
| | - Ewa K. Stürmer
- Department for Vascular Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Eva M. J. Peters
- Psychoneuroimmunology Laboratory, Klinik für Psychosomatik und Psychotherapie, Justus-Liebig Universität Gießen, Gießen, Germany
| | - Carola Berking
- Department of Dermatology, University Hospital Erlangen, FAU, Erlangen, Germany
| | - Elisabeth Zinser
- Department of Immune Modulation, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Alexander Steinkasserer
- Department of Immune Modulation, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
- *Correspondence: Dmytro Royzman, ; Alexander Steinkasserer,
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37
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Groves SM, Ildefonso GV, McAtee CO, Ozawa PMM, Ireland AS, Stauffer PE, Wasdin PT, Huang X, Qiao Y, Lim JS, Bader J, Liu Q, Simmons AJ, Lau KS, Iams WT, Hardin DP, Saff EB, Holmes WR, Tyson DR, Lovly CM, Rathmell JC, Marth G, Sage J, Oliver TG, Weaver AM, Quaranta V. Archetype tasks link intratumoral heterogeneity to plasticity and cancer hallmarks in small cell lung cancer. Cell Syst 2022; 13:690-710.e17. [PMID: 35981544 PMCID: PMC9615940 DOI: 10.1016/j.cels.2022.07.006] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Revised: 05/10/2022] [Accepted: 07/25/2022] [Indexed: 01/26/2023]
Abstract
Small cell lung cancer (SCLC) tumors comprise heterogeneous mixtures of cell states, categorized into neuroendocrine (NE) and non-neuroendocrine (non-NE) transcriptional subtypes. NE to non-NE state transitions, fueled by plasticity, likely underlie adaptability to treatment and dismal survival rates. Here, we apply an archetypal analysis to model plasticity by recasting SCLC phenotypic heterogeneity through multi-task evolutionary theory. Cell line and tumor transcriptomics data fit well in a five-dimensional convex polytope whose vertices optimize tasks reminiscent of pulmonary NE cells, the SCLC normal counterparts. These tasks, supported by knowledge and experimental data, include proliferation, slithering, metabolism, secretion, and injury repair, reflecting cancer hallmarks. SCLC subtypes, either at the population or single-cell level, can be positioned in archetypal space by bulk or single-cell transcriptomics, respectively, and characterized as task specialists or multi-task generalists by the distance from archetype vertex signatures. In the archetype space, modeling single-cell plasticity as a Markovian process along an underlying state manifold indicates that task trade-offs, in response to microenvironmental perturbations or treatment, may drive cell plasticity. Stifling phenotypic transitions and plasticity may provide new targets for much-needed translational advances in SCLC. A record of this paper's Transparent Peer Review process is included in the supplemental information.
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Affiliation(s)
- Sarah M Groves
- Department of Biochemistry, Vanderbilt University, Nashville, TN 37235, USA
| | - Geena V Ildefonso
- Department of Biochemistry, Vanderbilt University, Nashville, TN 37235, USA
| | - Caitlin O McAtee
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37235, USA
| | - Patricia M M Ozawa
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37235, USA
| | - Abbie S Ireland
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
| | - Philip E Stauffer
- Department of Biochemistry, Vanderbilt University, Nashville, TN 37235, USA
| | - Perry T Wasdin
- Department of Biochemistry, Vanderbilt University, Nashville, TN 37235, USA
| | - Xiaomeng Huang
- Utah Center for Genetic Discovery, Eccles Institute of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA
| | - Yi Qiao
- Utah Center for Genetic Discovery, Eccles Institute of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA
| | - Jing Shan Lim
- Department of Pediatrics and Genetics, Stanford University, Stanford, CA 94305, USA
| | - Jackie Bader
- Department of Pathology, Microbiology, and Immunology, Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Qi Liu
- Department of Biostatistics and Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN 37235, USA
| | - Alan J Simmons
- Epithelial Biology Center and Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37235, USA
| | - Ken S Lau
- Epithelial Biology Center and Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37235, USA
| | - Wade T Iams
- Division of Hematology-Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37235, USA
| | - Doug P Hardin
- Department of Mathematics and Department of Biomedical Informatics, Vanderbilt University, Nashville, TN 37235, USA
| | - Edward B Saff
- Department of Mathematics, Vanderbilt University, Nashville, TN 37235, USA
| | - William R Holmes
- Department of Mathematics, Vanderbilt University, Nashville, TN 37235, USA; Department of Physics, Vanderbilt University, Nashville, TN 37235, USA
| | - Darren R Tyson
- Department of Biochemistry, Vanderbilt University, Nashville, TN 37235, USA
| | - Christine M Lovly
- Department of Mathematics and Department of Biomedical Informatics, Vanderbilt University, Nashville, TN 37235, USA; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37235, USA
| | - Jeffrey C Rathmell
- Department of Pathology, Microbiology, and Immunology, Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Gabor Marth
- Utah Center for Genetic Discovery, Eccles Institute of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA
| | - Julien Sage
- Department of Pediatrics and Genetics, Stanford University, Stanford, CA 94305, USA
| | - Trudy G Oliver
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
| | - Alissa M Weaver
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37235, USA; Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN 37235, USA
| | - Vito Quaranta
- Department of Biochemistry, Vanderbilt University, Nashville, TN 37235, USA.
