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1
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Hu W, Wang Y, Han J, Zhang W, Chen J, Li X, Wang L. Microfluidic organ-on-a-chip models for the gut-liver axis: from structural mimicry to functional insights. Biomater Sci 2025; 13:1624-1656. [PMID: 40019226 DOI: 10.1039/d4bm01273a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/01/2025]
Abstract
The gut-liver axis plays a crucial role in maintaining metabolic balance and overall human health. It orchestrates various processes, such as blood flow, nutrient transfer, metabolite processing, and immune cell communication between the two organs. Traditional methods, such as animal models and two-dimensional (2D) cell cultures, are insufficient in fully replicating the intricate functions of the gut-liver axis. The emergence of microfluidic technology has revolutionized this field, facilitating the development of organ-on-a-chip (OOC) systems. These systems are capable of mimicking the complex structures and dynamic environments of the gut and liver in vitro and incorporating sensors for real-time monitoring. In this article, we review the latest progress in gut-on-a-chip (GOC) and liver-on-a-chip (LOC) systems, as well as the integrated gut-liver-on-a-chip (GLOC) models. Our focus lies in the simulation of physiological parameters, three-dimensional (3D) structural mimicry, microbiome integration, and multicellular co-culture. All these aspects are essential for constructing accurate in vitro models of the gut and liver. Furthermore, we explore the current applications of OOC technology in the study of the gut and liver, including its use in disease modeling, toxicity testing, and drug screening. Finally, we discuss the challenges that remain and outline potential future directions for advancing GOC and LOC development in vitro.
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Affiliation(s)
- Wanlin Hu
- School of Mechanical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China.
- Shandong Institute of Mechanical Design and Research, Jinan 250353, China
| | - Yushen Wang
- School of Mechanical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China.
- Shandong Institute of Mechanical Design and Research, Jinan 250353, China
| | - Junlei Han
- School of Mechanical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China.
- Shandong Institute of Mechanical Design and Research, Jinan 250353, China
| | - Wenhong Zhang
- College of Mechanical Engineering, Donghua University, Shanghai 201620, China
| | - Jun Chen
- School of Mechanical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China.
- Shandong Institute of Mechanical Design and Research, Jinan 250353, China
| | - Xinyu Li
- Department of Minimally Invasive Comprehensive Treatment of Cancer, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China.
| | - Li Wang
- School of Mechanical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China.
- Shandong Institute of Mechanical Design and Research, Jinan 250353, China
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2
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Ma X, Huang T, Chen X, Li Q, Liao M, Fu L, Huang J, Yuan K, Wang Z, Zeng Y. Molecular mechanisms in liver repair and regeneration: from physiology to therapeutics. Signal Transduct Target Ther 2025; 10:63. [PMID: 39920130 PMCID: PMC11806117 DOI: 10.1038/s41392-024-02104-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 09/02/2024] [Accepted: 12/12/2024] [Indexed: 02/09/2025] Open
Abstract
Liver repair and regeneration are crucial physiological responses to hepatic injury and are orchestrated through intricate cellular and molecular networks. This review systematically delineates advancements in the field, emphasizing the essential roles played by diverse liver cell types. Their coordinated actions, supported by complex crosstalk within the liver microenvironment, are pivotal to enhancing regenerative outcomes. Recent molecular investigations have elucidated key signaling pathways involved in liver injury and regeneration. Viewed through the lens of metabolic reprogramming, these pathways highlight how shifts in glucose, lipid, and amino acid metabolism support the cellular functions essential for liver repair and regeneration. An analysis of regenerative variability across pathological states reveals how disease conditions influence these dynamics, guiding the development of novel therapeutic strategies and advanced techniques to enhance liver repair and regeneration. Bridging laboratory findings with practical applications, recent clinical trials highlight the potential of optimizing liver regeneration strategies. These trials offer valuable insights into the effectiveness of novel therapies and underscore significant progress in translational research. In conclusion, this review intricately links molecular insights to therapeutic frontiers, systematically charting the trajectory from fundamental physiological mechanisms to innovative clinical applications in liver repair and regeneration.
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Affiliation(s)
- Xiao Ma
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Tengda Huang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Xiangzheng Chen
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Qian Li
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Mingheng Liao
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Li Fu
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Jiwei Huang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Kefei Yuan
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Zhen Wang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
| | - Yong Zeng
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
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Biswas N, Mori T, Ragava Chetty Nagaraj NK, Xin H, Diemer T, Li P, Su Y, Piermarocchi C, Ferrara N. Adenosine diphosphate stimulates VEGF-independent choroidal endothelial cell proliferation: A potential escape from anti-VEGF therapy. Proc Natl Acad Sci U S A 2025; 122:e2418752122. [PMID: 39835893 PMCID: PMC11789014 DOI: 10.1073/pnas.2418752122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Accepted: 12/10/2024] [Indexed: 01/22/2025] Open
Abstract
We hypothesized that a strategy employing tissue-specific endothelial cells (EC) might facilitate the identification of tissue- or organ-specific vascular functions of ubiquitous metabolites. An unbiased approach was employed to identify water-soluble small molecules with mitogenic activity on choroidal EC. We identified adenosine diphosphate (ADP) as a candidate, following biochemical purification from mouse EL4 lymphoma extracts. ADP stimulated the growth of bovine choroidal EC (BCEC) and other bovine or human eye-derived EC. ADP induced rapid phosphorylation of extracellular signal-regulated kinase in a dose- and time-dependent manner. ADP-induced BCEC proliferation could be blocked by pretreatment with specific antagonists of the purinergic receptor P2Y1 but not with a vascular endothelial growth factor (VEGF) inhibitor, indicating that the EC mitogenic effects of ADP are not mediated by stimulation of the VEGF pathway. Intravitreal administration of ADP expanded the neovascular area in a mouse model of choroidal neovascularization. Single-cell transcriptomics from human choroidal datasets show the expression of P2RY1, but not other ADP receptors, in EC with a pattern similar to VEGFR2. Although ADP has been reported to be a growth inhibitor for vascular EC, here we describe its growth-stimulating effects for BCEC and other eye-derived EC.
