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Lee C, Kim MJ, Kumar A, Lee HW, Yang Y, Kim Y. Vascular endothelial growth factor signaling in health and disease: from molecular mechanisms to therapeutic perspectives. Signal Transduct Target Ther 2025; 10:170. [PMID: 40383803 PMCID: PMC12086256 DOI: 10.1038/s41392-025-02249-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 03/09/2025] [Accepted: 04/21/2025] [Indexed: 05/20/2025] Open
Abstract
Vascular endothelial growth factor (VEGF) signaling is a critical regulator of vasculogenesis, angiogenesis, and lymphangiogenesis, processes that are vital for the development of vascular and lymphatic systems, tissue repair, and the maintenance of homeostasis. VEGF ligands and their receptors orchestrate endothelial cell proliferation, migration, and survival, playing a pivotal role in dynamic vascular remodeling. Dysregulated VEGF signaling drives diverse pathological conditions, including tumor angiogenesis, cardiovascular diseases, and ocular disorders. Excessive VEGF activity promotes tumor growth, invasion, and metastasis, while insufficient signaling contributes to impaired wound healing and ischemic diseases. VEGF-targeted therapies, such as monoclonal antibodies and tyrosine kinase inhibitors, have revolutionized the treatment of diseases involving pathological angiogenesis, offering significant clinical benefits in oncology and ophthalmology. These therapies inhibit angiogenesis and slow disease progression, but they often face challenges such as therapeutic resistance, suboptimal efficacy, and adverse effects. To further explore these issues, this review provides a comprehensive overview of VEGF ligands and receptors, elucidating their molecular mechanisms and regulatory networks. It evaluates the latest progress in VEGF-targeted therapies and examines strategies to address current challenges, such as resistance mechanisms. Moreover, the discussion includes emerging therapeutic strategies such as innovative drug delivery systems and combination therapies, highlighting the continuous efforts to improve the effectiveness and safety of VEGF-targeted treatments. This review highlights the translational potential of recent discoveries in VEGF biology for improving patient outcomes.
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Affiliation(s)
- Chunsik Lee
- Department of R&D, GEMCRO Inc, Seoul, Republic of Korea.
| | - Myung-Jin Kim
- Department of Biological Sciences and Research Institute of Women's Health, Sookmyung Women's University, Seoul, Republic of Korea
| | - Anil Kumar
- Center for Research and Innovations, Adichunchanagiri University, Mandya, Karnataka, India
| | - Han-Woong Lee
- Department of R&D, GEMCRO Inc, Seoul, Republic of Korea
| | - Yunlong Yang
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Yonghwan Kim
- Department of Biological Sciences and Research Institute of Women's Health, Sookmyung Women's University, Seoul, Republic of Korea.
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Bao JM, Hou T, Zhao L, Song YJ, Liu Y, Xing LP, Xu H, Wang XY, Li Q, Zhang L, Chang JL, Li W, Shi Q, Wang YJ, Liang QQ. Notoginsenoside R1 reduces acquired lymphedema and increases lymphangiogenesis by promoting VEGF-C expression via cAMP/PKA/CREB signaling. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 139:156554. [PMID: 40020630 DOI: 10.1016/j.phymed.2025.156554] [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: 08/10/2024] [Revised: 02/15/2025] [Accepted: 02/20/2025] [Indexed: 03/03/2025]
Abstract
BACKGROUND Acquired lymphedema is a global health concern with limited treatment options. While vascular endothelial growth factor C (VEGF-C) administration has shown promise for the treatment of this patient population, no small-molecule compounds have hitherto been identified to improve lymphedema by stimulating VEGF-C expression and lymphangiogenesis. OBJECTIVE This study investigated the therapeutic effect of notoginsenoside R1 (R1) on a mouse model of tail acquired lymphedema and explored the underlying mechanisms. METHODS C57BL/6J mice and lymphatic endothelial cells (LECs) specific VEGFR-3 knockout transgenic mice underwent surgical induction of tail acquired lymphedema. Tail circumference, lymphatic drainage function, VEGF-C expression, and lymphangiogenesis were measured. LECs' function was assessed using wound healing and tube formation assays. Quantitative PCR (q-PCR) and western blot were conducted to measure VEGF-C expression levels. In addition, RNA sequencing analysis and western blot were performed to elucidate the signal pathways involved. Luciferase reporter assays assessed VEGF-C promoter activity. RESULTS R1 treatment improved lymphedema, lymphatic function, and lymphangiogenesis in the mouse model. R1 enhanced migration, tube formation, and VEGF-C expression of LECs. These effects were abolished by VEGF-C siRNA and VEGFR-3 inhibitors. VEGFR3 knockout in LECs completely blocked R1's ability to promote lymphangiogenesis and lymphatic drainage while partially but significantly reducing its improvement on lymphedema. R1 activated the cAMP/PKA signaling pathway, leading to PKA and CREB phosphorylation. The PKA inhibitor and CREB siRNA inhibited R1-induced VEGF-C expression. Additionally, R1 activated VEGF-C promoter activity in a CREB-dependent manner. CONCLUSION R1 emerges as the first reported small natural compound to promote VEGF-C expression. It reduces acquired lymphedema and enhances lymphangiogenesis via the cAMP/PKA/CREB signaling pathway. These findings suggest R1 as a potential novel oral medication for treating acquired lymphedema patients.
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Affiliation(s)
- Jia-Min Bao
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Shanghai 200032, China; Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Shanghai 200032, China; School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China; Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China
| | - Tong Hou
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Shanghai 200032, China; Jing'an District Central Hospital, Shanghai 200040, China
| | - Li Zhao
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Shanghai 200032, China; Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Shanghai 200032, China; Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China
| | - Yong-Jia Song
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Shanghai 200032, China; Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Shanghai 200032, China; School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China; Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China
| | - Yang Liu
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Shanghai 200032, China; Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Shanghai 200032, China; Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China
| | - Lian-Ping Xing
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, United States
| | - Hao Xu
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Shanghai 200032, China; Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Shanghai 200032, China; Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China
| | - Xiao-Yun Wang
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Shanghai 200032, China; Shanghai Research Institute of Acupuncture and Meridian, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, Shanghai 200032, China
| | - Qing Li
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Shanghai 200032, China; Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Shanghai 200032, China; Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China
| | - Li Zhang
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Shanghai 200032, China; Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Shanghai 200032, China; Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China
| | - Jun-Li Chang
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Shanghai 200032, China; Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Shanghai 200032, China; Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China
| | - Wei Li
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Shanghai 200032, China; Jing'an District Central Hospital, Shanghai 200040, China
| | - Qi Shi
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Shanghai 200032, China; Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Shanghai 200032, China; School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China; Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China
| | - Yong-Jun Wang
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Shanghai 200032, China; Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Shanghai 200032, China; School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China; Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China.
| | - Qian-Qian Liang
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Shanghai 200032, China; Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Shanghai 200032, China; School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China; Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China.
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de la Cruz E, Cadenas V, Temiño S, Oliver G, Torres M. Epicardial VEGFC/D signaling is essential for coronary lymphangiogenesis. EMBO Rep 2025:10.1038/s44319-025-00431-7. [PMID: 40128409 DOI: 10.1038/s44319-025-00431-7] [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: 02/10/2023] [Revised: 02/08/2025] [Accepted: 03/03/2025] [Indexed: 03/26/2025] Open
Abstract
The contractile ability of the mammalian heart critically relies on blood coronary circulation, essential to provide oxygen and nutrients to myocardial cells. In addition, the lymphatic vasculature is essential for the myocardial immune response, extracellular fluid homeostasis and response to injury. Recent studies identified different origins of coronary lymphatic endothelial cells, however, the cues that govern coronary lymphangiogenesis remain unknown. Here we show that the coronary lymphatic vasculature develops in intimate contact with the epicardium and with epicardial-derived cells. The epicardium expresses the lymphangiogenic cytokine VEGFC and its conditional deletion in the epicardium abrogates coronary lymphatic vasculature development. Interestingly, VEGFD is also expressed in the epicardium and cooperates with VEGFC in coronary lymphangiogenesis, but it does so only in females, uncovering an unsuspected sex-specific role for this cytokine. These results identify the epicardium/subepicardium as a signaling niche required for coronary lymphangiogenesis and VEGFC/D as essential mediators of this role.
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Affiliation(s)
- Ester de la Cruz
- Cardiovascular Regeneration Program, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, 28029, Spain
| | - Vanessa Cadenas
- Cardiovascular Regeneration Program, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, 28029, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
| | - Susana Temiño
- Cardiovascular Regeneration Program, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, 28029, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
| | - Guillermo Oliver
- Center for Vascular and Developmental Biology, Feinberg Cardiovascular and Renal Research Institute, Northwestern University, Chicago, IL, 60611, USA
| | - Miguel Torres
- Cardiovascular Regeneration Program, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, 28029, Spain.
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain.
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Chen M, Zhao JB, Wu GB, Wu ZH, Luo GQ, Zhao ZF, Zhang CH, Lin JY, Li HJ, Qi XL, Huo HZ, Tuersun A, Fan Q, Zheng L, Luo M. Platelet activation relieves liver portal hypertension via the lymphatic system though the classical vascular endothelial growth factor receptor 3 signaling pathway. World J Gastroenterol 2025; 31:100194. [PMID: 40093669 PMCID: PMC11886527 DOI: 10.3748/wjg.v31.i10.100194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 12/16/2024] [Accepted: 01/21/2025] [Indexed: 02/26/2025] Open
Abstract
BACKGROUND Liver cirrhosis and portal hypertension (PHT) can lead to lymphatic abnormalities and coagulation dysfunction. Because lymphangiogenesis may relieve liver cirrhosis and PHT, the present study investigated the gene expression alterations in the lymphatic system and the effectiveness of platelet-mediated lymphangiogenesis in improving liver cirrhosis and PHT. AIM To investigate the role of lymphangiogenesis in preclinical PHT models. METHODS Immunohistochemistry and transcriptome sequencing of bile duct ligation (BDL) and control lymphatic samples were conducted to reveal the indicated signaling pathways. Functional enrichment analyses were performed on the differentially expressed genes and hub genes. Adenoviral infection of vascular endothelial growth factor C (VEGF-C), platelet-rich plasma (PRP), and VEGF3 receptor (VEGFR) inhibitor MAZ-51 was used as an intervention for the lymphatic system in PHT models. Histology, hemodynamic tests and western blot analyses were performed to demonstrate the effects of lymphatic intervention in PHT patients. RESULTS Lymphangiogenesis was increased in the BDL rat model. Transcriptome sequencing analysis of the extrahepatic lymphatic system revealed its close association with platelet adherence, aggregation, and activation. The role of PHT in the rat model was investigated by activating (PRP) and inhibiting (MAZ-51) the lymphatic system. PRP promoted lymphangiogenesis, which increased lymphatic drainage, alleviated portal pressure, reduced liver fibrosis, inhibited inflammation, inhibited angiogenesis, and suppressed mesenteric artery remodeling. MAZ-51 reversed the above improvements. CONCLUSION Via VEGF-C/VEGFR-3, platelets impede fibrosis, angiogenesis, and mesenteric artery remodeling, ultimately alleviating PHT. Thus, platelet intervention is a therapeutic approach for cirrhosis and PHT.
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Affiliation(s)
- Min Chen
- Department of General Surgery, Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
- Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Jin-Bo Zhao
- Department of General Surgery, Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Guang-Bo Wu
- Department of General Surgery, Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Zheng-Hao Wu
- Department of General Surgery, Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Gu-Qing Luo
- Department of General Surgery, Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Zhi-Feng Zhao
- Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi’an 710032, Shaanxi Province, China
| | - Chi-Hao Zhang
- Department of General Surgery, Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Jia-Yun Lin
- Department of General Surgery, Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Hong-Jie Li
- Department of General Surgery, Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Xiao-Liang Qi
- Department of General Surgery, Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Hai-Zhong Huo
- Department of General Surgery, Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Abudukadier Tuersun
- Department of General Surgery, Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Qiang Fan
- Department of General Surgery, Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Lei Zheng
- Department of General Surgery, Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Meng Luo
- Department of General Surgery, Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
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Ye F, Zhang Z, Shi L, Lu S, Li X, Mu W, Jiang Q, Yan B. Targeting glycolytic reprogramming by tsRNA-0032 for treating pathological lymphangiogenesis. Cell Death Dis 2025; 16:51. [PMID: 39870617 PMCID: PMC11772812 DOI: 10.1038/s41419-025-07366-w] [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: 08/11/2024] [Revised: 12/27/2024] [Accepted: 01/16/2025] [Indexed: 01/29/2025]
Abstract
Lymphangiogenesis is vital for tissue fluid homeostasis, immune function, and lipid absorption. Abnormal lymphangiogenesis has been implicated in several diseases such as cancers, inflammatory, and autoimmune diseases. In this study, we elucidate the role of tsRNA-0032 in lymphangiogenesis and its molecular mechanism. tsRNA-0032 expression is significantly decreased in corneal suture model and human lymphatic endothelial cell (HLEC) model under inflammatory condition. Overexpression of tsRNA-0032 exerts anti-lymphangiogenic effects by inhibiting HLEC proliferation, migration, and tube formation. Moreover, overexpression of tsRNA-0032 inhibits suture-induced corneal lymphangiogenesis. tsRNA-0032 is mainly located in the cytoplasm and interacts with Ago2 protein. Overexpression of tsRNA-0032 reduces ATP production and decreases pyruvate and lactate levels by targeting PKM2, a key enzyme in glycolysis. This regulation of glycolysis alters cellular energy and metabolic balance in HLECs, contributing to anti-lymphangiogenic effects. Clinical data reveals that tsRNA-0032 levels are significantly reduced in corneal tissues of transplant recipients compared to donors, while PKM2 expression is elevated, highlighting the clinical relevance of tsRNA-0032/PKM2 axis in corneal lymphangiogenesis. This study offers new insights into the regulation of lymphangiogenesis and presents potential therapeutic targets for lymphangiogenesis-related diseases.