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A dopamine-methacrylated hyaluronic acid hydrogel as an effective carrier for stem cells in skin regeneration therapy. Cell Death Dis 2022; 13:738. [PMID: 36030275 PMCID: PMC9420120 DOI: 10.1038/s41419-022-05060-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 05/05/2022] [Accepted: 07/01/2022] [Indexed: 01/21/2023]
Abstract
Adipose-derived stem cells (ADSCs) show potential in skin regeneration research. A previous study reported the failure of full-thickness skin self-repair in an injury area exceeding 4 cm in diameter. Stem cell therapies have shown promise in accelerating skin regeneration; however, the low survival rate of transplanted cells due to the lack of protection during and after transplantation leads to low efficacy. Hence, effective biomaterials for the delivery and retention of ADSCs are urgently needed for skin regeneration purposes. Here, we covalently crosslinked hyaluronic acid with methacrylic anhydride and then covalently crosslinked the product with dopamine to engineer dopamine-methacrylated hyaluronic acid (DA-MeHA). Our experiments suggested that the DA-MeHA hydrogel firmly adhered to the skin wound defect and promoted cell proliferation in vitro and skin defect regeneration in vivo. Mechanistic analyses revealed that the beneficial effect of the DA-MeHA hydrogel combined with ADSCs on skin defect repair may be closely related to the Notch signaling pathway. The ADSCs from the DA-MeHA hydrogel secrete high levels of growth factors and are thus highly efficacious for promoting skin wound healing. This DA-MeHA hydrogel may be used as an effective potential carrier for stem cells as it enhances the efficacy of ADSCs in skin regeneration.
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Xiaojie W, Banda J, Qi H, Chang AK, Bwalya C, Chao L, Li X. Scarless wound healing: Current insights from the perspectives of TGF-β, KGF-1, and KGF-2. Cytokine Growth Factor Rev 2022; 66:26-37. [PMID: 35690568 DOI: 10.1016/j.cytogfr.2022.03.001] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 03/22/2022] [Indexed: 11/03/2022]
Abstract
The process of wound healing involves a complex and vast interplay of growth factors and cytokines that coordinate the recruitment and interaction of various cell types. A series of events involving inflammation, proliferation, and remodeling eventually leads to the restoration of the damaged tissue. Abrogation in the regulation of these events has been shown to result in excessive scarring or non-healing wounds. While the process of wound healing is not fully elucidated, it has been documented that the early events of wound healing play a key role in the outcome of the wound. Furthermore, high levels of inflammation have been shown to lead to scarring. The regulation of these events may result in scarless wound healing, especially in adults. The inhibition of transforming growth factor-β (TGF-β) and the administration of keratinocyte growth factors (KGF), KGF-1 and KGF-2, has in recent years yielded positive results in the acceleration of wound closure and reduced scarring. Here, we encapsulate recent knowledge on the roles of TGF-β, KGF1, and KGF2 in wound healing and scar formation and highlight the areas that need further investigation. We also discuss potential future directions for the use of growth factors in wound management.