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Affiliation(s)
- Nilima Biswas
- Department of Pathology, University of California San Diego, La Jolla, CA92093
| | - Tommaso Mori
- Department of Pathology, University of California San Diego, La Jolla, CA92093
| | | | - Hong Xin
- Department of Pathology, University of California San Diego, La Jolla, CA92093
| | - Tanja Diemer
- Department of Pathology, University of California San Diego, La Jolla, CA92093
| | - Pin Li
- Department of Pathology, University of California San Diego, La Jolla, CA92093
| | - Yongxuan Su
- Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA92093
| | - Carlo Piermarocchi
- Department of Physics and Astronomy, Michigan State University, East Lansing, MI48824
| | - Napoleone Ferrara
- Department of Pathology, University of California San Diego, La Jolla, CA92093
- Department of Ophthalmology, University of California San Diego, La Jolla, CA92093
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Gibert-Ramos A, Andrés-Rozas M, Pastó R, Alfaro-Retamero P, Guixé-Muntet S, Gracia-Sancho J. Sinusoidal communication in chronic liver disease. Clin Mol Hepatol 2025; 31:32-55. [PMID: 39355871 PMCID: PMC11791556 DOI: 10.3350/cmh.2024.0734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 09/24/2024] [Accepted: 10/02/2024] [Indexed: 10/03/2024] Open
Abstract
The liver sinusoid, mainly composed of liver sinusoidal endothelial cells, hepatic macrophages and hepatic stellate cells, shapes the hepatic vasculature and is key to maintaining liver homeostasis and function. During chronic liver disease (CLD), the function of sinusoidal cells is impaired, being directly involved in the progression of liver fibrosis, cirrhosis, and main clinical complications including portal hypertension and hepatocellular carcinoma. In addition to their roles in liver diseases pathobiology, sinusoidal cells' paracrine communication or cross-talk is being studied as a mechanism of disease but also as a remarkable target for treatment. The aim of this review is to gather current knowledge of intercellular signalling in the hepatic sinusoid during the progression of liver disease. We summarise studies developed in pre-clinical models of CLD, especially emphasizing those pathways characterized in human-based clinically relevant models. Finally, we describe pharmacological treatments targeting sinusoidal communication as promising options to treat CLD and its clinical complications.
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Affiliation(s)
- Albert Gibert-Ramos
- Liver Vascular Biology Research Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - María Andrés-Rozas
- Liver Vascular Biology Research Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Barcelona, Spain
| | - Raül Pastó
- Liver Vascular Biology Research Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Barcelona, Spain
| | - Pablo Alfaro-Retamero
- Liver Vascular Biology Research Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Barcelona, Spain
| | - Sergi Guixé-Muntet
- Liver Vascular Biology Research Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Jordi Gracia-Sancho
- Liver Vascular Biology Research Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
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5
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Qian Y, Zhao J, Wu H, Kong X. Innate immune regulation in inflammation resolution and liver regeneration in drug-induced liver injury. Arch Toxicol 2025; 99:115-126. [PMID: 39395921 DOI: 10.1007/s00204-024-03886-0] [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: 08/25/2024] [Accepted: 10/02/2024] [Indexed: 10/14/2024]
Abstract
Drug-induced liver injury (DILI) is an acute liver injury that poses a significant threat to human health. In severe cases, it can progress into chronic DILI or even lead to liver failure. DILI is typically caused by either intrinsic hepatotoxicity or idiosyncratic metabolic or immune responses. In addition to the direct damage drugs inflict on hepatocytes, the immune responses and liver inflammation triggered by hepatocyte death can further exacerbate DILI. Initially, we briefly discussed the differences in immune cell activation based on the type of liver cell death (hepatocytes, cholangiocytes, and LSECs). We then focused on the role of various immune cells (including macrophages, monocytes, neutrophils, dendritic cells, liver sinusoidal endothelial cells, eosinophils, natural killer cells, and natural killer T cells) in both the liver injury and liver regeneration stages of DILI. This article primarily reviews the role of innate immune regulation mediated by these immune cells in resolving inflammation and promoting liver regeneration during DILI, as well as therapeutic approaches targeting these immune cells for the treatment of DILI. Finally, we discussed the activation and function of liver progenitor cells (LPCs) during APAP-induced massive hepatic necrosis and the involvement of chronic inflammation in DILI.
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Affiliation(s)
- Yihan Qian
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, China
| | - Jie Zhao
- Department of Liver Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Hailong Wu
- Shanghai Key Laboratory of Molecular Imaging, Collaborative Innovation Center for Biomedicines, Shanghai University of Medicine and Health Sciences, Shanghai, China.
| | - Xiaoni Kong
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, China.