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Affiliation(s)
- Fan Ye
- The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ziran Zhang
- The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China
| | - Lianjun Shi
- The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China
| | - Shuting Lu
- The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China
| | - Xiumiao Li
- The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China
| | - Wan Mu
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, China
| | - Qin Jiang
- The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China.
| | - Biao Yan
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Ge X, Du C, Fang L, Xu W, Xiang J, Liu J, Zhou M, Chen Y, Wang Z, Li Z. Long non-coding RNA CAR10 promotes angiogenesis of lung adenocarcinoma by mediating nuclear LDHA to epigenetically regulate VEGFA/C. Commun Biol 2025; 8:32. [PMID: 39789173 PMCID: PMC11718007 DOI: 10.1038/s42003-025-07452-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 12/31/2024] [Indexed: 01/30/2025] Open
Abstract
Angiogenesis is a significant character of lung adenocarcinoma (LUAD) and is an important reason leading to high mortality rates of LUAD patients. However, the molecular mechanisms of lncRNAs regulating the angiogenesis in LUAD have not been fully elucidated. Here we show lncRNA chromatin-associated RNA 10 (CAR10) was upregulated in the tumor tissue of patients with LUAD and enhanced tumor metastasis. Mechanistically, CAR10 could bind to Lactate Dehydrogenase A (LDHA) protein to regulate the phosphorylation and acetylation of LDHA and increase the dimerization of LDHA to promote its nuclear translocation, which increased the H3K79 methylation in Vascular Endothelial Growth Factor A (VEGFA) and Vascular Endothelial Growth Factor C (VEGFC) gene interval. CAR10 induced microvascular formation in vivo and in vitro by regulating LDHA-VEGFA/C axis. In addition, MYC and TP53 bonded to the promotor of CAR10 and reverse regulated its expression in LUAD cells. CAR10 regulates post-translational modification of LDHA and increases the H3K79 methylation of VEGFA/VEGFC to promote angiogenesis of LUAD, which is a potential therapeutic target for LUAD.
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Affiliation(s)
- Xiaolu Ge
- Shanghai Key Laboratory of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, PR China
| | - Chao Du
- The First Department of Thoracic Surgery, Hunan Cancer Hospital and the affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, PR China
| | - Li Fang
- NHC Key Laboratory of Carcinogenesis, Xiangya School of Basic Medical Sciences, Central South University, Changsha, Hunan, PR China
| | - Wei Xu
- The First Department of Thoracic Surgery, Hunan Cancer Hospital and the affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, PR China
| | - Juanjuan Xiang
- The First Department of Thoracic Surgery, Hunan Cancer Hospital and the affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, PR China
| | - Jiheng Liu
- Department of Hematology & Oncology, First Hospital of Changsha, Changsha, Hunan, PR China
| | - Ming Zhou
- The First Department of Thoracic Surgery, Hunan Cancer Hospital and the affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, PR China
| | - Yuejun Chen
- NHC Key Laboratory of Carcinogenesis, Xiangya School of Basic Medical Sciences, Central South University, Changsha, Hunan, PR China
| | - Ziyao Wang
- The First Department of Thoracic Surgery, Hunan Cancer Hospital and the affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, PR China.
- NHC Key Laboratory of Carcinogenesis, Xiangya School of Basic Medical Sciences, Central South University, Changsha, Hunan, PR China.
| | - Zheng Li
- The First Department of Thoracic Surgery, Hunan Cancer Hospital and the affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, PR China.
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Duca S, Xia Y, Abd Elmagid L, Bakis I, Qiu M, Cao Y, Guo Y, Eichenbaum JV, McCain ML, Kang J, Harrison MRM, Cao J. Differential vegfc expression dictates lymphatic response during zebrafish heart development and regeneration. Development 2024; 151:dev202947. [PMID: 39514676 PMCID: PMC11607685 DOI: 10.1242/dev.202947] [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: 04/11/2024] [Accepted: 10/21/2024] [Indexed: 11/16/2024]
Abstract
Vascular endothelial growth factor C (Vegfc) is crucial for lymphatic and blood vessel development, yet its cellular sources and specific functions in heart development remain unclear. To address this, we created a vegfc reporter and an inducible overexpression line in zebrafish. We found vegfc expression in large coronary arteries, circulating thrombocytes, cardiac adipocytes, and outflow tract smooth muscle cells. Notably, although coronary lymphangiogenesis aligns with Vegfc-expressing arteries in juveniles, it occurs only after coronary artery formation. Vegfc overexpression induced ectopic lymphatics on the ventricular surface prior to arterial formation, indicating that Vegfc abundance, rather than arterial presence, drives lymphatic development. However, this overexpression did not affect coronary artery coverage, suggesting a specific role for Vegfc in lymphatic, rather than arterial, development. Thrombocytes emerged as the initial Vegfc source during inflammation following heart injuries, transitioning to endocardial and myocardial expression during regeneration. Lower Vegfc levels in an amputation model corresponded with a lack of lymphatic expansion. Importantly, Vegfc overexpression enhanced lymphatic expansion and promoted scar resolution without affecting cardiomyocyte proliferation, highlighting its role in regulating lymphangiogenesis and promoting heart regeneration.
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Affiliation(s)
- Sierra Duca
- Cardiovascular Research Institute, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10021, USA
- Department of Cell and Developmental Biology, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10021, USA
| | - Yu Xia
- Cardiovascular Research Institute, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10021, USA
- Department of Cell and Developmental Biology, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10021, USA
| | - Laila Abd Elmagid
- Cardiovascular Research Institute, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10021, USA
- Department of Cell and Developmental Biology, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10021, USA
| | - Isaac Bakis
- Cardiovascular Research Institute, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10021, USA
- Department of Cell and Developmental Biology, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10021, USA
| | - Miaoyan Qiu
- Cardiovascular Research Institute, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10021, USA
- Department of Cell and Developmental Biology, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10021, USA
| | - Yingxi Cao
- Cardiovascular Research Institute, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10021, USA
- Department of Cell and Developmental Biology, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10021, USA
| | - Ylan Guo
- Cardiovascular Research Institute, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10021, USA
- Department of Cell and Developmental Biology, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10021, USA
| | - James V. Eichenbaum
- Alfred E. Mann Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA 90033, USA
| | - Megan L. McCain
- Alfred E. Mann Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA 90033, USA
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Junsu Kang
- Department of Cell and Regenerative Biology, School of Medicine and Public Health, University of Wisconsin – Madison, Madison, WI 53705, USA
| | - Michael R. M. Harrison
- Cardiovascular Research Institute, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10021, USA
- Department of Cell and Developmental Biology, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10021, USA
| | - Jingli Cao
- Cardiovascular Research Institute, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10021, USA
- Department of Cell and Developmental Biology, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10021, USA
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Lorenc P, Sikorska A, Molenda S, Guzniczak N, Dams-Kozlowska H, Florczak A. Physiological and tumor-associated angiogenesis: Key factors and therapy targeting VEGF/VEGFR pathway. Biomed Pharmacother 2024; 180:117585. [PMID: 39442237 DOI: 10.1016/j.biopha.2024.117585] [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: 08/01/2024] [Revised: 10/03/2024] [Accepted: 10/14/2024] [Indexed: 10/25/2024] Open
Abstract
Cancer remains one of the leading causes of death worldwide and poses a significant challenge to effective treatment due to its complexity. Angiogenesis, the formation of new blood vessels, is one of the cancer hallmarks and is a critical process in tumor growth and metastasis. The pivotal role of angiogenesis in cancer development has made antiangiogenic treatment a promising strategy for cancer therapy. To develop an effective therapy, it is essential to understand the basics of the physiological and tumor angiogenesis process. This review presents the primary factors related to physiological and tumor angiogenesis and the mechanisms of angiogenesis in tumors. We summarize potential molecular targets for cancer treatment by focusing on the vasculature, with the VEGF/VEGFR pathway being one of the most important and well-studied. Additionally, we present the advantages and limitations of currently used clinical protocols for cancer treatment targeting the VEGF/VEGFR pathway.
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Affiliation(s)
- Patryk Lorenc
- Chair of Medical Biotechnology, Department of Cancer Immunology, Poznan University of Medical Sciences, 8 Rokietnicka St, Poznan 60-806, Poland; Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 15 Garbary St, Poznan 61‑866, Poland; Doctoral School, Poznan University of Medical Sciences, 70 Bukowska St, Poznan 60-812, Poland
| | - Agata Sikorska
- Chair of Medical Biotechnology, Department of Cancer Immunology, Poznan University of Medical Sciences, 8 Rokietnicka St, Poznan 60-806, Poland; Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 15 Garbary St, Poznan 61‑866, Poland
| | - Sara Molenda
- Chair of Medical Biotechnology, Department of Cancer Immunology, Poznan University of Medical Sciences, 8 Rokietnicka St, Poznan 60-806, Poland; Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 15 Garbary St, Poznan 61‑866, Poland; Doctoral School, Poznan University of Medical Sciences, 70 Bukowska St, Poznan 60-812, Poland
| | - Natalia Guzniczak
- Chair of Medical Biotechnology, Department of Cancer Immunology, Poznan University of Medical Sciences, 8 Rokietnicka St, Poznan 60-806, Poland
| | - Hanna Dams-Kozlowska
- Chair of Medical Biotechnology, Department of Cancer Immunology, Poznan University of Medical Sciences, 8 Rokietnicka St, Poznan 60-806, Poland; Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 15 Garbary St, Poznan 61‑866, Poland
| | - Anna Florczak
- Chair of Medical Biotechnology, Department of Cancer Immunology, Poznan University of Medical Sciences, 8 Rokietnicka St, Poznan 60-806, Poland; Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 15 Garbary St, Poznan 61‑866, Poland.
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Ji M, Yuan Z, Ma H, Feng X, Ye C, Shi L, Chen X, Han F, Zhao C. Dandelion-shaped strontium-gallium microparticles for the hierarchical stimulation and comprehensive regulation of wound healing. Regen Biomater 2024; 11:rbae121. [PMID: 39544394 PMCID: PMC11561401 DOI: 10.1093/rb/rbae121] [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: 06/08/2024] [Revised: 09/12/2024] [Accepted: 10/05/2024] [Indexed: 11/17/2024] Open
Abstract
The management of full-thickness skin injuries continues to pose significant challenges. Currently, there is a dearth of comprehensive dressings capable of integrating all stages of wound healing to spatiotemporally regulate biological processes following full-thickness skin injuries. In this study, we report the synthesis of a dandelion-shaped mesoporous strontium-gallium microparticle (GE@SrTPP) achieved through dopamine-mediated strontium ion biomineralization and self-assembly, followed by functionalization with gallium metal polyphenol networks. As a multifunctional wound dressing, GE@SrTPP can release bioactive ions in a spatiotemporal manner akin to dandelion seeds. During the early stages of wound healing, GE@SrTPP demonstrates rapid and effective hemostatic performance while also exhibiting antibacterial properties. In the inflammatory phase, GE@SrTPP promotes M2 polarization of macrophages, suppresses the expression of pro-inflammatory factors, and decreases oxidative stress in wounds. Subsequently, during the stages of proliferation and tissue remodeling, GE@SrTPP facilitates angiogenesis through the activation of the Hypoxia-inducible factor-1α/vascular endothelial growth factor (HIF-1α/VEGF) pathway. Analogous to the dispersion and rooting of dandelion seeds, the root-like new blood vessels supply essential nutrients for wound healing. Ultimately, in a rat chronic wound model, GE@SrTPP achieved successful full-thickness wound repair. In summary, these dandelion-shaped GE@SrTPP microparticles demonstrate comprehensive regulatory effects in managing full-thickness wounds, making them highly promising materials for clinical applications.