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Affiliation(s)
| | | | - Hui Qi
- Wenzhou Medical University, China
| | | | | | - Lu Chao
- Wenzhou Medical University, China
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Wang Z, Lu H, Tang T, Liu L, Pan B, Chen J, Cheng D, Cai X, Sun Y, Zhu F, Zhu S. Tetrahedral framework nucleic acids promote diabetic wound healing via the Wnt signalling pathway. Cell Prolif 2022; 55:e13316. [PMID: 35869570 PMCID: PMC9628242 DOI: 10.1111/cpr.13316] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 06/28/2022] [Accepted: 07/01/2022] [Indexed: 02/05/2023] Open
Abstract
Objectives To determine the therapeutic effect of tetrahedral framework nucleic acids (tFNAs) on diabetic wound healing and the underlying mechanism. Materials and Methods The tFNAs were characterized by polyacrylamide gel electrophoresis (PAGE), atomic force microscopy (AFM), transmission electron microscopy (TEM), dynamic light scattering (DLS) and zeta potential assays. Cell Counting Kit‐8 (CCK‐8) and migration assays were performed to evaluate the effects of tFNAs on cellular proliferation and migration. Quantitative polymerase chain reaction (Q‐PCR) and enzyme‐linked immunosorbent assay (ELISA) were used to detect the effect of tFNAs on growth factors. The function and role of tFNAs in diabetic wound healing were investigated using diabetic wound models, histological analyses and western blotting. Results Cellular proliferation and migration were enhanced after treatment with tFNAs in a high‐glucose environment. The expression of growth factors was also facilitated by tFNAs in vitro. During in vivo experiments, tFNAs accelerated the healing process in diabetic wounds and promoted the regeneration of the epidermis, capillaries and collagen. Moreover, tFNAs increased the secretion of growth factors and activated the Wnt pathway in diabetic wounds. Conclusions This study indicates that tFNAs can accelerate diabetic wound healing and have potential for the treatment of diabetic wounds.
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Affiliation(s)
- Zejing Wang
- Burn Institute of PLA, Department of Burn Surgery the First Affiliated Hospital of Naval Medical University, Research Unit of Key Techniques for Treatment of Burns and Combined Burns and Trauma Injury, Chinese Academy of Medical Sciences Shanghai China
| | - Hao Lu
- Burn Institute of PLA, Department of Burn Surgery the First Affiliated Hospital of Naval Medical University, Research Unit of Key Techniques for Treatment of Burns and Combined Burns and Trauma Injury, Chinese Academy of Medical Sciences Shanghai China
| | - Tao Tang
- Burn Institute of PLA, Department of Burn Surgery the First Affiliated Hospital of Naval Medical University, Research Unit of Key Techniques for Treatment of Burns and Combined Burns and Trauma Injury, Chinese Academy of Medical Sciences Shanghai China
| | - Lei Liu
- Burn Institute of PLA, Department of Burn Surgery the First Affiliated Hospital of Naval Medical University, Research Unit of Key Techniques for Treatment of Burns and Combined Burns and Trauma Injury, Chinese Academy of Medical Sciences Shanghai China
| | - Bohan Pan
- Burn Institute of PLA, Department of Burn Surgery the First Affiliated Hospital of Naval Medical University, Research Unit of Key Techniques for Treatment of Burns and Combined Burns and Trauma Injury, Chinese Academy of Medical Sciences Shanghai China
| | - Jiqiu Chen
- Burn Institute of PLA, Department of Burn Surgery the First Affiliated Hospital of Naval Medical University, Research Unit of Key Techniques for Treatment of Burns and Combined Burns and Trauma Injury, Chinese Academy of Medical Sciences Shanghai China
| | - Dasheng Cheng
- Burn Institute of PLA, Department of Burn Surgery the First Affiliated Hospital of Naval Medical University, Research Unit of Key Techniques for Treatment of Burns and Combined Burns and Trauma Injury, Chinese Academy of Medical Sciences Shanghai China
| | - Xiaoxiao Cai
- State Key Laboratory of Oral Diseases National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University Chengdu China
| | - Yu Sun
- Burn Institute of PLA, Department of Burn Surgery the First Affiliated Hospital of Naval Medical University, Research Unit of Key Techniques for Treatment of Burns and Combined Burns and Trauma Injury, Chinese Academy of Medical Sciences Shanghai China
| | - Feng Zhu
- Burn Institute of PLA, Department of Burn Surgery the First Affiliated Hospital of Naval Medical University, Research Unit of Key Techniques for Treatment of Burns and Combined Burns and Trauma Injury, Chinese Academy of Medical Sciences Shanghai China
| | - Shihui Zhu
- Burn Institute of PLA, Department of Burn Surgery the First Affiliated Hospital of Naval Medical University, Research Unit of Key Techniques for Treatment of Burns and Combined Burns and Trauma Injury, Chinese Academy of Medical Sciences Shanghai China
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Wang X, Liu Y, He J, Wang J, Chen X, Yang R. Regulation of signaling pathways in hair follicle stem cells. BURNS & TRAUMA 2022; 10:tkac022. [PMID: 35795256 PMCID: PMC9250793 DOI: 10.1093/burnst/tkac022] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 02/07/2022] [Indexed: 11/21/2022]
Abstract
Hair follicle stem cells (HFSCs) reside in the bulge region of the outer root sheath of the hair follicle. They are considered slow-cycling cells that are endowed with multilineage differentiation potential and superior proliferative capacity. The normal morphology and periodic growth of HFSCs play a significant role in normal skin functions, wound repair and skin regeneration. The HFSCs involved in these pathophysiological processes are regulated by a series of cell signal transduction pathways, such as lymphoid enhancer factor/T-cell factor, Wnt/β-catenin, transforming growth factor-β/bone morphogenetic protein, Notch and Hedgehog. The mechanisms of the interactions among these signaling pathways and their regulatory effects on HFSCs have been previously studied, but many mechanisms are still unclear. This article reviews the regulation of hair follicles, HFSCs and related signaling pathways, with the aims of summarizing previous research results, revealing the regulatory mechanisms of HFSC proliferation and differentiation and providing important references and new ideas for treating clinical diseases.