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Godiyal Y, Maheshwari D, Taniguchi H, Zinzuwadia SS, Morera-Díaz Y, Tewari D, Bishayee A. Role of PD-1/PD-L1 signaling axis in oncogenesis and its targeting by bioactive natural compounds for cancer immunotherapy. Mil Med Res 2024; 11:82. [PMID: 39690423 DOI: 10.1186/s40779-024-00586-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Accepted: 11/29/2024] [Indexed: 12/19/2024] Open
Abstract
Cancer is a global health problem and one of the leading causes of mortality. Immune checkpoint inhibitors have revolutionized the field of oncology, emerging as a powerful treatment strategy. A key pathway that has garnered considerable attention is programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1). The interaction between PD-L1 expressed on tumor cells and PD-1 reduces the innate immune response and thus compromises the capability of the body's immune system. Furthermore, it controls the phenotype and functionality of innate and adaptive immune components. A range of monoclonal antibodies, including avelumab, atezolizumab, camrelizumab, dostarlimab, durvalumab, sinitilimab, toripalimab, and zimberelimab, have been developed for targeting the interaction between PD-1 and PD-L1. These agents can induce a broad spectrum of autoimmune-like complications that may affect any organ system. Recent studies have focused on the effect of various natural compounds that inhibit immune checkpoints. This could contribute to the existing arsenal of anticancer drugs. Several bioactive natural agents have been shown to affect the PD-1/PD-L1 signaling axis, promoting tumor cell apoptosis, influencing cell proliferation, and eventually leading to tumor cell death and inhibiting cancer progression. However, there is a substantial knowledge gap regarding the role of different natural compounds targeting PD-1 in the context of cancer. Hence, this review aims to provide a common connection between PD-1/PD-L1 blockade and the anticancer effects of distinct natural molecules. Moreover, the primary focus will be on the underlying mechanism of action as well as the clinical efficacy of bioactive molecules. Current challenges along with the scope of future research directions targeting PD-1/PD-L1 interactions through natural substances are also discussed.
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Affiliation(s)
- Yogesh Godiyal
- Department of Pharmacognosy and Phytochemistry, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, New Delhi, 110017, India
| | - Drishti Maheshwari
- Department of Pharmacognosy and Phytochemistry, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, New Delhi, 110017, India
| | - Hiroaki Taniguchi
- Department of Experimental Embryology, Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, Jastrzebiec, 05-552, Magdalenka, Poland
- African Genome Center, Mohammed VI Polytechnic University, Hay Moulay Rachid, 43150, Ben Guerir, Morocco
| | - Shweta S Zinzuwadia
- Department of Pharmacology, College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL, 34211, USA
| | - Yanelys Morera-Díaz
- Clinical Investigation and Biomedical Research Directions, Center for Genetic Engineering and Biotechnology, 11600, Havana, Cuba
| | - Devesh Tewari
- Department of Pharmacognosy and Phytochemistry, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, New Delhi, 110017, India.
| | - Anupam Bishayee
- Department of Pharmacology, College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL, 34211, USA.
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Mori T, Naresh Kumar RN, Ferrara N. Elucidating VEGF Biology: A Journey of Discovery and Clinical Translation. Arterioscler Thromb Vasc Biol 2024; 44:2361-2365. [PMID: 39602505 PMCID: PMC11606529 DOI: 10.1161/atvbaha.124.319574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Affiliation(s)
- Tommaso Mori
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
- Department of Pathology, University of California, San Diego, La Jolla, CA, USA
| | - R. N. Naresh Kumar
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
- Department of Pathology, University of California, San Diego, La Jolla, CA, USA
| | - Napoleone Ferrara
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
- Department of Pathology, University of California, San Diego, La Jolla, CA, USA
- Department of Ophthalmology, University of California San Diego, La Jolla, CA, USA
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Kasahara N, Teratani T, Doi J, Yokota S, Shimodaira K, Kaneko Y, Ohzawa H, Sakuma Y, Sasanuma H, Fujimoto Y, Urahashi T, Yoshitomi H, Yamaguchi H, Kitayama J, Sata N. Controlled release of hydrogel-encapsulated mesenchymal stem cells-conditioned medium promotes functional liver regeneration after hepatectomy in metabolic dysfunction-associated steatotic liver disease. Stem Cell Res Ther 2024; 15:395. [PMID: 39497124 PMCID: PMC11536549 DOI: 10.1186/s13287-024-03993-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Accepted: 10/10/2024] [Indexed: 11/06/2024] Open
Abstract
BACKGROUND Globally, prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing, and there is an urgent need to develop innovative therapies that promote liver regeneration following hepatectomy for this disease. Surgical excision is a key therapeutic approach with curative potential for liver tumors. However, hepatic steatosis can lead to delayed liver regeneration and higher post-operative complication risk. Mesenchymal stem cells-conditioned medium (MSC-CM) is considered a rich source of paracrine factors that can repair tissues and restore function of damaged organs. Meanwhile, hydrogels have been widely recognized to load MSC secretome and achieve sustained release. This study aimed to evaluate the therapeutic effect of hydrogel-encapsulated MSC-CM on liver regeneration following partial hepatectomy (PHx) in a rodent model of diet-induced hepatic steatosis. METHODS Male Lewis rats were fed with a methionine and choline-deficient diet. After 3 weeks of feeding, PHx was performed and rats were randomly allocated into two groups that received hydrogel-encapsulated MSC-CM or vehicle via the intra-mesenteric space of the superior mesenteric vein (SMV). RESULTS The regeneration of the remnant liver at 30 and 168 h after PHx was significantly accelerated, and the expressions of proliferating cell nuclear antigen were significantly enhanced in the MSC-CM group. MSC-CM treatment significantly increased hepatic ATP and β-hydroxybutyrate content at 168 h after PHx, indicating that MSC-CM fosters regeneration not only in volume but also in functionality. The number of each TUNEL- and cleaved caspase-3 positive nuclei in hepatocytes at 9 h after PHx were significantly decreased in the MSC-CM group, suggesting that MSC-CM suppressed apoptosis. MSC-CM increased serum immunoregulatory cytokine interleukin-10 and interleukin-13 at 30 h after PHx. Additionally, mitotic figures and cyclin D1 expression decreased and hepatocyte size increased in the MSC-CM group, implying that this mode of regeneration was mainly through cell hypertrophy rather than cell division. CONCLUSIONS MSC-CM represents a novel therapeutic approach for patients with MASLD requiring PHx.