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Affiliation(s)
- Minrui Ji
- Department of Dermatology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
- Department of Orthopaedics, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Zaixin Yuan
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Hongdong Ma
- Department of Orthopaedics, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Xian Feng
- Department of Orthopaedics, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Cong Ye
- Department of Orthopaedics, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Lei Shi
- Department of Orthopaedics, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Xiaodong Chen
- Department of Dermatology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Fei Han
- Department of Orthopaedics, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Caichou Zhao
- Department of Dermatology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
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Nishioka H, Takashimizu I, Yuzuriha S. Upper eyelid lymphatic anatomy is associated with blepharoplasty recovery. J Plast Reconstr Aesthet Surg 2024; 99:248-255. [PMID: 39388768 DOI: 10.1016/j.bjps.2024.09.079] [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: 06/07/2024] [Revised: 09/19/2024] [Accepted: 09/24/2024] [Indexed: 10/12/2024]
Abstract
BACKGROUND Lymphatic vessels support wound recovery and absorb excess fluid. Blepharoplasty involves excess tissue excision, and this study investigated the relationship between lymph vessel density in excised tissue and the postoperative course. METHODS Forty eyelids from 21 patients with blepharoptosis who underwent blepharoplasty were included. Each resected excess tissue sample was divided into 4 parts by 3 parasagittal cuts-medial, central, and lateral. The area percentages occupied by lymphatic vessels and elastic fibers in the inner tissue between skin and muscle, exposed by these cuts, were determined histologically. The wound-healing process was assessed at 2 weeks and 1, 3, and 6 months postoperatively, using a visual analog scale (VAS) to estimate edema and the Vancouver Scar Scale (VSS) for scar assessment. RESULTS With increasing age, the area percentage of lymphatic vessels declined significantly (r = -0.581, p < 0.001), while an increase in solar elastosis was observed. The percentage of lymphatic vessels was highest on the medial side of the eyelid (p < 0.05), where their relative distribution to the "shallow layer" close to the skin was also the highest (p < 0.01). Independent of age, the VSS values at 2 weeks and 1 month postoperatively were significantly lower in patients with a higher area percentage of lymphatic vessels (2 weeks: p < 0.05; 1 month: p < 0.01). CONCLUSIONS In patients undergoing blepharoplasty, the percentage of lymphatic vessels in the upper eyelid tissue decreased with advancing age. Higher proportions of lymphatic vessels were associated with improved wound-healing outcomes.
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Affiliation(s)
- Hiroshi Nishioka
- Department of Plastic and Reconstructive Surgery, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi 470-1192, Japan; Department of Plastic and Reconstructive Surgery, Shinshu University School of Medicine, 3-1-1 Asahi Matsumoto, Nagano 390-8621, Japan.
| | - Ikkei Takashimizu
- Department of Plastic and Reconstructive Surgery, Shinshu University School of Medicine, 3-1-1 Asahi Matsumoto, Nagano 390-8621, Japan
| | - Shunsuke Yuzuriha
- Department of Plastic and Reconstructive Surgery, Shinshu University School of Medicine, 3-1-1 Asahi Matsumoto, Nagano 390-8621, Japan
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11
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Jian Y, Li Y, Zhang Y, Tang M, Deng M, Liu C, Cheng M, Xiao S, Deng C, Wei Z. Lymphangiogenesis: novel strategies to promote cutaneous wound healing. BURNS & TRAUMA 2024; 12:tkae040. [PMID: 39328366 PMCID: PMC11427083 DOI: 10.1093/burnst/tkae040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 05/31/2024] [Accepted: 06/05/2024] [Indexed: 09/28/2024]
Abstract
The cutaneous lymphatic system regulates tissue inflammation, fluid balance and immunological responses. Lymphangiogenesis or lymphatic dysfunction may lead to lymphedema, immune deficiency, chronic inflammation etc. Tissue regeneration and healing depend on angiogenesis and lymphangiogenesis during wound healing. Tissue oedema and chronic inflammation can slow wound healing due to impaired lymphangiogenesis or lymphatic dysfunction. For example, impaired lymphangiogenesis or lymphatic dysfunction has been detected in nonhealing wounds such as diabetic ulcers, venous ulcers and bedsores. This review summarizes the structure and function of the cutaneous lymphatic vessel system and lymphangiogenesis in wounds. Furthermore, we review wound lymphangiogenesis processes and remodelling, especially the influence of the inflammatory phase. Finally, we outline how to control lymphangiogenesis to promote wound healing, assess the possibility of targeting lymphangiogenesis as a novel treatment strategy for chronic wounds and provide an analysis of the possible problems that need to be addressed.
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Affiliation(s)
- Yang Jian
- Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University, No. 149 Dalian Road, Hui chuan District, Zunyi, Guizhou, 563003, China
| | - Yanqi Li
- Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University, No. 149 Dalian Road, Hui chuan District, Zunyi, Guizhou, 563003, China
| | - Yanji Zhang
- Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University, No. 149 Dalian Road, Hui chuan District, Zunyi, Guizhou, 563003, China
| | - Mingyuan Tang
- Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University, No. 149 Dalian Road, Hui chuan District, Zunyi, Guizhou, 563003, China
| | - Mingfu Deng
- Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University, No. 149 Dalian Road, Hui chuan District, Zunyi, Guizhou, 563003, China
| | - Chenxiaoxiao Liu
- Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University, No. 149 Dalian Road, Hui chuan District, Zunyi, Guizhou, 563003, China
| | - Maolin Cheng
- Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University, No. 149 Dalian Road, Hui chuan District, Zunyi, Guizhou, 563003, China
| | - Shune Xiao
- Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University, No. 149 Dalian Road, Hui chuan District, Zunyi, Guizhou, 563003, China
- The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, No. 6 West Xuefu Road, Xinpu District, Zunyi, Guizhou, 563003, China
| | - Chengliang Deng
- Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University, No. 149 Dalian Road, Hui chuan District, Zunyi, Guizhou, 563003, China
- The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, No. 6 West Xuefu Road, Xinpu District, Zunyi, Guizhou, 563003, China
| | - Zairong Wei
- Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University, No. 149 Dalian Road, Hui chuan District, Zunyi, Guizhou, 563003, China
- The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, No. 6 West Xuefu Road, Xinpu District, Zunyi, Guizhou, 563003, China
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Huang J, Liao C, Yang J, Zhang L. The role of vascular and lymphatic networks in bone and joint homeostasis and pathology. Front Endocrinol (Lausanne) 2024; 15:1465816. [PMID: 39324127 PMCID: PMC11422228 DOI: 10.3389/fendo.2024.1465816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 08/23/2024] [Indexed: 09/27/2024] Open
Abstract
The vascular and lymphatic systems are integral to maintaining skeletal homeostasis and responding to pathological conditions in bone and joint tissues. This review explores the interplay between blood vessels and lymphatic vessels in bones and joints, focusing on their roles in homeostasis, regeneration, and disease progression. Type H blood vessels, characterized by high expression of CD31 and endomucin, are crucial for coupling angiogenesis with osteogenesis, thus supporting bone homeostasis and repair. These vessels facilitate nutrient delivery and waste removal, and their dysfunction can lead to conditions such as ischemia and arthritis. Recent discoveries have highlighted the presence and significance of lymphatic vessels within bone tissue, challenging the traditional view that bones are devoid of lymphatics. Lymphatic vessels contribute to interstitial fluid regulation, immune cell trafficking, and tissue repair through lymphangiocrine signaling. The pathological alterations in these networks are closely linked to inflammatory joint diseases, emphasizing the need for further research into their co-regulatory mechanisms. This comprehensive review summarizes the current understanding of the structural and functional aspects of vascular and lymphatic networks in bone and joint tissues, their roles in homeostasis, and the implications of their dysfunction in disease. By elucidating the dynamic interactions between these systems, we aim to enhance the understanding of their contributions to skeletal health and disease, potentially informing the development of targeted therapeutic strategies.
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Affiliation(s)
- Jingxiong Huang
- Center of Stomatology, West China Xiamen Hospital of Sichuan University, Xiamen, Fujian, China
| | - Chengcheng Liao
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
- Department of Orthodontics II, Affiliated Stomatological Hospital of Zunyi Medical University, Guizhou, Zunyi, China
| | - Jian Yang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Liang Zhang
- Center of Stomatology, West China Xiamen Hospital of Sichuan University, Xiamen, Fujian, China
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
- Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
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Zhao Y, Liu M, Li W, Tao G. Topical lyophilized thrombin application improves wound healing for posterior spinal surgery. Heliyon 2024; 10:e31335. [PMID: 38813190 PMCID: PMC11133810 DOI: 10.1016/j.heliyon.2024.e31335] [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: 05/23/2023] [Revised: 04/23/2024] [Accepted: 05/14/2024] [Indexed: 05/31/2024] Open
Abstract
Background The erector spinae plane block (ESPB) was proposed as a part of the postoperative multimodal analgesic regimen to improve pain management after posterior spinal surgery. However, ESPB might cause more surgical incisional wound exudate and poor wound healing, which might be improved after topical lyophilized thrombin application. Materials and methods We performed a retrospective study on patients who received posterior spinal surgery between January 2018 and December 2021. These patients were assigned into three groups: group A (general anesthesia), group B (general anesthesia with ESPB), and group C (general anesthesia with ESPB and topical 1000-unit thrombin application). Postoperative outcomes, including times of dressing changes, duration of suture removal, and incisional wound healing, were compared among these groups. Results Our study included 89 patients, with 48, 20, and 21 patients in groups A, B, and C, respectively. Baseline demographics, height, weight, comorbidities, and operation duration were comparable among the three groups. Group B required statistically significantly more dressing changes and had a prolonged duration of suture removal than group A (9.4 ± 4.7 versus 6.5 ± 2.0 times, 16.2 ± 3.7 versus 14.2 ± 1.4 days, respectively), which could be statistically significantly improved after the thrombin application in group C. Group B also had more frequent poor wound healing (25.0 %), which could also be improved after the thrombin application (0.0 %). Conclusions ESPB could cause more dressing changes and poor surgical wound healing after posterior spinal surgery, which could be improved by topical lyophilized thrombin powder application.
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Affiliation(s)
- Yinjie Zhao
- Department of Anesthesiology, Guiqian International General Hospital, Guiyang, 550024, China
| | - Ming Liu
- Department of Orthopedics and Sports Medicine, Heyou International Hospital, Guangdong, 528000, China
| | - Wenyao Li
- Department of Pain Management, Guigian International General Hospital, Gui Yang, 550024, China
| | - Guocai Tao
- Department of Anesthesiology, Guiqian International General Hospital, Guiyang, 550024, China
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14
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Jiang Y, Perez-Moreno M. Translational frontiers: insight from lymphatics in skin regeneration. Front Physiol 2024; 15:1347558. [PMID: 38487264 PMCID: PMC10937408 DOI: 10.3389/fphys.2024.1347558] [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: 12/01/2023] [Accepted: 02/01/2024] [Indexed: 03/17/2024] Open
Abstract
The remarkable regenerative ability of the skin, governed by complex molecular mechanisms, offers profound insights into the skin repair processes and the pathogenesis of various dermatological conditions. This understanding, derived from studies in human skin and various model systems, has not only deepened our knowledge of skin regeneration but also facilitated the development of skin substitutes in clinical practice. Recent research highlights the crucial role of lymphatic vessels in skin regeneration. Traditionally associated with fluid dynamics and immune modulation, these vessels are now recognized for interacting with skin stem cells and coordinating regeneration. This Mini Review provides an overview of recent advancements in basic and translational research related to skin regeneration, focusing on the dynamic interplay between lymphatic vessels and skin biology. Key highlights include the critical role of stem cell-lymphatic vessel crosstalk in orchestrating skin regeneration, emerging translational approaches, and their implications for skin diseases. Additionally, the review identifies research gaps and proposes potential future directions, underscoring the significance of this rapidly evolving research arena.
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Affiliation(s)
| | - Mirna Perez-Moreno
- Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark
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Hu Z, Zhao X, Wu Z, Qu B, Yuan M, Xing Y, Song Y, Wang Z. Lymphatic vessel: origin, heterogeneity, biological functions, and therapeutic targets. Signal Transduct Target Ther 2024; 9:9. [PMID: 38172098 PMCID: PMC10764842 DOI: 10.1038/s41392-023-01723-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Revised: 11/03/2023] [Accepted: 11/23/2023] [Indexed: 01/05/2024] Open
Abstract
Lymphatic vessels, comprising the secondary circulatory system in human body, play a multifaceted role in maintaining homeostasis among various tissues and organs. They are tasked with a serious of responsibilities, including the regulation of lymph absorption and transport, the orchestration of immune surveillance and responses. Lymphatic vessel development undergoes a series of sophisticated regulatory signaling pathways governing heterogeneous-origin cell populations stepwise to assemble into the highly specialized lymphatic vessel networks. Lymphangiogenesis, as defined by new lymphatic vessels sprouting from preexisting lymphatic vessels/embryonic veins, is the main developmental mechanism underlying the formation and expansion of lymphatic vessel networks in an embryo. However, abnormal lymphangiogenesis could be observed in many pathological conditions and has a close relationship with the development and progression of various diseases. Mechanistic studies have revealed a set of lymphangiogenic factors and cascades that may serve as the potential targets for regulating abnormal lymphangiogenesis, to further modulate the progression of diseases. Actually, an increasing number of clinical trials have demonstrated the promising interventions and showed the feasibility of currently available treatments for future clinical translation. Targeting lymphangiogenic promoters or inhibitors not only directly regulates abnormal lymphangiogenesis, but improves the efficacy of diverse treatments. In conclusion, we present a comprehensive overview of lymphatic vessel development and physiological functions, and describe the critical involvement of abnormal lymphangiogenesis in multiple diseases. Moreover, we summarize the targeting therapeutic values of abnormal lymphangiogenesis, providing novel perspectives for treatment strategy of multiple human diseases.