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Affiliation(s)
| | | | - Jia He
- Department of Burn Surgery, The First People’s Hospital of Foshan, Foshan 528000, China
| | - Jingru Wang
- Department of Burn Surgery, The First People’s Hospital of Foshan, Foshan 528000, China
| | - Xiaodong Chen
- Correspondence. Xiaodong Chen, E-mail: ; Ronghua Yang,
| | - Ronghua Yang
- Correspondence. Xiaodong Chen, E-mail: ; Ronghua Yang,
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Wiśniewska J, Słyszewska M, Kopcewicz M, Walendzik K, Machcińska S, Stałanowska K, Gawrońska-Kozak B. Comparative studies on the effect of pig adipose-derived stem cells (pASCs) preconditioned with hypoxia or normoxia on skin wound healing in mice. Exp Cell Res 2022; 418:113263. [PMID: 35718003 DOI: 10.1016/j.yexcr.2022.113263] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 06/10/2022] [Accepted: 06/12/2022] [Indexed: 11/04/2022]
Abstract
Adipose-derived stem cells (ASCs) from human and animal fat have emerged as therapeutic alternatives for damaged tissues. Pre-conditioning of ASCs with hypoxia results in their functional enhancement, which might facilitate the process of healing. However, there is still a critical need for large-scale preclinical studies to reinforce the translation of these findings into clinical practice for humans and in veterinary medicine. Here, we adapted a full-thickness excisional skin wound mouse model to evaluate and compare the effect of pig adipose-derived stem cells (pASCs) cultured under normoxia (pASCs-Nor) or hypoxia (pASCs-Hyp) on the healing process. We show that pASCs-Hyp accelerated re-epithelialization, increased hyaluronic acid (HA) content, and decreased scar elevation index (SEI) during the late stage of healing (day 21). Transplantation of pASCs-Hyp also promoted expression of angiogenic marker VegfA and decreased levels of pro-scarring Tgfβ1. Mice tolerated xenotransplantation of the pASCs with no impact on macrophage (CD68 -positive cell) content. However, wounds treated with pASCs-Hyp exhibited decreased elasticity at the early stage of healing and increased expression of Wnt signaling members including Wnt10a, Wnt11, and β-catenin, which are associated with scar-forming wound repair. In conclusion, pASCs treatment may provide a critical step toward the evaluation of pASCs as therapeutically relevant cells in the context of wound healing.
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Affiliation(s)
- Joanna Wiśniewska
- Institute of Animal Reproduction and Food Research, Polish Academy of Sciences in Olsztyn, 10-748 Olsztyn, Poland.
| | - Magda Słyszewska
- Institute of Animal Reproduction and Food Research, Polish Academy of Sciences in Olsztyn, 10-748 Olsztyn, Poland.
| | - Marta Kopcewicz
- Institute of Animal Reproduction and Food Research, Polish Academy of Sciences in Olsztyn, 10-748 Olsztyn, Poland.
| | - Katarzyna Walendzik
- Institute of Animal Reproduction and Food Research, Polish Academy of Sciences in Olsztyn, 10-748 Olsztyn, Poland.
| | - Sylwia Machcińska
- Institute of Animal Reproduction and Food Research, Polish Academy of Sciences in Olsztyn, 10-748 Olsztyn, Poland.
| | - Karolina Stałanowska
- Department of Plant Physiology, Genetics and Biotechnology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland.
| | - Barbara Gawrońska-Kozak
- Institute of Animal Reproduction and Food Research, Polish Academy of Sciences in Olsztyn, 10-748 Olsztyn, Poland.