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Affiliation(s)
- Naoya Kasahara
- Department of Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Takumi Teratani
- Division of Translational Research, Jichi Medical University, Shimotsuke, Japan.
| | - Junshi Doi
- Department of Surgery, Japanese Red Cross Otsu Hospital, Otsu, Japan
| | | | | | - Yuki Kaneko
- Department of Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Hideyuki Ohzawa
- Department of Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Yasunaru Sakuma
- Department of Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Hideki Sasanuma
- Department of Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Yasuhiro Fujimoto
- Department of Transplant Surgery, Nagoya University Hospital, Nagoya, Japan
| | - Taizen Urahashi
- Department of Surgery, Dokkyo Medical University Saitama Medical Center, Koshigaya, Japan
| | - Hideyuki Yoshitomi
- Department of Surgery, Dokkyo Medical University Saitama Medical Center, Koshigaya, Japan
| | | | - Joji Kitayama
- Department of Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Naohiro Sata
- Department of Surgery, Jichi Medical University, Shimotsuke, Japan
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9
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Gao J, Lan T, Kostallari E, Guo Y, Lai E, Guillot A, Ding B, Tacke F, Tang C, Shah VH. Angiocrine signaling in sinusoidal homeostasis and liver diseases. J Hepatol 2024; 81:543-561. [PMID: 38763358 PMCID: PMC11906189 DOI: 10.1016/j.jhep.2024.05.014] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 04/29/2024] [Accepted: 05/10/2024] [Indexed: 05/21/2024]
Abstract
The hepatic sinusoids are composed of liver sinusoidal endothelial cells (LSECs), which are surrounded by hepatic stellate cells (HSCs) and contain liver-resident macrophages called Kupffer cells, and other patrolling immune cells. All these cells communicate with each other and with hepatocytes to maintain sinusoidal homeostasis and a spectrum of hepatic functions under healthy conditions. Sinusoidal homeostasis is disrupted by metabolites, toxins, viruses, and other pathological factors, leading to liver injury, chronic liver diseases, and cirrhosis. Alterations in hepatic sinusoids are linked to fibrosis progression and portal hypertension. LSECs are crucial regulators of cellular crosstalk within their microenvironment via angiocrine signaling. This review discusses the mechanisms by which angiocrine signaling orchestrates sinusoidal homeostasis, as well as the development of liver diseases. Here, we summarise the crosstalk between LSECs, HSCs, hepatocytes, cholangiocytes, and immune cells in health and disease and comment on potential novel therapeutic methods for treating liver diseases.
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Affiliation(s)
- Jinhang Gao
- Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Tian Lan
- Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China; Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Enis Kostallari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Yangkun Guo
- Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Enjiang Lai
- Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Adrien Guillot
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Bisen Ding
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany.
| | - Chengwei Tang
- Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China.
| | - Vijay H Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
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10
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Perez-Gutierrez L, Li P, Ferrara N. Endothelial cell diversity: the many facets of the crystal. FEBS J 2024; 291:3287-3302. [PMID: 36266750 DOI: 10.1111/febs.16660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 10/03/2022] [Accepted: 10/19/2022] [Indexed: 11/06/2022]
Abstract
Endothelial cells (ECs) form the inner lining of blood vessels and play crucial roles in angiogenesis. While it has been known for a long time that there are considerable differences among ECs from lymphatic and blood vessels, as well as among arteries, veins and capillaries, the full repertoire of endothelial diversity is only beginning to be elucidated. It has become apparent that the role of ECs is not just limited to their exchange functions. Indeed, a multitude of organ-specific functions, including release of growth factors, regulation of immune functions, have been linked to ECs. Recent years have seen a surge into the identification of spatiotemporal molecular and functional heterogeneity of ECs, supported by technologies such as single-cell RNA sequencing (scRNA-seq), lineage tracing and intersectional genetics. Together, these techniques have spurred the generation of epigenomic, transcriptomic and proteomic signatures of ECs. It is now clear that ECs across organs and in different vascular beds, but even within the same vessel, have unique molecular identities and employ specialized molecular mechanisms to fulfil highly specialized needs. Here, we focus on the molecular heterogeneity of the endothelium in different organs and pathological conditions.
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Affiliation(s)
- Lorena Perez-Gutierrez
- Department of Pathology, Moores Cancer Center, University of California, San Diego, CA, USA
| | - Pin Li
- Department of Pathology, Moores Cancer Center, University of California, San Diego, CA, USA
| | - Napoleone Ferrara
- Department of Pathology, Moores Cancer Center, University of California, San Diego, CA, USA
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11
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Gazzini S, Cerullo R, Soloperto D. VEGF as a Key Actor in Recurrent Respiratory Papillomatosis: A Narrative Review. Curr Issues Mol Biol 2024; 46:6757-6768. [PMID: 39057045 PMCID: PMC11275356 DOI: 10.3390/cimb46070403] [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: 05/17/2024] [Revised: 06/20/2024] [Accepted: 06/25/2024] [Indexed: 07/28/2024] Open
Abstract
Recurrent respiratory papillomatosis (RRP) is a benign disease of the upper aerodigestive tract caused by human papillomavirus (HPV) types 6 and 11. The clinical course is unpredictable and some patients, especially younger children, experience a high rate of recurrence with a significant impact on their quality of life. The molecular mechanisms of HPV infection in keratinocytes have been extensively studied throughout the years, with particular regard to its role in causing malignant tumors, like cervical cancer and head and neck carcinomas. A minor but not negligible amount of the literature has investigated the molecular landscape of RRP patients, and some papers have studied the role of angiogenesis (the growth of blood vessels from pre-existing vasculature) in this disease. A central role in this process is played by vascular endothelial growth factor (VEGF), which activates different signaling cascades on multiple levels. The increased knowledge has led to the introduction of the VEGF inhibitor bevacizumab in recent years as an adjuvant treatment in some patients, with good results. This review summarizes the current evidence about the role of VEGF in the pathophysiology of RRP, the molecular pathways activated by binding with its receptors, and the current and future roles of anti-angiogenic treatment.