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Affiliation(s)
- Zhaoliang Hu
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors (China Medical University), Ministry of Education, 155 North Nanjing Street, Heping District, Shenyang, 110001, China
| | - Xushi Zhao
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors (China Medical University), Ministry of Education, 155 North Nanjing Street, Heping District, Shenyang, 110001, China
| | - Zhonghua Wu
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors (China Medical University), Ministry of Education, 155 North Nanjing Street, Heping District, Shenyang, 110001, China
| | - Bicheng Qu
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors (China Medical University), Ministry of Education, 155 North Nanjing Street, Heping District, Shenyang, 110001, China
| | - Minxian Yuan
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors (China Medical University), Ministry of Education, 155 North Nanjing Street, Heping District, Shenyang, 110001, China
| | - Yanan Xing
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors (China Medical University), Ministry of Education, 155 North Nanjing Street, Heping District, Shenyang, 110001, China.
| | - Yongxi Song
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors (China Medical University), Ministry of Education, 155 North Nanjing Street, Heping District, Shenyang, 110001, China.
| | - Zhenning Wang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors (China Medical University), Ministry of Education, 155 North Nanjing Street, Heping District, Shenyang, 110001, China.
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Tsukiji N, Suzuki-Inoue K. Impact of Hemostasis on the Lymphatic System in Development and Disease. Arterioscler Thromb Vasc Biol 2023; 43:1747-1754. [PMID: 37534465 DOI: 10.1161/atvbaha.123.318824] [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: 03/13/2023] [Accepted: 07/20/2023] [Indexed: 08/04/2023]
Abstract
Lymphatic vessels form a systemic network that maintains interstitial fluid homeostasis and regulates immune responses and is strictly separated from the circulatory system. During embryonic development, lymphatic endothelial cells originate from blood vascular endothelial cells in the cardinal veins and form lymph sacs. Platelets are critical for separating lymph sacs from the cardinal veins through interactions between CLEC-2 (C-type lectin-like receptor-2) and PDPN (podoplanin) in lymphatic endothelial cells. Therefore, deficiencies of these genes cause blood-filled lymphatic vessels, leading to abnormal lymphatic vessel maturation. The junction between the thoracic duct and the subclavian vein has valves and forms physiological thrombi dependent on CLEC-2/PDPN signaling to prevent blood backflow into the thoracic duct. In addition, platelets regulate lymphangiogenesis and maintain blood/lymphatic separation in pathological conditions, such as wound healing and inflammatory diseases. More recently, it was reported that the entire hemostatic system is involved in lymphangiogenesis. Thus, the hemostatic system plays a crucial role in the establishment, maintenance, and rearrangement of lymphatic networks and contributes to body fluid homeostasis, which suggests that the hemostatic system is a potential target for treating lymphatic disorders. This review comprehensively summarizes the role of the hemostatic system in lymphangiogenesis and lymphatic vessel function and discusses challenges and future perspectives.
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Affiliation(s)
- Nagaharu Tsukiji
- Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Japan
| | - Katsue Suzuki-Inoue
- Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Japan
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Chachaj A, Stanimirova I, Chabowski M, Gomułkiewicz A, Hodurek P, Glatzel-Plucińska N, Olbromski M, Piotrowska A, Kuzan A, Grzegrzółka J, Ratajczak-Wielgomas K, Nowak A, Szahidewicz-Krupska E, Wiśniewski J, Bromke MA, Podhorska-Okołów M, Gamian A, Janczak D, Dzięgiel P, Szuba A. Sodium accumulation in the skin is associated with higher density of skin lymphatic vessels in patients with arterial hypertension. Adv Med Sci 2023; 68:276-289. [PMID: 37639949 DOI: 10.1016/j.advms.2023.08.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Revised: 06/20/2023] [Accepted: 08/17/2023] [Indexed: 08/31/2023]
Abstract
PURPOSE Recent studies, conducted mainly on the rodent model, have demonstrated that regulatory pathway in the skin provided by glycosaminoglycans, nuclear factor of activated T cells 5 (NFAT5), vascular endothelial growth factor C (VEGF-C) and process of lymphangiogenesis may play an important role in extrarenal regulation of sodium (Na+) balance, body water volume, and blood pressure. We aimed to investigate the concentrations and relations among the main factors of this pathway in human skin to confirm that this regulatory axis also exists in humans. PATIENTS AND METHODS Skin specimens from patients diagnosed with arterial hypertension and from control group were histologically and molecularly examined. RESULTS The primary hypertensive and control groups did not differ in Na+ concentrations in the skin. However, the patients with hypertension and higher skin Na+ concentration had significantly greater density of skin lymphatic vessels. Higher skin Na+concentration was associated with higher skin water content. In turn, skin water content correlated with factors associated with lymphangiogenesis, i.e. NFAT5, VEGF-C, and podoplanin (PDPN) mRNA expression in the skin. The strong mutual pairwise correlations of the expressions of NFAT5, VEGF-C, vascular endothelial growth factor D (VEGF-D) and PDPN mRNA were noted in the skin in all of the studied groups. CONCLUSIONS Our study confirms that skin interstitium and the lymphatic system may be important players in the pathophysiology of arterial hypertension in humans. Based on the results of our study and existing literature in this field, we propose the hypothetical model which might explain the phenomenon of salt-sensitivity.
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Affiliation(s)
- Angelika Chachaj
- Department of Angiology and Internal Medicine, Wroclaw Medical University, Wroclaw, Poland.
| | | | - Mariusz Chabowski
- Department of Surgery, 4th Military Hospital in Wroclaw, Wroclaw, Poland; Department of Nursing and Obstetrics, Division of Anesthesiological and Surgical Nursing, Faculty of Health Science, Wroclaw Medical University, Wroclaw, Poland
| | - Agnieszka Gomułkiewicz
- Division of Histology and Embryology, Department of Human Embryology and Morphology, Wroclaw Medical University, Wroclaw, Poland
| | - Paweł Hodurek
- Department of Medical Biochemistry, Wroclaw Medical University, Wroclaw, Poland
| | - Natalia Glatzel-Plucińska
- Division of Histology and Embryology, Department of Human Embryology and Morphology, Wroclaw Medical University, Wroclaw, Poland
| | - Mateusz Olbromski
- Division of Histology and Embryology, Department of Human Embryology and Morphology, Wroclaw Medical University, Wroclaw, Poland
| | - Aleksandra Piotrowska
- Division of Histology and Embryology, Department of Human Embryology and Morphology, Wroclaw Medical University, Wroclaw, Poland
| | - Aleksandra Kuzan
- Department of Medical Biochemistry, Wroclaw Medical University, Wroclaw, Poland
| | - Jędrzej Grzegrzółka
- Division of Histology and Embryology, Department of Human Embryology and Morphology, Wroclaw Medical University, Wroclaw, Poland
| | - Katarzyna Ratajczak-Wielgomas
- Division of Histology and Embryology, Department of Human Embryology and Morphology, Wroclaw Medical University, Wroclaw, Poland
| | - Aleksandra Nowak
- Division of Histology and Embryology, Department of Human Embryology and Morphology, Wroclaw Medical University, Wroclaw, Poland
| | - Ewa Szahidewicz-Krupska
- Department of Internal and Occupational Diseases, Hypertension and Clinical Oncology, Wroclaw Medical University, Wroclaw, Poland
| | - Jerzy Wiśniewski
- Wroclaw University of Science and Technology, Faculty of Chemistry, Wroclaw, Poland
| | - Mariusz A Bromke
- Department of Medical Biochemistry, Wroclaw Medical University, Wroclaw, Poland
| | | | - Andrzej Gamian
- Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
| | - Dariusz Janczak
- Department of Vascular, General and Transplantation Surgery, Wroclaw Medical University, Wroclaw, Poland
| | - Piotr Dzięgiel
- Division of Histology and Embryology, Department of Human Embryology and Morphology, Wroclaw Medical University, Wroclaw, Poland; Department of Physiotherapy, Wroclaw University, School of Physical Education, Wroclaw, Poland
| | - Andrzej Szuba
- Department of Angiology and Internal Medicine, Wroclaw Medical University, Wroclaw, Poland
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18
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Wang Y, luo M, Li T, Xie C, Li S, Lei B. Multi-layer-structured bioactive glass nanopowder for multistage-stimulated hemostasis and wound repair. Bioact Mater 2023; 25:319-332. [PMID: 36844363 PMCID: PMC9946820 DOI: 10.1016/j.bioactmat.2023.01.019] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 01/24/2023] [Accepted: 01/26/2023] [Indexed: 02/13/2023] Open
Abstract
Current treatments for full-thickness skin injuries are still unsatisfactory due to the lack of hierarchically stimulated dressings that can integrate the rapid hemostasis, inflammation regulation, and skin tissue remodeling into the one system instead of single-stage boosting. In this work, a multilayer-structured bioactive glass nanopowder (BGN@PTE) is developed by coating the poly-tannic acid and ε-polylysine onto the BGN via facile layer-by-layer assembly as an integrative and multilevel dressing for the sequential management of wounds. In comparison to BGN and poly-tannic acid coated BGN, BGN@PTE exhibited the better hemostatic performance because of its multiple dependent approaches to induce the platelet adhesion/activation, red blood cells (RBCs) aggregation and fibrin network formation. Simultaneously, the bioactive ions from BGN facilitate the regulation of the inflammatory response while the poly-tannic acid and antibacterial ε-polylysine prevent the wound infection, promoting the wound healing during the inflammatory stage. In addition, BGN@PTE can serve as a reactive oxygen species scavenger, alleviate the oxidation stress in wound injury, induce the cell migration and angiogenesis, and promote the proliferation stage of wound repair. Therefore, BGN@PTE demonstrated the significantly higher wound repair capacity than the commercial bioglass dressing Dermlin™. This multifunctional BGN@PTE is a potentially valuable dressing for full-thickness wound management and may be expected to extend to the other wounds therapy.
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Affiliation(s)
- Yidan Wang
- Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, 710054, China
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, 710054, China
| | - Meng luo
- Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, 710054, China
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, 710054, China
| | - Ting Li
- Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, 710054, China
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, 710054, China
| | - Chenxi Xie
- Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, 710054, China
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, 710054, China
| | - Sihua Li
- Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, 710054, China
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, 710054, China
| | - Bo Lei
- Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, 710054, China
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, 710054, China
- State Key Laboratory for Mechanical Behavior of Materials, Xi'an Jiaotong University, Xi'an, 710054, China
- Instrument Analysis Center, Xi'an Jiaotong University, Xi'an, 710054, China
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19
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Xiao H, Chen X, Shan J, Liu X, Sun Y, Shen J, Chai Y, We G, Yu Y. A spatiotemporal release hydrogel based on an M1-to-M2 immunoenvironment for wound management. J Mater Chem B 2023; 11:3994-4004. [PMID: 37165902 DOI: 10.1039/d3tb00463e] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/12/2023]
Abstract
Cutaneous wounds remain a major clinical challenge that urgently requires the development of advanced and functional wound dressings. During the wound healing process, macrophages are well known to exhibit temporal dynamics with a pro-inflammatory phenotype at early stages and a pro-healing phenotype at late stages, thus playing an important role in regulating inflammatory responses and tissue regeneration. Meanwhile, disrupted temporal dynamics of macrophages caused by poor wound local conditions and deficiency of macrophage function always impair the wound-healing progression. Here in this work, we proposed a novel controllable strategy to construct a spatiotemporal dynamical immune-microenvironment for the treatment of cutaneous wounds. To achieve this goal, a concentric decellularized dermal hydrogel was constructed with the combination of type 1 and type 2 macrophage-associated cytokine complexes in the sheath portion and core portion, respectively. The in vitro degradation experiment exhibited a sequential cascade release of pro-inflammatory cytokines and pro-healing cytokines. The enhanced cell biocompatibility and tube formation of HUVECs were confirmed. A full-thickness skin defect model of rats was developed to analyze the effect of the spatiotemporal dynamical bioactive hydrogels on wound healing. Remarkable angiogenesis, rapid wound restoration, moderate extracellular matrix deposition and obvious skin appendage neogenesis were identified at different time points after treatment with the macrophage cytokine-based decellularized hydrogels. Consequently, the concentric decellularized hydrogels with spatiotemporal dynamics of immune cytokines have considerable potential for cell-free therapy for wound healing.
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Affiliation(s)
- Huimin Xiao
- College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, 201306, China.
- Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Xin Chen
- College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, 201306, China.
- Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Jianyang Shan
- Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Xuanzhe Liu
- Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Yi Sun
- Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Junjie Shen
- Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Yimin Chai
- Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Gen We
- College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, 201306, China.
- Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Yaling Yu
- Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
- Institute of Microsurgery on Extremities, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
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20
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Wang T, Peng R, Ni H, Zhong L, Zhang H, Wang T, Cheng H, Bao T, Jia X, Ling S. Effects of chemokine receptor CCR7 in the pathophysiology and clinical features of the immuno-inflammatory response in primary pterygium. Int Immunopharmacol 2023; 118:110086. [PMID: 37030121 DOI: 10.1016/j.intimp.2023.110086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 03/20/2023] [Accepted: 03/21/2023] [Indexed: 04/08/2023]
Abstract
OBJECTIVE Chemokine receptor 7 (CCR7) has been considered a critical biomarker in inflammation and the immune response; however, little is known about CCR7 in pterygia. This study aimed to investigate whether CCR7 participates in the pathogenesis of primary pterygia and how CCR7 affects the progression of pterygia. METHODS This was an experimental study. Slip-lamp photographs of 85 pterygium patients were used to measure the width, extent, and area of pterygia with computer software. Pterygium blood vessels and general ocular redness were quantitatively analyzed with a specific algorithm. The expression of CCR7 and its ligands C-C motif ligand 19 (CCL19) and C-C motif ligand 21 (CCL21) in control conjunctivae and excised pterygia collected during surgery were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) and immunofluorescence staining. The phenotype of CCR7-expressing cells was identified by costaining for major histocompatibility complex II (MHC II), CD11b or CD11c. RESULTS The CCR7 level was significantly increased by 9.6-fold in pterygia compared with control conjunctivae (p = 0.008). The higher the expression of CCR7 was, the more blood vessels appeared in pterygia (r = 0.437, p = 0.002) and the more general ocular redness was (r = 0.51, p < 0.001) in pterygium patients. CCR7 was significantly associated with pterygium extent (r = 0.286, p = 0.048). In addition, we found that CCR7 colocalized with CD11b, CD11c or MHC II in dendritic cells, and immunofluorescence staining showed that CCR7-CCL21 is a potential chemokine axis in pterygium. CONCLUSIONS This work verified that CCR7 impacts the extent of primary pterygia invading the cornea and inflammation at the ocular surface, which may provide a possibility for a further in-depth understanding of the immunological mechanism in pterygia.
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21
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Abstract
The epithelial tissues that line our body, such as the skin and gut, have remarkable regenerative prowess and continually renew throughout our lifetimes. Owing to their barrier function, these tissues have also evolved sophisticated repair mechanisms to swiftly heal and limit the penetration of harmful agents following injury. Researchers now appreciate that epithelial regeneration and repair are not autonomous processes but rely on a dynamic cross talk with immunity. A wealth of clinical and experimental data point to the functional coupling of reparative and inflammatory responses as two sides of the same coin. Here we bring to the fore the immunological signals that underlie homeostatic epithelial regeneration and restitution following damage. We review our current understanding of how immune cells contribute to distinct phases of repair. When unchecked, immune-mediated repair programs are co-opted to fuel epithelial pathologies such as cancer, psoriasis, and inflammatory bowel diseases. Thus, understanding the reparative functions of immunity may advance therapeutic innovation in regenerative medicine and epithelial inflammatory diseases.
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Affiliation(s)
- Laure Guenin-Mace
- Department of Pathology, NYU Langone Health, New York, NY, USA;
- Immunobiology and Therapy Unit, INSERM U1224, Institut Pasteur, Paris, France
| | - Piotr Konieczny
- Department of Pathology, NYU Langone Health, New York, NY, USA;
| | - Shruti Naik
- Department of Pathology, NYU Langone Health, New York, NY, USA;
- Department of Medicine, Ronald O. Perelman Department of Dermatology, and Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA
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22
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Interactions between Platelets and Tumor Microenvironment Components in Ovarian Cancer and Their Implications for Treatment and Clinical Outcomes. Cancers (Basel) 2023; 15:cancers15041282. [PMID: 36831623 PMCID: PMC9953912 DOI: 10.3390/cancers15041282] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 02/07/2023] [Accepted: 02/13/2023] [Indexed: 02/19/2023] Open
Abstract
Platelets, the primary operatives of hemostasis that contribute to blood coagulation and wound healing after blood vessel injury, are also involved in pathological conditions, including cancer. Malignancy-associated thrombosis is common in ovarian cancer patients and is associated with poor clinical outcomes. Platelets extravasate into the tumor microenvironment in ovarian cancer and interact with cancer cells and non-cancerous elements. Ovarian cancer cells also activate platelets. The communication between activated platelets, cancer cells, and the tumor microenvironment is via various platelet membrane proteins or mediators released through degranulation or the secretion of microvesicles from platelets. These interactions trigger signaling cascades in tumors that promote ovarian cancer progression, metastasis, and neoangiogenesis. This review discusses how interactions between platelets, cancer cells, cancer stem cells, stromal cells, and the extracellular matrix in the tumor microenvironment influence ovarian cancer progression. It also presents novel potential therapeutic approaches toward this gynecological cancer.
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23
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Donnan MD, Deb DK, Onay T, Scott RP, Ni E, Zhou Y, Quaggin SE. Formation of the glomerular microvasculature is regulated by VEGFR-3. Am J Physiol Renal Physiol 2023; 324:F91-F105. [PMID: 36395385 PMCID: PMC9836230 DOI: 10.1152/ajprenal.00066.2022] [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: 03/15/2022] [Revised: 10/12/2022] [Accepted: 11/02/2022] [Indexed: 11/18/2022] Open
Abstract
Microvascular dysfunction is a key driver of kidney disease. Pathophysiological changes in the kidney vasculature are regulated by vascular endothelial growth factor receptors (VEGFRs), supporting them as potential therapeutic targets. The tyrosine kinase receptor VEGFR-3, encoded by FLT4 and activated by the ligands VEGF-C and VEGF-D, is best known for its role in lymphangiogenesis. Therapeutically targeting VEGFR-3 to modulate lymphangiogenesis has been proposed as a strategy to treat kidney disease. However, outside the lymphatics, VEGFR-3 is also expressed in blood vascular endothelial cells in several tissues including the kidney. Here, we show that Vegfr-3 is expressed in fenestrated microvascular beds within the developing and adult mouse kidney, which include the glomerular capillary loops. We found that expression levels of VEGFR-3 are dynamic during glomerular capillary loop development, with the highest expression observed during endothelial cell migration into the S-shaped glomerular body. We developed a conditional knockout mouse model for Vegfr-3 and found that loss of Vegfr-3 resulted in a striking glomerular phenotype characterized by aneurysmal dilation of capillary loops, absence of mesangial structure, abnormal interendothelial cell junctions, and poor attachment between glomerular endothelial cells and the basement membrane. In addition, we demonstrated that expression of the VEGFR-3 ligand VEGF-C by podocytes and mesangial cells is dispensable for glomerular development. Instead, VEGFR-3 in glomerular endothelial cells attenuates VEGFR-2 phosphorylation. Together, the results of our study support a VEGF-C-independent functional role for VEGFR-3 in the kidney microvasculature outside of lymphatic vessels, which has implications for clinical therapies that target this receptor.NEW & NOTEWORTHY Targeting VEGFR-3 in kidney lymphatics has been proposed as a method to treat kidney disease. However, expression of VEGFR-3 is not lymphatic-specific. We demonstrated developmental expression of VEGFR-3 in glomerular endothelial cells, with loss of Vegfr-3 leading to malformation of glomerular capillary loops. Furthermore, we showed that VEGFR-3 attenuates VEGFR-2 activity in glomerular endothelial cells independent of paracrine VEGF-C signaling. Together, these data provide valuable information for therapeutic development targeting these pathways.
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Affiliation(s)
- Michael D Donnan
- Northwestern University Feinberg School of Medicine, Feinberg Cardiovascular and Renal Research Institute, Chicago, Illinois
| | - Dilip K Deb
- Northwestern University Feinberg School of Medicine, Feinberg Cardiovascular and Renal Research Institute, Chicago, Illinois
| | - Tuncer Onay
- Northwestern University Feinberg School of Medicine, Feinberg Cardiovascular and Renal Research Institute, Chicago, Illinois
| | - Rizaldy P Scott
- Northwestern University Feinberg School of Medicine, Feinberg Cardiovascular and Renal Research Institute, Chicago, Illinois
| | - Eric Ni
- Lake Erie College of Osteopathic Medicine, Greensburg, Pennsylvania
| | - Yalu Zhou
- Northwestern University Feinberg School of Medicine, Feinberg Cardiovascular and Renal Research Institute, Chicago, Illinois
| | - Susan E Quaggin
- Northwestern University Feinberg School of Medicine, Feinberg Cardiovascular and Renal Research Institute, Chicago, Illinois
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24
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Rauniyar K, Akhondzadeh S, Gąciarz A, Künnapuu J, Jeltsch M. Bioactive VEGF-C from E. coli. Sci Rep 2022; 12:18157. [PMID: 36307539 PMCID: PMC9616921 DOI: 10.1038/s41598-022-22960-0] [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: 06/20/2022] [Accepted: 10/21/2022] [Indexed: 12/31/2022] Open
Abstract
Vascular endothelial growth factor-C (VEGF-C) stimulates lymphatic vessel growth in transgenic models, via viral gene delivery, and as a recombinant protein. Expressing eukaryotic proteins like VEGF-C in bacterial cells has limitations, as these cells lack specific posttranslational modifications and provisions for disulfide bond formation. However, given the cost and time savings associated with bacterial expression systems, there is considerable value in expressing VEGF-C using bacterial cells. We identified two approaches that result in biologically active Escherichia coli-derived VEGF-C. Expectedly, VEGF-C expressed from a truncated cDNA became bioactive after in vitro folding from inclusion bodies. Given that VEGF-C is one of the cysteine-richest growth factors in humans, it was unclear whether known methods to facilitate correct cysteine bond formation allow for the direct expression of bioactive VEGF-C in the cytoplasm. By fusing VEGF-C to maltose-binding protein and expressing these fusions in the redox-modified cytoplasm of the Origami (DE3) strain, we could recover biological activity for deletion mutants lacking the propeptides of VEGF-C. This is the first report of a bioactive VEGF growth factor obtained from E. coli cells circumventing in-vitro folding.
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Affiliation(s)
- Khushbu Rauniyar
- grid.7737.40000 0004 0410 2071Drug Research Program, Faculty of Pharmacy, Biocenter 2, University of Helsinki, P.O.B. 56 (Viikinkaari 5E), 00014 Helsinki, Finland
| | - Soheila Akhondzadeh
- grid.7737.40000 0004 0410 2071Drug Research Program, Faculty of Pharmacy, Biocenter 2, University of Helsinki, P.O.B. 56 (Viikinkaari 5E), 00014 Helsinki, Finland
| | - Anna Gąciarz
- grid.7737.40000 0004 0410 2071Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland
| | - Jaana Künnapuu
- grid.7737.40000 0004 0410 2071Drug Research Program, Faculty of Pharmacy, Biocenter 2, University of Helsinki, P.O.B. 56 (Viikinkaari 5E), 00014 Helsinki, Finland
| | - Michael Jeltsch
- grid.7737.40000 0004 0410 2071Drug Research Program, Faculty of Pharmacy, Biocenter 2, University of Helsinki, P.O.B. 56 (Viikinkaari 5E), 00014 Helsinki, Finland ,grid.7737.40000 0004 0410 2071Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland ,grid.452042.50000 0004 0442 6391Wihuri Research Institute, Helsinki, Finland
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25
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Ma J, Wu C. Bioactive inorganic particles-based biomaterials for skin tissue engineering. EXPLORATION (BEIJING, CHINA) 2022; 2:20210083. [PMID: 37325498 PMCID: PMC10190985 DOI: 10.1002/exp.20210083] [Citation(s) in RCA: 73] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 02/09/2022] [Indexed: 06/15/2023]
Abstract
The challenge for treatment of severe cutaneous wound poses an urgent clinical need for the development of biomaterials to promote skin regeneration. In the past few decades, introduction of inorganic components into material system has become a promising strategy for improving performances of biomaterials in the process of tissue repair. In this review, we provide a current overview of the development of bioactive inorganic particles-based biomaterials used for skin tissue engineering. We highlight the three stages in the evolution of the bioactive inorganic biomaterials applied to wound management, including single inorganic materials, inorganic/organic composite materials, and inorganic particles-based cell-encapsulated living systems. At every stage, the primary types of bioactive inorganic biomaterials are described, followed by citation of the related representative studies completed in recent years. Then we offer a brief exposition of typical approaches to construct the composite material systems with incorporation of inorganic components for wound healing. Finally, the conclusions and future directions are suggested for the development of novel bioactive inorganic particles-based biomaterials in the field of skin regeneration.
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Affiliation(s)
- Jingge Ma
- State Key Laboratory of High Performance Ceramics and Superfine MicrostructureShanghai Institute of CeramicsChinese Academy of SciencesShanghaiP. R. China
- Center of Materials Science and Optoelectronics EngineeringUniversity of Chinese Academy of SciencesBeijingP. R. China
| | - Chengtie Wu
- State Key Laboratory of High Performance Ceramics and Superfine MicrostructureShanghai Institute of CeramicsChinese Academy of SciencesShanghaiP. R. China
- Center of Materials Science and Optoelectronics EngineeringUniversity of Chinese Academy of SciencesBeijingP. R. China
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26
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Li Q, Chen Y, Feng W, Cai J, Gao J, Ge F, Zhou T, Wang Z, Ding F, Marshall C, Sheng C, Zhang Y, Sun M, Shi J, Xiao M. Drainage of senescent astrocytes from brain via meningeal lymphatic routes. Brain Behav Immun 2022; 103:85-96. [PMID: 35427759 DOI: 10.1016/j.bbi.2022.04.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 03/16/2022] [Accepted: 04/10/2022] [Indexed: 12/30/2022] Open
Abstract
Recent progress on the central lymphatic system has greatly increased our understanding of how the brain maintains its own waste homeostasis. Here, we showed that perivascular spaces and meningeal lymphatic vessels form a functional route for clearance of senescent astrocytes from the aging brain. Blocking meningeal lymphatic drainage by ligation of the deep cervical lymph nodes impaired clearance of senescent astrocytes from brain parenchyma, subsequently increasing neuroinflammation in aged mice. By contrast, enhancing meningeal lymphatic vessel diameter by a recombinant adeno-associated virus encoding mouse vascular endothelial growth factor-C (VEGF-C) improved clearance of senescent astrocytes and mitigated neuroinflammation. Mechanistically, VEGF-C was highly expressed in senescent astrocytes, contributing themselves to migrate across lymphatic vessels along C-C motif chemokine ligand 21 (CCL21) gradient by interacting with VEGF receptor 3. Moreover, intra-cisternal injection of antibody against CCL21 hampered senescent astrocytes into the lymphatic vessels and exacerbated short memory defects of aged mice. Together, these findings reveal a new perspective for the meningeal lymphatics in the removal of senescent astrocytes, thus offering a valuable target for therapeutic intervention.