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Mi Y, Zhong L, Lu S, Hu P, Pan Y, Ma X, Yan B, Wei Z, Yang G. Quercetin promotes cutaneous wound healing in mice through Wnt/β-catenin signaling pathway. JOURNAL OF ETHNOPHARMACOLOGY 2022; 290:115066. [PMID: 35122975 DOI: 10.1016/j.jep.2022.115066] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 01/17/2022] [Accepted: 01/30/2022] [Indexed: 06/14/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Oxytropis falcata Bunge is a legume distributed in Northwest China, which is mainly used to treat knife wounds and inflammation. Quercetin is a bioactive flavonoid in O. falcata and becomes a promising healing compound for its angiogenic and anti-inflammatory activities. However, the healing mechanism of quercetin in cutaneous wound remains elusive. AIM OF THE STUDY The purpose of this study was to evaluate the healing effect of quercetin on cutaneous wound models in vivo and in vitro, and to reveal the Wnt/β-catenin pathway and Telomerase reverse transcriptase (TERT) involved mechanisms. MATERIALS AND METHODS The effects of quercetin on the proliferation and migration of 4 kinds of skin cells were determined by CCK-8 and scratch assay. The wound-healing capacity of quercetin was evaluated in cutaneous wound model of C57BL/6 mice and the wound healing degree was observed by histological staining. The expressions of inflammatory factors, growth factors and the related proteins were detected via Western blot and RT-qPCR analyses. The molecular docking was adopted to evaluate the binding ability of quercetin and TERT. RESULTS Quercetin could promote both proliferation and migration of fibroblasts, and enhance cutaneous wound healing capacity in mice. Compared to the control group, the wound healing rates in low (1.5 mg/mL), medium (3.0 mg/mL) and high dose (6.0 mg/mL) quercetin groups reached 94.67%, 97.31% and 98.42%, respectively. Moreover, the dermal structure in quercetin treated mice restored normal and the content of collagen fiber became abundant after administration. The levels of inflammatory factors, including tumor necrosis factor-α, interleukin-1β and interleukin-6 were significantly reduced after quercetin administration. Among which, the level of IL-1β in cutaneous wound was 0.007 times higher than that of the control group when treated with quercetin of high dose (6.0 mg/mL). The improved level of GSH in quercetin treated cutaneous wounds also indicated its higher antioxidant ability. In addition, dose-dependent positive associations were found in the expression levels of vascular endothelial growth factor, fibroblast growth factor and alpha smooth muscle actin in quercetin treated cutaneous wounds. The significantly upregulated protein levels of Wnt and β-catenin further indicated the important role of quercetin in promoting wound healing in mice. According to molecular docking analysis, the formed hydrogen bonds between quercetin and Ala195, Gln308, Asn369 and Lys372 residues of TERT also indicated the indispensable role of TERT in improving wound healing capacity. CONCLUSION Quercetin effectively promoted cutaneous wound healing by enhancing the proliferation and migration of fibroblasts, as well as inhibiting inflammation and increasing the expression of growth factors in mice via Wnt/β-catenin signaling pathway and TERT. It provides a basis for a more thorough understanding of mechanism of action of O. falcata Bunge in the treatment of knife wounds and burns.
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Affiliation(s)
- Yuhui Mi
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, PR China
| | - Lei Zhong
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, PR China
| | - Saijian Lu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, PR China
| | - Po Hu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, PR China
| | - Yang Pan
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, PR China.
| | - Xuelin Ma
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, PR China
| | - Binghui Yan
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, PR China
| | - Zhenhuan Wei
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, PR China
| | - Guangming Yang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, PR China.
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Sultan MT, Hong H, Lee OJ, Ajiteru O, Lee YJ, Lee JS, Lee H, Kim SH, Park CH. Silk Fibroin-Based Biomaterials for Hemostatic Applications. Biomolecules 2022; 12:biom12050660. [PMID: 35625588 PMCID: PMC9138874 DOI: 10.3390/biom12050660] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 04/15/2022] [Accepted: 04/28/2022] [Indexed: 02/05/2023] Open
Abstract
Hemostasis plays an essential role in all surgical procedures. Uncontrolled hemorrhage is the primary cause of death during surgeries, and effective blood loss control can significantly reduce mortality. For modern surgeons to select the right agent at the right time, they must understand the mechanisms of action, the effectiveness, and the possible adverse effects of each agent. Over the past decade, various hemostatic agents have grown intensely. These agents vary from absorbable topical hemostats, including collagen, gelatins, microfibrillar, and regenerated oxidized cellulose, to biologically active topical hemostats such as thrombin, biological adhesives, and other combined agents. Commercially available products have since expanded to include topical hemostats, surgical sealants, and adhesives. Silk is a natural protein consisting of fibroin and sericin. Silk fibroin (SF), derived from silkworm Bombyx mori, is a fibrous protein that has been used mostly in fashion textiles and surgical sutures. Additionally, SF has been widely applied as a potential biomaterial in several biomedical and biotechnological fields. Furthermore, SF has been employed as a hemostatic agent in several studies. In this review, we summarize the several morphologic forms of SF and the latest technological advances on the use of SF-based hemostatic agents.