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Affiliation(s)
- Sandra Gazzini
- Division of Otolaryngology, Head and Neck Surgery Department, University Hospital of Verona, 37134 Verona, Italy
| | - Raffaele Cerullo
- Division of Otolaryngology, Hospital of Treviso, 31100 Treviso, Italy
| | - Davide Soloperto
- Department of Otorhinolaryngology, University Hospital of Modena, 41125 Modena, Italy
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12
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Wang Y, Piao C, Liu T, Lu X, Ma Y, Zhang J, Ma H, Wang H. Exosomes Derived from Adipose Mesenchymal Stem Cells Promote Regeneration of Injured Liver in Minipigs. Int J Mol Sci 2024; 25:6604. [PMID: 38928308 PMCID: PMC11203699 DOI: 10.3390/ijms25126604] [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: 04/28/2024] [Revised: 06/04/2024] [Accepted: 06/11/2024] [Indexed: 06/28/2024] Open
Abstract
Hepatic ischemia/reperfusion injury (IRI) is an important factor affecting liver regeneration and functional recovery postoperatively. Many studies have suggested that mesenchymal stem cells (MSCs) contribute to hepatic tissue repair and functional recovery through paracrine mechanisms mediated by exosomes. Minipigs exhibit much more similar characteristics of the liver to those of humans than rodents. This study aimed to explore whether exosomes from adipose-derived MSCs (ADSCs-exo) could actively promote liver regeneration after hepatectomy combined with HIRI in minipigs and the role they play in the cell proliferation process. This study also compared the effects and differences in the role of ADSCs and ADSCs-exo in the inflammatory response and liver regeneration. The results showed that ADSCs-exo suppressed histopathological changes and reduced inflammatory infiltration in the liver; significantly decreased levels of ALT, TBIL, HA, and the pro-inflammatory cytokines TNF-α, IL-6, and CRP; increased levels of the anti-inflammatory cytokine IL-10 and the pro-regeneration factors Ki67, PCNA, CyclinD1, HGF, STAT3, VEGF, ANG1, ANG2; and decreased levels of the anti-regeneration factors SOCS3 and TGF-β. These indicators above showed similar changes with the ADSCs intervention group. Indicating that ADSCs-exo can exert the same role as ADSCs in regulating inflammatory responses and promoting liver regeneration. Our findings provide experimental evidence for the possibility that ADSCs-exo could be considered a safe and effective cell-free therapy to promote regeneration of injured livers.
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Affiliation(s)
| | | | | | | | | | | | | | - Hongbin Wang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China; (Y.W.); (C.P.); (T.L.); (X.L.); (Y.M.); (J.Z.); (H.M.)
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13
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Srkalovic G, Nijim S, Srkalovic MB, Fajgenbaum D. Increase in Vascular Endothelial Growth Factor (VEGF) Expression and the Pathogenesis of iMCD-TAFRO. Biomedicines 2024; 12:1328. [PMID: 38927535 PMCID: PMC11201201 DOI: 10.3390/biomedicines12061328] [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: 04/30/2024] [Revised: 05/31/2024] [Accepted: 06/06/2024] [Indexed: 06/28/2024] Open
Abstract
TAFRO (thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (F/R), renal failure (R), and organomegaly (O)) is a heterogeneous clinical subtype of idiopathic multicentric Castleman disease (iMCD) associated with a significantly poorer prognosis than other subtypes of iMCD. TAFRO symptomatology can also be seen in pathological contexts outside of iMCD, but it is unclear if those cases should be considered representative of a different disease entity or simply a severe presentation of other infectious, malignant, and rheumatological diseases. While interleukin-6 (IL-6) is an established driver of iMCD-TAFRO pathogenesis in a subset of patients, the etiology is unknown. Recent case reports and literature reviews on TAFRO patients suggest that vascular endothelial growth factor (VEGF), and the interplay of VEGF and IL-6 in concert, rather than IL-6 as a single cytokine, may be drivers for iMCD-TAFRO pathophysiology, especially renal injury. In this review, we discuss the possible role of VEGF in the pathophysiology and clinical manifestations of iMCD-TAFRO. In particular, VEGF may be involved in iMCD-TAFRO pathology through its ability to activate RAS/RAF/MEK/ERK and PI3K/AKT/mTOR signaling pathways. Further elucidating a role for the VEGF-IL-6 axis and additional disease drivers may shed light on therapeutic options for the treatment of TAFRO patients who do not respond to, or otherwise relapse following, treatment with IL-6 targeting drugs. This review investigates the potential role of VEGF in the pathophysiology of iMCD-TAFRO and the potential for targeting related signaling pathways in the future.
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Affiliation(s)
- Gordan Srkalovic
- Herbert-Herman Cancer Center, University of Michigan Health-Sparrow, Lansing, MI 48912, USA
| | - Sally Nijim
- Center for Cytokine Storm Treatment & Laboratory, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; (S.N.); (D.F.)
| | | | - David Fajgenbaum
- Center for Cytokine Storm Treatment & Laboratory, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; (S.N.); (D.F.)
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14
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Long L, Fei X, Chen L, Yao L, Lei X. Potential therapeutic targets of the JAK2/STAT3 signaling pathway in triple-negative breast cancer. Front Oncol 2024; 14:1381251. [PMID: 38699644 PMCID: PMC11063389 DOI: 10.3389/fonc.2024.1381251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Accepted: 04/08/2024] [Indexed: 05/05/2024] Open
Abstract
Triple-negative breast cancer (TNBC) poses a significant clinical challenge due to its propensity for metastasis and poor prognosis. TNBC evades the body's immune system recognition and attack through various mechanisms, including the Janus Kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. This pathway, characterized by heightened activity in numerous solid tumors, exhibits pronounced activation in specific TNBC subtypes. Consequently, targeting the JAK2/STAT3 signaling pathway emerges as a promising and precise therapeutic strategy for TNBC. The signal transduction cascade of the JAK2/STAT3 pathway predominantly involves receptor tyrosine kinases, the tyrosine kinase JAK2, and the transcription factor STAT3. Ongoing preclinical studies and clinical research are actively investigating this pathway as a potential therapeutic target for TNBC treatment. This article comprehensively reviews preclinical and clinical investigations into TNBC treatment by targeting the JAK2/STAT3 signaling pathway using small molecule compounds. The review explores the role of the JAK2/STAT3 pathway in TNBC therapeutics, evaluating the benefits and limitations of active inhibitors and proteolysis-targeting chimeras in TNBC treatment. The aim is to facilitate the development of novel small-molecule compounds that target TNBC effectively. Ultimately, this work seeks to contribute to enhancing therapeutic efficacy for patients with TNBC.