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Affiliation(s)
- Qian Li
- Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, China; Department of Neurology, the Affiliated Nanjing Brain Hospital of Nanjing Medical University, Nanjing, 210029, China; Center for Global Health, Nanjing Medical University, Nanjing, 211166, China
| | - Yan Chen
- Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, China; Department of Neurology, the Affiliated Nanjing Brain Hospital of Nanjing Medical University, Nanjing, 210029, China; Center for Global Health, Nanjing Medical University, Nanjing, 211166, China
| | - Weixi Feng
- Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, China; Department of Neurology, the Affiliated Nanjing Brain Hospital of Nanjing Medical University, Nanjing, 210029, China; Center for Global Health, Nanjing Medical University, Nanjing, 211166, China
| | - Jiachen Cai
- Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, China
| | - Junying Gao
- Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, China; Department of Anatomy, Nanjing Medical University, Nanjing, 211166, China
| | - Feifei Ge
- Department of Neurology, the Affiliated Nanjing Brain Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Tiantian Zhou
- Department of Anesthesia, Nanjing Integrated Traditional Chinese and Western Medicine Hospital, Nanjing, 210028, China
| | - Ze Wang
- Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, China
| | - Fengfei Ding
- Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY, 14642, United States
| | - Charles Marshall
- Department of Physical Therapy, University of Kentucky Center of Excellence in Rural Health, Hazard, KY, 41701, USA
| | - Chengyu Sheng
- Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, China
| | - Yongjie Zhang
- Department of Anatomy, Nanjing Medical University, Nanjing, 211166, China
| | - Mingkuan Sun
- Department of Toxicology, Nanjing Medical University, Nanjing, 211166, China
| | - Jingping Shi
- Department of Neurology, the Affiliated Nanjing Brain Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Ming Xiao
- Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, China; Department of Neurology, the Affiliated Nanjing Brain Hospital of Nanjing Medical University, Nanjing, 210029, China; Center for Global Health, Nanjing Medical University, Nanjing, 211166, China.
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27
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Glinton KE, Ma W, Lantz C, Grigoryeva LS, DeBerge M, Liu X, Febbraio M, Kahn M, Oliver G, Thorp EB. Macrophage-produced VEGFC is induced by efferocytosis to ameliorate cardiac injury and inflammation. J Clin Invest 2022; 132:e140685. [PMID: 35271504 PMCID: PMC9057589 DOI: 10.1172/jci140685] [Citation(s) in RCA: 97] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 03/08/2022] [Indexed: 11/17/2022] Open
Abstract
Clearance of dying cells by efferocytosis is necessary for cardiac repair after myocardial infarction (MI). Recent reports have suggested a protective role for vascular endothelial growth factor C (VEGFC) during acute cardiac lymphangiogenesis after MI. Here, we report that defective efferocytosis by macrophages after experimental MI led to a reduction in cardiac lymphangiogenesis and Vegfc expression. Cell-intrinsic evidence for efferocytic induction of Vegfc was revealed after adding apoptotic cells to cultured primary macrophages, which subsequently triggered Vegfc transcription and VEGFC secretion. Similarly, cardiac macrophages elevated Vegfc expression levels after MI, and mice deficient for myeloid Vegfc exhibited impaired ventricular contractility, adverse tissue remodeling, and reduced lymphangiogenesis. These results were observed in mouse models of permanent coronary occlusion and clinically relevant ischemia and reperfusion. Interestingly, myeloid Vegfc deficiency also led to increases in acute infarct size, prior to the amplitude of the acute cardiac lymphangiogenesis response. RNA-Seq and cardiac flow cytometry revealed that myeloid Vegfc deficiency was also characterized by a defective inflammatory response, and macrophage-produced VEGFC was directly effective at suppressing proinflammatory macrophage activation. Taken together, our findings indicate that cardiac macrophages promote healing through the promotion of myocardial lymphangiogenesis and the suppression of inflammatory cytokines.
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Affiliation(s)
- Kristofor E. Glinton
- Department of Pathology
- Feinberg Cardiovascular and Renal Research Institute, and
| | - Wanshu Ma
- Feinberg Cardiovascular and Renal Research Institute, and
- Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Connor Lantz
- Department of Pathology
- Feinberg Cardiovascular and Renal Research Institute, and
| | - Lubov S. Grigoryeva
- Department of Pathology
- Feinberg Cardiovascular and Renal Research Institute, and
| | - Matthew DeBerge
- Department of Pathology
- Feinberg Cardiovascular and Renal Research Institute, and
| | - Xiaolei Liu
- Feinberg Cardiovascular and Renal Research Institute, and
- Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Maria Febbraio
- Department of Dentistry and Dental Hygiene, University of Alberta, Edmonton, Alberta, Canada
| | - Mark Kahn
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Guillermo Oliver
- Feinberg Cardiovascular and Renal Research Institute, and
- Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Edward B. Thorp
- Department of Pathology
- Feinberg Cardiovascular and Renal Research Institute, and
- Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
- The Heart Center at Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois, USA
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Le Chapelain O, Ho-Tin-Noé B. Intratumoral Platelets: Harmful or Incidental Bystanders of the Tumor Microenvironment? Cancers (Basel) 2022; 14:cancers14092192. [PMID: 35565321 PMCID: PMC9105443 DOI: 10.3390/cancers14092192] [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: 04/04/2022] [Revised: 04/23/2022] [Accepted: 04/25/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary The tumor microenvironment (TME) is the complex and heterogenous ecosystem of solid tumors known to influence their growth and their progression. Besides tumor cells, the TME comprises a variety of host-derived cell types, ranging from endothelial cells to fibroblasts and immune cells. Clinical and experimental data are converging to indicate that platelets, originally known for their fundamental hemostatic function, also participate in tumor development and shaping of the TME. Considering the abundance of antiplatelet drugs, understanding if and how platelets contribute to the TME may lead to new therapeutic tools for improved cancer prevention and treatments. Abstract The tumor microenvironment (TME) has gained considerable interest because of its decisive impact on cancer progression, response to treatment, and disease recurrence. The TME can favor the proliferation, dissemination, and immune evasion of cancer cells. Likewise, there is accumulating evidence that intratumoral platelets could favor the development and aggressiveness of solid tumors, notably by influencing tumor cell phenotype and shaping the vascular and immune TME components. Yet, in contrast to other tumor-associated cell types like macrophages and fibroblasts, platelets are still often overlooked as components of the TME. This might be due, in part, to a deficit in investigating and reporting the presence of platelets in the TME and its relationships with cancer characteristics. This review summarizes available evidence from clinical and animal studies supporting the notion that tumor-associated platelets are not incidental bystanders but instead integral and active components of the TME. A particular emphasis is given to the description of intratumoral platelets, as well as to the functional consequences and possible mechanisms of intratumoral platelet accumulation.
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Coagulome and the tumor microenvironment: an actionable interplay. Trends Cancer 2022; 8:369-383. [PMID: 35027336 DOI: 10.1016/j.trecan.2021.12.008] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 11/19/2021] [Accepted: 12/15/2021] [Indexed: 12/14/2022]
Abstract
Human tumors often trigger a hypercoagulable state that promotes hemostatic complications, including venous thromboembolism. The recent application of systems biology to the study of the coagulome highlighted its link to shaping the tumor microenvironment (TME), both within and outside of the vascular space. Addressing this link provides the opportunity to revisit the significance of biomarkers of hemostasis and assess the communication between vasculature and tumor parenchyma, an important topic considering the advent of immune checkpoint inhibitors and vascular normalization strategies. Understanding how the coagulome and TME influence each other offers exciting new prospects for predicting hemostatic complications and boosting the effectiveness of cancer treatment.
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Koistinen H, Künnapuu J, Jeltsch M. KLK3 in the Regulation of Angiogenesis-Tumorigenic or Not? Int J Mol Sci 2021; 22:ijms222413545. [PMID: 34948344 PMCID: PMC8704207 DOI: 10.3390/ijms222413545] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 12/10/2021] [Accepted: 12/14/2021] [Indexed: 02/07/2023] Open
Abstract
In this focused review, we address the role of the kallikrein-related peptidase 3 (KLK3), also known as prostate-specific antigen (PSA), in the regulation of angiogenesis. Early studies suggest that KLK3 is able to inhibit angiogenic processes, which is most likely dependent on its proteolytic activity. However, more recent evidence suggests that KLK3 may also have an opposite role, mediated by the ability of KLK3 to activate the (lymph)angiogenic vascular endothelial growth factors VEGF-C and VEGF-D, further discussed in the review.
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Affiliation(s)
- Hannu Koistinen
- Department of Clinical Chemistry, Helsinki University Hospital and University of Helsinki, 00290 Helsinki, Finland
- Correspondence: (H.K.); (M.J.)
| | - Jaana Künnapuu
- Drug Research Program, University of Helsinki, 00014 Helsinki, Finland;
| | - Michael Jeltsch
- Drug Research Program, University of Helsinki, 00014 Helsinki, Finland;
- Individualized Drug Therapy Research Program, University of Helsinki, 00014 Helsinki, Finland
- Wihuri Research Institute, 00290 Helsinki, Finland
- Correspondence: (H.K.); (M.J.)
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31
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Carpino G, Cardinale V, Di Giamberardino A, Overi D, Donsante S, Colasanti T, Amato G, Mennini G, Franchitto M, Conti F, Rossi M, Riminucci M, Gaudio E, Alvaro D, Mancone C. Thrombospondin 1 and 2 along with PEDF inhibit angiogenesis and promote lymphangiogenesis in intrahepatic cholangiocarcinoma. J Hepatol 2021; 75:1377-1386. [PMID: 34329660 DOI: 10.1016/j.jhep.2021.07.016] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 07/13/2021] [Accepted: 07/15/2021] [Indexed: 12/27/2022]
Abstract
BACKGROUND & AIMS The microenvironment of intrahepatic cholangiocarcinoma (iCCA) is hypovascularized, with an extensive lymphatic network. This leads to rapid cancer spread into regional lymph nodes and the liver parenchyma, precluding curative treatments. Herein, we investigated which factors released in the iCCA stroma drive the inhibition of angiogenesis and promote lymphangiogenesis. METHODS Quantitative proteomics was performed on extracellular fluid (ECF) proteins extracted both from cancerous and non-cancerous tissues (NCT) of patients with iCCA. Computational biology was applied on a proteomic dataset to identify proteins involved in the regulation of vessel formation. Endothelial cells incubated with ECF from either iCCA or NCT specimens were used to assess the role of candidate proteins in 3D vascular assembly, cell migration, proliferation and viability. Angiogenesis and lymphangiogenesis were further investigated in vivo by a heterotopic transplantation of bone marrow stromal cells, along with endothelial cells in SCID/beige mice. RESULTS Functional analysis of upregulated proteins in iCCA unveils a soluble angio-inhibitory milieu made up of thrombospondin (THBS)1, THBS2 and pigment epithelium-derived factor (PEDF). iCCA ECF was able to inhibit in vitro vessel morphogenesis and viability. Antibodies blocking THBS1, THBS2 and PEDF restored tube formation and endothelial cell viability to levels observed in NCT ECF. Moreover, in transplanted mice, the inhibition of blood vessel formation, the de novo generation of the lymphatic network and the dissemination of iCCA cells in lymph nodes were shown to depend on THBS1, THBS2 and PEDF expression. CONCLUSIONS THBS1, THBS2 and PEDF reduce blood vessel formation and promote tumor-associated lymphangiogenesis in iCCA. Our results identify new potential targets for interventions to counteract the dissemination process in iCCA. LAY SUMMARY Intrahepatic cholangiocarcinoma is a highly aggressive cancer arising from epithelial cells lining the biliary tree, characterized by dissemination into the liver parenchyma via lymphatic vessels. Herein, we show that the proteins THBS1, THBS2 and PEDF, once released in the tumor microenvironment, inhibit vascular growth, while promoting cancer-associated lymphangiogenesis. Therefore, targeting THBS1, THBS2 and PEDF may be a promising strategy to reduce cancer-associated lymphangiogenesis and counteract the invasiveness of intrahepatic cholangiocarcinoma.