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Affiliation(s)
- Md. Tipu Sultan
- Nano-Bio Regenerative Medical Institute (NBRM), Hallym University, Chuncheon 24252, Korea; (M.T.S.); (H.H.); (O.J.L.); (O.A.); (Y.J.L.); (J.S.L.); (H.L.); (S.H.K.)
| | - Heesun Hong
- Nano-Bio Regenerative Medical Institute (NBRM), Hallym University, Chuncheon 24252, Korea; (M.T.S.); (H.H.); (O.J.L.); (O.A.); (Y.J.L.); (J.S.L.); (H.L.); (S.H.K.)
| | - Ok Joo Lee
- Nano-Bio Regenerative Medical Institute (NBRM), Hallym University, Chuncheon 24252, Korea; (M.T.S.); (H.H.); (O.J.L.); (O.A.); (Y.J.L.); (J.S.L.); (H.L.); (S.H.K.)
| | - Olatunji Ajiteru
- Nano-Bio Regenerative Medical Institute (NBRM), Hallym University, Chuncheon 24252, Korea; (M.T.S.); (H.H.); (O.J.L.); (O.A.); (Y.J.L.); (J.S.L.); (H.L.); (S.H.K.)
| | - Young Jin Lee
- Nano-Bio Regenerative Medical Institute (NBRM), Hallym University, Chuncheon 24252, Korea; (M.T.S.); (H.H.); (O.J.L.); (O.A.); (Y.J.L.); (J.S.L.); (H.L.); (S.H.K.)
| | - Ji Seung Lee
- Nano-Bio Regenerative Medical Institute (NBRM), Hallym University, Chuncheon 24252, Korea; (M.T.S.); (H.H.); (O.J.L.); (O.A.); (Y.J.L.); (J.S.L.); (H.L.); (S.H.K.)
| | - Hanna Lee
- Nano-Bio Regenerative Medical Institute (NBRM), Hallym University, Chuncheon 24252, Korea; (M.T.S.); (H.H.); (O.J.L.); (O.A.); (Y.J.L.); (J.S.L.); (H.L.); (S.H.K.)
| | - Soon Hee Kim
- Nano-Bio Regenerative Medical Institute (NBRM), Hallym University, Chuncheon 24252, Korea; (M.T.S.); (H.H.); (O.J.L.); (O.A.); (Y.J.L.); (J.S.L.); (H.L.); (S.H.K.)
| | - Chan Hum Park
- Nano-Bio Regenerative Medical Institute (NBRM), Hallym University, Chuncheon 24252, Korea; (M.T.S.); (H.H.); (O.J.L.); (O.A.); (Y.J.L.); (J.S.L.); (H.L.); (S.H.K.)
- Department of Otorhinolaryngology-Head and Neck Surgery, Chuncheon Sacred Heart Hospital, Chuncheon 24253, Korea
- Correspondence:
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Regulatory Processes of the Canonical Wnt/β-Catenin Pathway and Photobiomodulation in Diabetic Wound Repair. Int J Mol Sci 2022; 23:ijms23084210. [PMID: 35457028 PMCID: PMC9028270 DOI: 10.3390/ijms23084210] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 02/09/2022] [Accepted: 02/10/2022] [Indexed: 11/17/2022] Open
Abstract
Skin is a biological system composed of different types of cells within a firmly structured extracellular matrix and is exposed to various external and internal insults that can break its configuration. The restoration of skin's anatomic continuity and function following injury is a multifaceted, dynamic, well-coordinated process that is highly dependent on signalling pathways, including the canonical Wnt/β catenin pathway, all aimed at restoring the skin's protective barrier. Compromised and inappropriate tissue restoration processes are often the source of wound chronicity. Diabetic patients have a high risk of developing major impediments including wound contamination and limb amputation due to chronic, non-healing wounds. Photobiomodulation (PBM) involves the application of low-powered light at specific wavelengths to influence different biological activities that incite and quicken tissue restoration. PBM has been shown to modulate cellular behaviour through a variety of signal transduction pathways, including the Wnt/β catenin pathway; however, the role of Wnt/β catenin in chronic wound healing in response to PBM has not been fully defined. This review largely focuses on the role of key signalling pathways in human skin wound repair, specifically, the canonical Wnt/β-catenin pathway, and the effects of PBM on chronic wound healing.