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Affiliation(s)
- Lin Long
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, China
- The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Xiangyu Fei
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, China
| | - Liucui Chen
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, China
| | - Liang Yao
- Department of Pharmacy, Central Hospital of Hengyang, Hengyang, China
| | - Xiaoyong Lei
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, China
- The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China
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15
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Furtado J, Eichmann A. Vascular development, remodeling and maturation. Curr Top Dev Biol 2024; 159:344-370. [PMID: 38729681 DOI: 10.1016/bs.ctdb.2024.02.001] [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] [Indexed: 05/12/2024]
Abstract
The development of the vascular system is crucial in supporting the growth and health of all other organs in the body, and vascular system dysfunction is the major cause of human morbidity and mortality. This chapter discusses three successive processes that govern vascular system development, starting with the differentiation of the primitive vascular system in early embryonic development, followed by its remodeling into a functional circulatory system composed of arteries and veins, and its final maturation and acquisition of an organ specific semi-permeable barrier that controls nutrient uptake into tissues and hence controls organ physiology. Along these steps, endothelial cells forming the inner lining of all blood vessels acquire extensive heterogeneity in terms of gene expression patterns and function, that we are only beginning to understand. These advances contribute to overall knowledge of vascular biology and are predicted to unlock the unprecedented therapeutic potential of the endothelium as an avenue for treatment of diseases associated with dysfunctional vasculature.
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Affiliation(s)
- Jessica Furtado
- Department of Molecular and Cellular Physiology, Yale University School of Medicine, New Haven, CT, United States; Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, United States
| | - Anne Eichmann
- Department of Molecular and Cellular Physiology, Yale University School of Medicine, New Haven, CT, United States; Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, United States; Paris Cardiovascular Research Center, Inserm U970, Université Paris, Paris, France.
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16
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Fernández-Iglesias A, Gracia-Sancho J. Role of liver sinusoidal endothelial cells in the diagnosis and treatment of liver diseases. SINUSOIDAL CELLS IN LIVER DISEASES 2024:467-481. [DOI: 10.1016/b978-0-323-95262-0.00023-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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17
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Tavakoli Pirzaman A, Alishah A, Babajani B, Ebrahimi P, Sheikhi SA, Moosaei F, Salarfar A, Doostmohamadian S, Kazemi S. The Role of microRNAs in Hepatocellular Cancer: A Narrative Review Focused on Tumor Microenvironment and Drug Resistance. Technol Cancer Res Treat 2024; 23:15330338241239188. [PMID: 38634139 PMCID: PMC11025440 DOI: 10.1177/15330338241239188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 01/26/2024] [Accepted: 02/26/2024] [Indexed: 04/19/2024] Open
Abstract
Globally, hepatic cancer ranks fourth in terms of cancer-related mortality and is the sixth most frequent kind of cancer. Around 80% of liver cancers are hepatocellular carcinomas (HCC), which are the leading cause of cancer death. It is well known that HCC may develop resistance to the available chemotherapy treatments very fast. One of the biggest obstacles in providing cancer patients with appropriate care is drug resistance. According to reports, more than 90% of cancer-specific fatalities are caused by treatment resistance. By binding to the 3'-untranslated region of target messenger RNAs (mRNAs), microRNAs (miRNAs), a group of noncoding RNAs which are around 17 to 25 nucleotides long, regulate target gene expression. Moreover, they play role in the control of signaling pathways, cell proliferation, and cell death. As a result, miRNAs play an important role in the microenvironment of HCC by changing immune phenotypes, hypoxic conditions, and acidification, as well as angiogenesis and extracellular matrix components. Moreover, changes in miRNA levels in HCC can effectively resist cancer cells to chemotherapy by affecting various cellular processes such as autophagy, apoptosis, and membrane transporter activity. In the current work, we narratively reviewed the role of miRNAs in HCC, with a special focus on tumor microenvironment and drug resistance.