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Affiliation(s)
- Guido Carpino
- Division of Health Sciences, Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", Rome, Italy
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza University of Rome, Rome, Italy
| | | | - Diletta Overi
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Samantha Donsante
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Tania Colasanti
- Rheumatology Unit, Department of Clinical Internal, Anesthetic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - Gaia Amato
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Gianluca Mennini
- General Surgery and Organ Transplantation Unit, Department of General Surgery and Surgical Specialties P. Stefanini, Sapienza University of Rome, Rome, Italy
| | - Matteo Franchitto
- Department of Medical-Surgical Sciences and Translation Medicine, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy
| | - Fabrizio Conti
- Rheumatology Unit, Department of Clinical Internal, Anesthetic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - Massimo Rossi
- General Surgery and Organ Transplantation Unit, Department of General Surgery and Surgical Specialties P. Stefanini, Sapienza University of Rome, Rome, Italy
| | - Mara Riminucci
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Domenico Alvaro
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Carmine Mancone
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
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Keller Iv TCS, Lim L, Shewale SV, McDaid K, Marti-Pamies I, Tang AT, Wittig C, Guerrero AA, Sterling S, Leu NA, Scherrer-Crosbie M, Gimotty PA, Kahn ML. Genetic blockade of lymphangiogenesis does not impair cardiac function after myocardial infarction. J Clin Invest 2021; 131:e147070. [PMID: 34403369 DOI: 10.1172/jci147070] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 08/12/2021] [Indexed: 11/17/2022] Open
Abstract
In recent decades, treatments for myocardial infarction (MI), such as stem and progenitor cell therapy, have attracted considerable scientific and clinical attention but failed to improve patient outcomes. These efforts indicate that more rigorous mechanistic and functional testing of potential MI therapies is required. Recent studies have suggested that augmenting post-MI lymphatic growth via VEGF-C administration improves cardiac function. However, the mechanisms underlying this proposed therapeutic approach remain vague and untested. To more rigorously test the role of lymphatic vessel growth after MI, we examined the post-MI cardiac function of mice in which lymphangiogenesis had been blocked genetically by pan-endothelial or lymphatic endothelial loss of the lymphangiogenic receptor VEGFR3 or global loss of the VEGF-C and VEGF-D ligands. The results obtained using all three genetic approaches were highly concordant and demonstrated that loss of lymphatic vessel growth did not impair left ventricular ejection fraction two weeks after MI in mice. We observed a trend toward excess fluid in the infarcted region of the left ventricle, but immune cell infiltration and clearance were unchanged with loss of expanded lymphatics. These studies refute the hypothesis that lymphangiogenesis contributes significantly to cardiac function after MI, and suggest that any effect of exogenous VEGF-C is likely to be mediated by non-lymphangiogenic mechanisms.
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Affiliation(s)
- T C Stevenson Keller Iv
- Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, United States of America
| | - Lillian Lim
- Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, United States of America
| | - Swapnil V Shewale
- Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, United States of America
| | - Kendra McDaid
- Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, United States of America
| | - Ingrid Marti-Pamies
- Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, United States of America
| | - Alan T Tang
- Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, United States of America
| | - Carl Wittig
- Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, United States of America
| | - Andrea A Guerrero
- Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, United States of America
| | - Stephanie Sterling
- Department of Biomedical Sciences and Mouse Transgenic Core, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, United States of America
| | - N Adrian Leu
- Department of Biomedical Sciences and Mouse Transgenic Core, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, United States of America
| | - Marielle Scherrer-Crosbie
- Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, United States of America
| | - Phyllis A Gimotty
- Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America
| | - Mark L Kahn
- Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, United States of America
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33
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Božič D, Vozel D, Hočevar M, Jeran M, Jan Z, Pajnič M, Pađen L, Iglič A, Battelino S, Kralj-Iglič V. Enrichment of plasma in platelets and extracellular vesicles by the counterflow to erythrocyte settling. Platelets 2021; 33:592-602. [PMID: 34384320 DOI: 10.1080/09537104.2021.1961716] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
In order to prepare optimal platelet and extracellular vesicle (EV)-rich plasma for the treatment of chronic temporal bone inflammation, we studied effects of centrifugation parameters on redistribution of blood constituents in blood samples of 23 patients and 20 volunteers with no record of disease. Concentrations of blood cells and EVs were measured by flow cytometry. Sample content was inspected by scanning electron microscopy. A mathematical model was constructed to interpret the experimental results. The observed enrichment of plasma in platelets and EVs after a single spin of blood depended on the erythrocyte sedimentation rate, thereby indicating the presence of a flow of plasma that carried platelets and EVs in the direction opposite to settling of erythrocytes. Prolonged handling time correlated with the decrease of concentration of platelets and larger EVs in platelet and EV-rich plasma (PVRP), R = -0.538, p = 0.003, indicating cell fragmentation during the processing of samples. In further centrifugation of the obtained plasma, platelet and EV enrichment depended on the average distance of the sample from the centrifuge rotor axis. Based on the agreement of the model predictions with observations, we propose the centrifugation protocol optimal for platelet and EV enrichment and recovery in an individual sample, adjusted to the dimensions of the centrifuge rotor, volume of blood and erythrocyte sedimentation rate.[Figure: see text].
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Affiliation(s)
- Darja Božič
- University of Ljubljana, Faculty of Health Sciences, Laboratory of Clinical Biophysics, Ljubljana, Slovenia.,University of Ljubljana, Faculty of Electrical Engineering, Laboratory of Physics, Ljubljana, Slovenia
| | - Domen Vozel
- University Medical Centre Ljubljana, Department of Otorhinolaryngology and Cervicofacial Surgery, Ljubljana, Slovenia.,University of Ljubljana, Faculty of Medicine, Department of Otorhinolaryngology, Ljubljana, Slovenia
| | - Matej Hočevar
- Department of Physics and Chemistry of Materials, Institute of Metals and Technology, Ljubljana, Slovenia
| | - Marko Jeran
- University of Ljubljana, Faculty of Health Sciences, Laboratory of Clinical Biophysics, Ljubljana, Slovenia.,University of Ljubljana, Faculty of Electrical Engineering, Laboratory of Physics, Ljubljana, Slovenia
| | - Zala Jan
- University of Ljubljana, Faculty of Health Sciences, Laboratory of Clinical Biophysics, Ljubljana, Slovenia
| | - Manca Pajnič
- University of Ljubljana, Faculty of Health Sciences, Laboratory of Clinical Biophysics, Ljubljana, Slovenia
| | - Ljubiša Pađen
- University of Ljubljana, Faculty of Health Sciences, Laboratory of Clinical Biophysics, Ljubljana, Slovenia
| | - Aleš Iglič
- University of Ljubljana, Faculty of Electrical Engineering, Laboratory of Physics, Ljubljana, Slovenia.,University of Ljubljana, Faculty of Medicine, Chair of Orthopedics, Laboratory of Clinical Biophysics, Ljubljana, Slovenia
| | - Saba Battelino
- University Medical Centre Ljubljana, Department of Otorhinolaryngology and Cervicofacial Surgery, Ljubljana, Slovenia.,University of Ljubljana, Faculty of Medicine, Department of Otorhinolaryngology, Ljubljana, Slovenia
| | - Veronika Kralj-Iglič
- University of Ljubljana, Faculty of Health Sciences, Laboratory of Clinical Biophysics, Ljubljana, Slovenia
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Stritt S, Koltowska K, Mäkinen T. Homeostatic maintenance of the lymphatic vasculature. Trends Mol Med 2021; 27:955-970. [PMID: 34332911 DOI: 10.1016/j.molmed.2021.07.003] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 06/30/2021] [Accepted: 07/06/2021] [Indexed: 12/24/2022]
Abstract
The lymphatic vasculature is emerging as a multifaceted regulator of tissue homeostasis and regeneration. Lymphatic vessels drain fluid, macromolecules, and immune cells from peripheral tissues to lymph nodes (LNs) and the systemic circulation. Their recently uncovered functions extend beyond drainage and include direct modulation of adaptive immunity and paracrine regulation of organ growth. The developmental mechanisms controlling lymphatic vessel growth have been described with increasing precision. It is less clear how the essential functional features of lymphatic vessels are established and maintained. We discuss the mechanisms that maintain lymphatic vessel integrity in adult tissues and control vessel repair and regeneration. This knowledge is crucial for understanding the pathological vessel changes that contribute to disease, and provides an opportunity for therapy development.
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Affiliation(s)
- Simon Stritt
- Uppsala University, Department of Immunology, Genetics, and Pathology, 751 85 Uppsala, Sweden
| | - Katarzyna Koltowska
- Uppsala University, Department of Immunology, Genetics, and Pathology, 751 85 Uppsala, Sweden
| | - Taija Mäkinen
- Uppsala University, Department of Immunology, Genetics, and Pathology, 751 85 Uppsala, Sweden.
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35
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Regulation of VEGFR Signalling in Lymphatic Vascular Development and Disease: An Update. Int J Mol Sci 2021; 22:ijms22147760. [PMID: 34299378 PMCID: PMC8306507 DOI: 10.3390/ijms22147760] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 07/02/2021] [Accepted: 07/14/2021] [Indexed: 12/13/2022] Open
Abstract
The importance of lymphatic vessels in a myriad of human diseases is rapidly gaining recognition; lymphatic vessel dysfunction is a feature of disorders including congenital lymphatic anomalies, primary lymphoedema and obesity, while improved lymphatic vessel function increases the efficacy of immunotherapy for cancer and neurological disease and promotes cardiac repair following myocardial infarction. Understanding how the growth and function of lymphatic vessels is precisely regulated therefore stands to inform the development of novel therapeutics applicable to a wide range of human diseases. Lymphatic vascular development is initiated during embryogenesis following establishment of the major blood vessels and the onset of blood flow. Lymphatic endothelial progenitor cells arise from a combination of venous and non-venous sources to generate the initial lymphatic vascular structures in the vertebrate embryo, which are then further ramified and remodelled to elaborate an extensive lymphatic vascular network. Signalling mediated via vascular endothelial growth factor (VEGF) family members and vascular endothelial growth factor receptor (VEGFR) tyrosine kinases is crucial for development of both the blood and lymphatic vascular networks, though distinct components are utilised to different degrees in each vascular compartment. Although much is known about the regulation of VEGFA/VEGFR2 signalling in the blood vasculature, less is understood regarding the mechanisms by which VEGFC/VEGFD/VEGFR3 signalling is regulated during lymphatic vascular development. This review will focus on recent advances in our understanding of the cellular and molecular mechanisms regulating VEGFA-, VEGFC- and VEGFD-mediated signalling via VEGFRs which are important for driving the construction of lymphatic vessels during development and disease.
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36
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Shen Y, Xu G, Huang H, Wang K, Wang H, Lang M, Gao H, Zhao S. Sequential Release of Small Extracellular Vesicles from Bilayered Thiolated Alginate/Polyethylene Glycol Diacrylate Hydrogels for Scarless Wound Healing. ACS NANO 2021; 15:6352-6368. [PMID: 33723994 DOI: 10.1021/acsnano.0c07714] [Citation(s) in RCA: 103] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Excessive scar formation has adverse physiological and psychological effects on patients; therefore, a therapeutic strategy for rapid wound healing and reduced scar formation is urgently needed. Herein, bilayered thiolated alginate/PEG diacrylate (BSSPD) hydrogels were fabricated for sequential release of small extracellular vesicles (sEVs), which acted in different wound healing phases, to achieve rapid and scarless wound healing. The sEVs secreted by bone marrow derived mesenchymal stem cells (B-sEVs) were released from the lower layer of the hydrogels to promote angiogenesis and collagen deposition by accelerating fibroblast and endothelial cell proliferation and migration during the early inflammation and proliferation phases, while sEVs secreted by miR-29b-3p-enriched bone marrow derived mesenchymal stem cells were released from the upper layer of the hydrogels and suppressed excessive capillary proliferation and collagen deposition during the late proliferation and maturation phases. In a full-thickness skin defect model of rats and rabbit ears, the wound repair rate, angiogenesis, and collagen deposition were evaluated at different time points after treatment with BSSPD loaded with B-sEVs. Interestingly, during the end of the maturation phase in the in vivo model, tissues in the groups treated with BSSPD loaded with sEVs for sequential release (SR-sEVs@BSSPD) exhibited a more uniform vascular structure distribution, more regular collagen arrangement, and lower volume of hyperplastic scar tissue than tissues in the other groups. Hence, SR-sEVs@BSSPD based on skin repair phases was successfully designed and has considerable potential as a cell-free therapy for scarless wound healing.