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Zhu P, Chen C, Wu D, Chen G, Tan R, Ran J. AGEs-induced MMP-9 activation mediated by Notch1 signaling is involved in impaired wound healing in diabetic rats. Diabetes Res Clin Pract 2022; 186:109831. [PMID: 35306046 DOI: 10.1016/j.diabres.2022.109831] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 03/08/2022] [Accepted: 03/12/2022] [Indexed: 11/03/2022]
Abstract
AIMS To elucidate the relationship between advanced glycation end products (AGEs), Notch1 signaling, nuclear factor-kappa B (NF-κB), and matrix metalloproteinase-9 (MMP-9) in diabetic wound healing in vitro and in vivo. METHODS We incubated primary keratinocytes with AGEs alone or AGEs along with γ-secretase inhibitor DAPT, and established diabetic rat wound model by intraperitoneal streptozotocin treatment. The Notch1 signaling components and MMP-9 expression were detected by qPCR, western blotting and gelatin zymography. RESULTS The exposure of primary keratinocytes to AGEs led to a significant increase in Notch intracellular domain (NICD), Delta-like 4 (Dll4), and Hes1; however, Notch1 expression was inhibited by the RAGE siRNA. Furthermore, MMP-9 activation was up-regulated, secondary to AGEs treatment. In contrast, increased MMP-9 expression by AGEs-stimulation was eliminated after treatment with DAPT. NF-κB activation participated in the Notch1-modulated MMP-9 expression. Notably, in the diabetic animal model, inhibition of the Notch signaling pathway with DAPT attenuated NICD and MMP-9 overexpression, improved collagen accumulation, and ultimately accelerated diabetic wound healing. CONCLUSIONS These findings identified that activation of the Notch1/NF-κB/MMP-9 pathway, in part, mediates the repressive effects of AGEs on diabetic wound healing and that targeting this pathway may be a potential strategy to improve impaired diabetic wound healing.
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Affiliation(s)
- Ping Zhu
- Department of Endocrinology and Metabolism, Guangzhou Red Cross Hospital, Jinan University, Guangzhou 510220, China
| | - Chuping Chen
- Department of Endocrinology and Metabolism, Guangzhou Red Cross Hospital, Jinan University, Guangzhou 510220, China
| | - Daoai Wu
- Department of Endocrinology and Metabolism, The First Affiliated Hospital, Bengbu Medical College, Bengbu 233099, China
| | - Guangshu Chen
- Department of Endocrinology and Metabolism, Guangzhou Red Cross Hospital, Jinan University, Guangzhou 510220, China
| | - Rongshao Tan
- Guangzhou Institute of Disease-Oriented Nutritional Research, Guangzhou Red Cross Hospital, Jinan University, Guangzhou 510220, China
| | - Jianmin Ran
- Department of Endocrinology and Metabolism, Guangzhou Red Cross Hospital, Jinan University, Guangzhou 510220, China.
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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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Canonical Wnt Signaling in the Pathology of Iron Overload-Induced Oxidative Stress and Age-Related Diseases. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:7163326. [PMID: 35116092 PMCID: PMC8807048 DOI: 10.1155/2022/7163326] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 01/04/2022] [Indexed: 12/26/2022]
Abstract
Iron accumulates in the vital organs with aging. This is associated with oxidative stress, inflammation, and mitochondrial dysfunction leading to age-related disorders. Abnormal iron levels are linked to neurodegenerative diseases, liver injury, cancer, and ocular diseases. Canonical Wnt signaling is an evolutionarily conserved signaling pathway that regulates many cellular functions including cell proliferation, apoptosis, cell migration, and stem cell renewal. Recent evidences indicate that iron regulates Wnt signaling, and iron chelators like deferoxamine and deferasirox can inhibit Wnt signaling and cell growth. Canonical Wnt signaling is implicated in the pathogenesis of many diseases, and there are significant efforts ongoing to develop innovative therapies targeting the aberrant Wnt signaling. This review examines how intracellular iron accumulation regulates Wnt signaling in various tissues and their potential contribution in the progression of age-related diseases.