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Affiliation(s)
| | - Ali Alishah
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Bahareh Babajani
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Pouyan Ebrahimi
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Seyyed Ali Sheikhi
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Farhad Moosaei
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | | | | | - Sohrab Kazemi
- Cellular and Molecular Biology Research Center, Health Research Center, Babol University of Medical Sciences, Babol, Iran
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18
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Ren X, Deng L, Dong X, Bai Y, Li G, Wang Y. Adverse reactions of immune checkpoint inhibitors combined with angiogenesis inhibitors: A pharmacovigilance analysis of drug-drug interactions. Int J Immunopathol Pharmacol 2024; 38:3946320241305390. [PMID: 39660594 PMCID: PMC11632882 DOI: 10.1177/03946320241305390] [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: 04/27/2024] [Accepted: 11/20/2024] [Indexed: 12/12/2024] Open
Abstract
The combination of immune checkpoint inhibitors (ICIs) and angiogenesis inhibitors (AGIs) is widely used in cancer treatment; however, drug-drug reactions (DDIs) remain unknown. We aimed to identify interaction signals for the concomitant use of ICIs and AGIs. Data were obtained from the US FDA Adverse Event Reporting System (FAERS) from January 1, 2015, to December 31, 2023. Disproportionality analysis was used for data mining by calculating the reporting odds ratio (ROR) and 95% confidence interval (95% CI). Adjusted RORs were analysed using logistic regression analysis, considering age, sex and reporting year. Further confirmation was assessed via additive and multiplicative models. We identified 75,936 reports on ICIs combined with AGIs. Significant interaction signals were observed for hepatobiliary disorders (RORcrude: 5.25, 95% CI: 5.07-5.44, RORadj: 5.01, 95% CI: 4.82-5.22, additive models: 0.2323), investigations (RORcrude: 1.66, 95% CI: 1.62-1.70, RORadj: 1.63, 95% CI: 1.58-1.67, additive models: 0.2187, multiplicative models: 1.1265), renal and urinary disorders (RORcrude: 1.87, 95% CI: 1.80-1.95, RORadj: 1.72, 95% CI: 1.64-1.79, additive models: 0.3239, multiplicative models: 1.1799) and vascular disorders (RORcrude: 1.94, 95% CI: 1.87-2.02, RORadj: 1.87, 95% CI: 1.80-1.95, additive models: 0.5823, multiplicative models: 1.5676). Subset data analysis showed positive interaction signals for PDL-1/CTLA-4 inhibitors + AGI in hepatobiliary disorders, PD-1 inhibitors + AGI in investigations, or PD-1/PDL-1 inhibitors + AGI in renal and urinary/ vascular disorders. Based on FAERS data, four systemic disorders were identified as having DDIs related to the combined use of ICIs and AGIs. Pre-clinical trials are required to explore the mechanisms underlying these interactions.
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Affiliation(s)
- Xiayang Ren
- Department of Pharmacy, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lei Deng
- Department of Radiation Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xin Dong
- Department of Clinical Laboratory, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ying Bai
- Clinical Trials Center, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Guohui Li
- Department of Pharmacy, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yanfeng Wang
- Department of Comprehensive Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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19
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Rizvi F, Lee YR, Diaz-Aragon R, Bawa PS, So J, Florentino RM, Wu S, Sarjoo A, Truong E, Smith AR, Wang F, Everton E, Ostrowska A, Jung K, Tam Y, Muramatsu H, Pardi N, Weissman D, Soto-Gutierrez A, Shin D, Gouon-Evans V. VEGFA mRNA-LNP promotes biliary epithelial cell-to-hepatocyte conversion in acute and chronic liver diseases and reverses steatosis and fibrosis. Cell Stem Cell 2023; 30:1640-1657.e8. [PMID: 38029740 PMCID: PMC10843608 DOI: 10.1016/j.stem.2023.10.008] [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: 08/29/2022] [Revised: 09/07/2023] [Accepted: 10/31/2023] [Indexed: 12/01/2023]
Abstract
The liver is known for its remarkable regenerative ability through proliferation of hepatocytes. Yet, during chronic injury or severe hepatocyte death, proliferation of hepatocytes is exhausted. To overcome this hurdle, we propose vascular-endothelial-growth-factor A (VEGFA) as a therapeutic means to accelerate biliary epithelial-cell (BEC)-to-hepatocyte conversion. Investigation in zebrafish establishes that blocking VEGF receptors abrogates BEC-driven liver repair, while VEGFA overexpression promotes it. Delivery of VEGFA via nonintegrative and safe nucleoside-modified mRNA encapsulated into lipid nanoparticles (mRNA-LNPs) in acutely or chronically injured mouse livers induces robust BEC-to-hepatocyte conversion and elimination of steatosis and fibrosis. In human and murine diseased livers, we further identified VEGFA-receptor KDR-expressing BECs associated with KDR-expressing cell-derived hepatocytes. This work defines KDR-expressing cells, most likely being BECs, as facultative progenitors. This study reveals unexpected therapeutic benefits of VEGFA delivered via nucleoside-modified mRNA-LNP, whose safety is widely validated with COVID-19 vaccines, for harnessing BEC-driven repair to potentially treat liver diseases.
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Affiliation(s)
- Fatima Rizvi
- Center for Regenerative Medicine, Department of Medicine, Section of Gastroenterology, Boston University and Boston Medical Center, Boston, MA 02118, USA
| | - Yu-Ri Lee
- Department of Developmental Biology, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA
| | - Ricardo Diaz-Aragon
- Department of Pathology, Center for Transcriptional Medicine, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Pushpinder S Bawa
- Center for Regenerative Medicine, Department of Medicine, Section of Gastroenterology, Boston University and Boston Medical Center, Boston, MA 02118, USA
| | - Juhoon So
- Department of Developmental Biology, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA
| | - Rodrigo M Florentino
- Department of Pathology, Center for Transcriptional Medicine, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Susan Wu
- Center for Regenerative Medicine, Department of Medicine, Section of Gastroenterology, Boston University and Boston Medical Center, Boston, MA 02118, USA
| | - Arianna Sarjoo
- Center for Regenerative Medicine, Department of Medicine, Section of Gastroenterology, Boston University and Boston Medical Center, Boston, MA 02118, USA
| | - Emily Truong
- Center for Regenerative Medicine, Department of Medicine, Section of Gastroenterology, Boston University and Boston Medical Center, Boston, MA 02118, USA
| | - Anna R Smith
- Center for Regenerative Medicine, Department of Medicine, Section of Gastroenterology, Boston University and Boston Medical Center, Boston, MA 02118, USA
| | - Feiya Wang
- Center for Regenerative Medicine, Department of Medicine, Section of Gastroenterology, Boston University and Boston Medical Center, Boston, MA 02118, USA
| | - Elissa Everton
- Center for Regenerative Medicine, Department of Medicine, Section of Gastroenterology, Boston University and Boston Medical Center, Boston, MA 02118, USA
| | - Alina Ostrowska
- Department of Pathology, Center for Transcriptional Medicine, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Kyounghwa Jung
- Department of Developmental Biology, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA
| | - Ying Tam
- Acuitas Therapeutics, Vancouver, BC V6T 1Z3, Canada
| | - Hiromi Muramatsu
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Norbert Pardi
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Drew Weissman
- Department of Medicine, Infectious Diseases Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 10104, USA
| | - Alejandro Soto-Gutierrez
- Department of Pathology, Center for Transcriptional Medicine, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Donghun Shin
- Department of Developmental Biology, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA
| | - Valerie Gouon-Evans
- Center for Regenerative Medicine, Department of Medicine, Section of Gastroenterology, Boston University and Boston Medical Center, Boston, MA 02118, USA.