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Affiliation(s)
- Yifan Shen
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Guanzhe Xu
- Shanghai Key Laboratory of Advanced Polymeric Materials, Key Laboratory for Ultrafine Materials of Ministry of Education, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai 200237, China
- Internet of Things Research Center, Advanced Institute of Information Technology, Peking University, Hangzhou 311200, China
| | - Huanxuan Huang
- Shanghai Key Laboratory of Advanced Polymeric Materials, Key Laboratory for Ultrafine Materials of Ministry of Education, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai 200237, China
| | - Kaiyang Wang
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Hui Wang
- Green Chemical Engineering Technology Research Center, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201210, China
| | - Meidong Lang
- Shanghai Key Laboratory of Advanced Polymeric Materials, Key Laboratory for Ultrafine Materials of Ministry of Education, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai 200237, China
| | - Hong Gao
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Shichang Zhao
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
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37
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Ping Q, Shi Y, Yang M, Li H, Zhong Y, Li J, Bi X, Wang C. LncRNA DANCR regulates lymphatic metastasis of bladder cancer via the miR-335/VEGF-C axis. Transl Androl Urol 2021; 10:1743-1753. [PMID: 33968662 PMCID: PMC8100837 DOI: 10.21037/tau-21-226] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Background Substantial evidence indicate that long non-coding RNA (lncRNA) and microRNA (miRNA) act as key role in bladder cancer. Differentiation antagonistic ncRNA (DANCR) could be used as a biomarker in the occurrence and development of cancer. This study aims to explore the mechanism of DANCR/miR-335/VEGF-C axis affecting lymphatic metastasis of bladder cancer. Methods qRT-PCR detects the expression of DANCR in bladder cancer cell lines (SW780, 5637, T24, UM-UC-3) and normal bladder cell lines (SV-HUC-1), and selects T24 cell lines for subsequent experiments. The expression levels of DANCR, miR-335 and VEGF were measured by qRT-PCR, and the dual luciferase reporter gene verified the targeted regulation of DANCR on miR-335 and miR-335 on VEGF. CCK-8, Transwell and Wound healing assay detect the proliferation, invasion and migration ability of bladder cancer cells, Endothelial cell adhesion assay and Western blot further prove the lymphatic metastasis of bladder cancer. Results In this study, DANCR was highly expressed in bladder cancer cell lines. Transfection of si-DANCR significantly inhibits the proliferation, migration, invasion and lymphatic metastasis of bladder cancer cells. Dual luciferase assay confirmed that DANCR targets miR-335/VEGF-C. Transfection of miR-335 mimic promotes the proliferation, migration, invasion and lymphatic metastasis of bladder cancer cells, overexpression of DANCR eliminates the promotion of miR-335 mimic on bladder cancer cells. Further experiments proved that inhibition of miR-335 and overexpression of VEGF-C can reverse the inhibitory effect of silencing DANCR on bladder cancer cells. Conclusions In bladder cancer, DARCR plays an important role, which regulates the proliferation, migration, invasion and lymphatic metastasis of bladder cancer cells through the miR-335/VEGF-C molecular axis.
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Affiliation(s)
- Qinrong Ping
- Department of Urology, Yan'an Hospital Affiliated to Kunming Medical University, Kunming, China
| | - Yunqiang Shi
- Department of Urology, Yan'an Hospital Affiliated to Kunming Medical University, Kunming, China
| | - Meng Yang
- Department of Urology, Yan'an Hospital Affiliated to Kunming Medical University, Kunming, China
| | - Hui Li
- Department of Urology, Yan'an Hospital Affiliated to Kunming Medical University, Kunming, China
| | - Yiming Zhong
- Department of Urology, Yan'an Hospital Affiliated to Kunming Medical University, Kunming, China
| | - Jian Li
- Department of Urology, Yan'an Hospital Affiliated to Kunming Medical University, Kunming, China
| | - Xiaofang Bi
- Department of Urology, Yan'an Hospital Affiliated to Kunming Medical University, Kunming, China
| | - Chunhui Wang
- Department of Urology, Yan'an Hospital Affiliated to Kunming Medical University, Kunming, China
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38
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Künnapuu J, Bokharaie H, Jeltsch M. Proteolytic Cleavages in the VEGF Family: Generating Diversity among Angiogenic VEGFs, Essential for the Activation of Lymphangiogenic VEGFs. BIOLOGY 2021; 10:167. [PMID: 33672235 PMCID: PMC7926383 DOI: 10.3390/biology10020167] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 02/15/2021] [Accepted: 02/18/2021] [Indexed: 12/24/2022]
Abstract
Specific proteolytic cleavages turn on, modify, or turn off the activity of vascular endothelial growth factors (VEGFs). Proteolysis is most prominent among the lymph-angiogenic VEGF-C and VEGF-D, which are synthesized as precursors that need to undergo enzymatic removal of their C- and N-terminal propeptides before they can activate their receptors. At least five different proteases mediate the activating cleavage of VEGF-C: plasmin, ADAMTS3, prostate-specific antigen, cathepsin D, and thrombin. All of these proteases except for ADAMTS3 can also activate VEGF-D. Processing by different proteases results in distinct forms of the "mature" growth factors, which differ in affinity and receptor activation potential. The "default" VEGF-C-activating enzyme ADAMTS3 does not activate VEGF-D, and therefore, VEGF-C and VEGF-D do function in different contexts. VEGF-C itself is also regulated in different contexts by distinct proteases. During embryonic development, ADAMTS3 activates VEGF-C. The other activating proteases are likely important for non-developmental lymphangiogenesis during, e.g., tissue regeneration, inflammation, immune response, and pathological tumor-associated lymphangiogenesis. The better we understand these events at the molecular level, the greater our chances of developing successful therapies targeting VEGF-C and VEGF-D for diseases involving the lymphatics such as lymphedema or cancer.
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Affiliation(s)
- Jaana Künnapuu
- Drug Research Program, Faculty of Pharmacy, University of Helsinki, 00014 Helsinki, Finland; (J.K.); (H.B.)
| | - Honey Bokharaie
- Drug Research Program, Faculty of Pharmacy, University of Helsinki, 00014 Helsinki, Finland; (J.K.); (H.B.)
| | - Michael Jeltsch
- Drug Research Program, Faculty of Pharmacy, University of Helsinki, 00014 Helsinki, Finland; (J.K.); (H.B.)
- Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland
- Wihuri Research Institute, 00290 Helsinki, Finland
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González-Loyola A, Petrova TV. Development and aging of the lymphatic vascular system. Adv Drug Deliv Rev 2021; 169:63-78. [PMID: 33316347 DOI: 10.1016/j.addr.2020.12.005] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 11/22/2020] [Accepted: 12/07/2020] [Indexed: 12/13/2022]
Abstract
The lymphatic vasculature has a pivotal role in regulating body fluid homeostasis, immune surveillance and dietary fat absorption. The increasing number of in vitro and in vivo studies in the last decades has shed light on the processes of lymphatic vascular development and function. Here, we will discuss the current progress in lymphatic vascular biology such as the mechanisms of lymphangiogenesis, lymphatic vascular maturation and maintenance and the emerging mechanisms of lymphatic vascular aging.
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Affiliation(s)
- Alejandra González-Loyola
- Department of Oncology, Ludwig Institute for Cancer Research Lausanne, University of Lausanne, Switzerland.
| | - Tatiana V Petrova
- Department of Oncology, Ludwig Institute for Cancer Research Lausanne, University of Lausanne, Switzerland.
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40
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Baluk P, Naikawadi RP, Kim S, Rodriguez F, Choi D, Hong YK, Wolters PJ, McDonald DM. Lymphatic Proliferation Ameliorates Pulmonary Fibrosis after Lung Injury. THE AMERICAN JOURNAL OF PATHOLOGY 2020; 190:2355-2375. [PMID: 33039355 DOI: 10.1016/j.ajpath.2020.08.018] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 08/09/2020] [Accepted: 08/27/2020] [Indexed: 12/11/2022]
Abstract
Despite many reports about pulmonary blood vessels in lung fibrosis, the contribution of lymphatics to fibrosis is unknown. We examined the mechanism and consequences of lymphatic remodeling in mice with lung fibrosis after bleomycin injury or telomere dysfunction. Widespread lymphangiogenesis was observed after bleomycin treatment and in fibrotic lungs of prospero homeobox 1-enhanced green fluorescent protein (Prox1-EGFP) transgenic mice with telomere dysfunction. In loss-of-function studies, blocking antibodies revealed that lymphangiogenesis 14 days after bleomycin treatment was dependent on vascular endothelial growth factor (Vegf) receptor 3 signaling, but not on Vegf receptor 2. Vegfc gene and protein expression increased specifically. Extensive extravasated plasma, platelets, and macrophages at sites of lymphatic growth were potential sources of Vegfc. Lymphangiogenesis peaked at 14 to 28 days after bleomycin challenge, was accompanied by doubling of chemokine (C-C motif) ligand 21 in lung lymphatics and tertiary lymphoid organ formation, and then decreased as lung injury resolved by 56 days. In gain-of-function studies, expansion of the lung lymphatic network by transgenic overexpression of Vegfc in club cell secretory protein (CCSP)/VEGF-C mice reduced macrophage accumulation and fibrosis and accelerated recovery after bleomycin treatment. These findings suggest that lymphatics have an overall protective effect in lung injury and fibrosis and fit with a mechanism whereby lung lymphatic network expansion reduces lymph stasis and increases clearance of fluid and cells, including profibrotic macrophages.
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Affiliation(s)
- Peter Baluk
- Department of Anatomy, University of California, San Francisco, San Francisco, California; Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California; UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.
| | - Ram P Naikawadi
- Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, University of California, San Francisco, San Francisco, California
| | - Shineui Kim
- Department of Anatomy, University of California, San Francisco, San Francisco, California
| | - Felipe Rodriguez
- Department of Anatomy, University of California, San Francisco, San Francisco, California
| | - Dongwon Choi
- Department of Surgery, University of Southern California, Los Angeles, California
| | - Young-Kwon Hong
- Department of Surgery, University of Southern California, Los Angeles, California
| | - Paul J Wolters
- Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, University of California, San Francisco, San Francisco, California
| | - Donald M McDonald
- Department of Anatomy, University of California, San Francisco, San Francisco, California; Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California; UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.
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41
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Qu CH, Li T, Tang ZP, Zhu XR, Han JY, Tian H. Platelet Count is Associated with the Rate of Lymph Node Metastasis in Lung Adenocarcinoma. Cancer Manag Res 2020; 12:9765-9774. [PMID: 33116836 PMCID: PMC7548228 DOI: 10.2147/cmar.s273328] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 09/08/2020] [Indexed: 12/14/2022] Open
Abstract
Purpose Emerging studies have revealed that platelets are involved in tumor metastasis in lung adenocarcinoma (ADC). The solid pathological subtype of lung ADC is associated with metastasis, recurrence, and poor prognosis. However, there is no study exploring the relationship between platelets and different lung pathological subtypes. Patients and Methods The association between platelet counts and lymph node metastasis was analyzed in 852 patients with lung ADC who underwent surgery and lymph node dissection. Multivariate logistic analysis was conducted to identify the risk factors of lymph node metastasis. Then, lymph node metastasis and other factors were analyzed to determine their correlation with platelet count and histological subtype. Results We found that the platelet count was associated with lymph node metastasis (P = 0.01) in multivariable analysis, independent of tumor size, predominant subtype, visceral pleural invasion, and microvessel invasion. In patients with a platelet count ≥300 × 109/L, the rate of lymph node metastasis was 38.5%, almost twice as high as that in patients with a platelet count <300 × 109/L (23.2%). Additionally, elevated platelet counts, even those within the normal range, were significantly associated with a higher rate of lymph node metastasis. The mean platelet count in patients with solid-predominant histology (269.70 ± 69.38 × 109/L) was significantly higher than that in patients with other histologies (P < 0.001). Conclusion Elevated platelet counts are significantly associated with a higher rate of lymph node metastasis, even if the platelet counts are within the reference range. Platelet counts were significantly higher in patients with solid-predominant histology than in patients with other histologies. In addition, VEGF-C may play an important role in lymphatic metastasis in patients with lung ADC. We hypothesize that antiplatelet therapy may reduce lymph node metastasis in lung ADC patients.
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Affiliation(s)
- Cheng-Hao Qu
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, People's Republic of China.,Department of Thoracic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, People's Republic of China
| | - Tong Li
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, People's Republic of China.,Department of Thoracic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, People's Republic of China
| | - Zhan-Peng Tang
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, People's Republic of China.,Department of Thoracic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, People's Republic of China
| | - Xi-Rui Zhu
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, People's Republic of China.,Department of Thoracic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, People's Republic of China
| | - Jing-Yi Han
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, People's Republic of China.,Department of Thoracic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, People's Republic of China
| | - Hui Tian
- Department of Thoracic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, People's Republic of China
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Wong BW. Lymphatic vessels in solid organ transplantation and immunobiology. Am J Transplant 2020; 20:1992-2000. [PMID: 32027464 DOI: 10.1111/ajt.15806] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 01/14/2020] [Accepted: 01/31/2020] [Indexed: 01/25/2023]
Abstract
With the recent advances in our understanding of the function and biology of the lymphatic vascular system, it is clear that the lymphatic system plays an integral role in physiology, and in pathological settings, may contribute to either enhance or repress inflammation and disease progression. Inflammation is central to both acute and chronic rejection in the context of solid organ transplantation, and emerging evidence suggests the lymphatic system plays a key role in shaping outcomes. The goals of this review are to highlight and contextualize the roles of lymphatic vessels and lymphangiogenesis in immunobiology, the impact immunosuppressive therapies have on the lymphatic system and emerging evidence of organ-specific heterogeneity of lymphatic vessels in the context of solid organ transplantation.
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Affiliation(s)
- Brian W Wong
- Laboratory of Lymphatic Metabolism + Epigenetics, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA
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Suzuki-Inoue K, Tsukiji N, Otake S. Crosstalk between hemostasis and lymphangiogenesis. J Thromb Haemost 2020; 18:767-770. [PMID: 32233027 DOI: 10.1111/jth.14726] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 12/23/2019] [Accepted: 12/27/2019] [Indexed: 11/30/2022]
Affiliation(s)
- Katsue Suzuki-Inoue
- Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Nagaharu Tsukiji
- Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Shimon Otake
- Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
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