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Zhang F, Liu Y, Wang S, Yan X, Lin Y, Chen D, Tan Q, Wu Z. Interleukin-25-Mediated-IL-17RB Upregulation Promotes Cutaneous Wound Healing in Diabetic Mice by Improving Endothelial Cell Functions. Front Immunol 2022; 13:809755. [PMID: 35126394 PMCID: PMC8810642 DOI: 10.3389/fimmu.2022.809755] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 01/03/2022] [Indexed: 12/27/2022] Open
Abstract
Diabetic foot ulcer (DFU) frequently leads to non-traumatic amputation and finally even death. However, the mechanism of DFU is not fully understood. Interleukin 25 (IL-25), an alarmin cytokine that responds to tissue injury, has been reported to participate in tissue regeneration and maintaining glucose homeostasis. However, the role of IL-25 in diabetic wound healing remains unknown. Here, we showed that interleukin 17 receptor B (IL-17RB), the functional receptor of IL-25, was significantly inhibited in the wound skin of both diabetic patients with DFU and streptozotocin (STZ)-induced diabetic mice. Topical administration of recombinant IL-25 protein improved angiogenesis and collagen deposition in the wound bed and thus ameliorated delayed diabetic wound healing. IL-25 increased endothelial-specific CD31 expression in diabetic wounds and exogenous IL-25 protected endothelial cells from high glucose-impaired cell migration and tube formation in vitro. We further revealed that IL-25-mediated-IL-17RB signaling rescued the downregulation of Wnt/β-catenin pathway both in vivo in diabetic mice and in vitro in HUVECs and induced the phosphorylation of AKT and ERK 1/2 in HUVECs under high glucose conditions. This study defines a positive regulatory role of IL-25-mediated-IL-17RB signaling in diabetic wound healing and suggests that induction of IL-25-mediated-IL-17RB signaling may be a novel therapeutic strategy for treating poor healing diabetic wounds.
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Affiliation(s)
- Fang Zhang
- Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- Center for Public Health Research, Medical School, Nanjing University, Nanjing, China
| | - Ye Liu
- Center for Public Health Research, Medical School, Nanjing University, Nanjing, China
| | - Shiqi Wang
- Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Xin Yan
- Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Yue Lin
- Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Deyan Chen
- Center for Public Health Research, Medical School, Nanjing University, Nanjing, China
- *Correspondence: Zhiwei Wu, ; Qian Tan, ; Deyan Chen,
| | - Qian Tan
- Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- *Correspondence: Zhiwei Wu, ; Qian Tan, ; Deyan Chen,
| | - Zhiwei Wu
- Center for Public Health Research, Medical School, Nanjing University, Nanjing, China
- State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, China
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, China
- *Correspondence: Zhiwei Wu, ; Qian Tan, ; Deyan Chen,
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ROS Promote Hypoxia-Induced Keratinocyte Epithelial-Mesenchymal Transition by Inducing SOX2 Expression and Subsequent Activation of Wnt/ β-Catenin. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:1084006. [PMID: 35035654 PMCID: PMC8758332 DOI: 10.1155/2022/1084006] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 10/21/2021] [Accepted: 11/03/2021] [Indexed: 12/12/2022]
Abstract
We previously showed that wound-induced hypoxia is related to keratinocyte migration. The ability of keratinocytes within wound healing to undergo epithelial to mesenchymal transition (EMT) contributes significantly to the acquisition of migratory properties. However, the effect of hypoxia on keratinocyte EMT on wound healing and the potential mechanism are poorly documented. This study first demonstrated that reactive oxygen species (ROS) appear to be an essential signalling mediator in keratinocytes with increased EMT and migration subjected to hypoxic conditions. Next, we showed that the expression of sex-determining region Y-box 2 (SOX2), a stemness-associated molecule, is ROS-dependent under hypoxia and that SOX2 inhibition in keratinocytes dramatically prevented hypoxia-induced EMT and migration. In addition, β-catenin was found to be a potential molecular target of SOX2, and the activation of Wnt/β-catenin was required for hypoxia-induced EMT and migration. Using an in vitro skin culture model and an in vivo skin wound model, our study further reinforced the critical role of ROS in inducing EMT through SOX2 expression and subsequent activation of Wnt/β-catenin, allowing for rapid reepithelialization of the wound area. Taken together, our findings reveal a previously unknown mechanism by which hypoxia promotes wound healing by promoting reepithelialization through the production of ROS, inducing keratinocyte EMT and migration via the enhancement of SOX2 and activation of Wnt/β-catenin.
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