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20
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Pérez-Gutiérrez L, Ferrara N. Biology and therapeutic targeting of vascular endothelial growth factor A. Nat Rev Mol Cell Biol 2023; 24:816-834. [PMID: 37491579 DOI: 10.1038/s41580-023-00631-w] [Citation(s) in RCA: 153] [Impact Index Per Article: 76.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/16/2023] [Indexed: 07/27/2023]
Abstract
The formation of new blood vessels, called angiogenesis, is an essential pathophysiological process in which several families of regulators have been implicated. Among these, vascular endothelial growth factor A (VEGFA; also known as VEGF) and its two tyrosine kinase receptors, VEGFR1 and VEGFR2, represent a key signalling pathway mediating physiological angiogenesis and are also major therapeutic targets. VEGFA is a member of the gene family that includes VEGFB, VEGFC, VEGFD and placental growth factor (PLGF). Three decades after its initial isolation and cloning, VEGFA is arguably the most extensively investigated signalling system in angiogenesis. Although many mediators of angiogenesis have been identified, including members of the FGF family, angiopoietins, TGFβ and sphingosine 1-phosphate, all current FDA-approved anti-angiogenic drugs target the VEGF pathway. Anti-VEGF agents are widely used in oncology and, in combination with chemotherapy or immunotherapy, are now the standard of care in multiple malignancies. Anti-VEGF drugs have also revolutionized the treatment of neovascular eye disorders such as age-related macular degeneration and ischaemic retinal disorders. In this Review, we emphasize the molecular, structural and cellular basis of VEGFA action as well as recent findings illustrating unexpected interactions with other pathways and provocative reports on the role of VEGFA in regenerative medicine. We also discuss clinical and translational aspects of VEGFA. Given the crucial role that VEGFA plays in regulating angiogenesis in health and disease, this molecule is largely the focus of this Review.
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Affiliation(s)
- Lorena Pérez-Gutiérrez
- Department of Pathology, University of California San Diego, La Jolla, CA, USA
- Department of Ophthalmology, University of California San Diego, La Jolla, CA, USA
- Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
| | - Napoleone Ferrara
- Department of Pathology, University of California San Diego, La Jolla, CA, USA.
- Department of Ophthalmology, University of California San Diego, La Jolla, CA, USA.
- Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
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21
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Shannon AH, Manne A, Diaz Pardo DA, Pawlik TM. Combined radiotherapy and immune checkpoint inhibition for the treatment of advanced hepatocellular carcinoma. Front Oncol 2023; 13:1193762. [PMID: 37554167 PMCID: PMC10405730 DOI: 10.3389/fonc.2023.1193762] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Accepted: 07/03/2023] [Indexed: 08/10/2023] Open
Abstract
Hepatocellular Carcinoma (HCC) is one of the most common cancers and a leading cause of cancer related death worldwide. Until recently, systemic therapy for advanced HCC, defined as Barcelona Clinic Liver Cancer (BCLC) stage B or C, was limited and ineffective in terms of long-term survival. However, over the past decade, immune check point inhibitors (ICI) combinations have emerged as a potential therapeutic option for patients with nonresectable disease. ICI modulate the tumor microenvironment to prevent progression of the tumor. Radiotherapy is a crucial tool in treating unresectable HCC and may enhance the efficacy of ICI by manipulating the tumor microenvironment and decreasing tumor resistance to certain therapies. We herein review developments in the field of ICI combined with radiotherapy for the treatment of HCC, as well as look at challenges associated with these treatment modalities, and review future directions of combination therapy.
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Affiliation(s)
- Alexander H. Shannon
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Ashish Manne
- Department of Internal Medicine, Division of Medical Oncology at the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States
| | - Dayssy A. Diaz Pardo
- Department of Radiation Oncology, The Ohio State University, Comprehensive Cancer Center-James Hospital and Solove Research Institute, Columbus, OH, United States
| | - Timothy M. Pawlik
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, United States
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22
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Kern AE, Ortmayr G, Assinger A, Starlinger P. The role of microRNAs in the different phases of liver regeneration. Expert Rev Gastroenterol Hepatol 2023; 17:959-973. [PMID: 37811642 DOI: 10.1080/17474124.2023.2267422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 10/03/2023] [Indexed: 10/10/2023]
Abstract
INTRODUCTION Since the first discovery of microRNAs (miRs) extensive evidence reveals their indispensable role in different patho-physiological processes. They are recognized as critical regulators of hepatic regeneration, as they modulate multiple complex signaling pathways affecting liver regeneration. MiR-related translational suppression and degradation of target mRNAs and proteins are not limited to one specific gene, but act on multiple targets. AREAS COVERED In this review, we are going to explore the role of miRs in the context of liver regeneration and discuss the regulatory effects attributed to specific miRs. Moreover, specific pathways crucial for liver regeneration will be discussed, with a particular emphasis on the involvement of miRs within the respective signaling cascades. EXPERT OPINION The considerable amount of studies exploring miR functions in a variety of diseases paved the way for the development of miR-directed therapeutics. Clinical implementation has already shown promising results, but additional research is warranted to assure safe and efficient delivery. Nevertheless, given the broad functional properties of miRs and their critical involvement during hepatic regeneration, they represent an attractive treatment target to promote liver recovery after hepatic resection.
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Affiliation(s)
- Anna Emilia Kern
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Gregor Ortmayr
- Center for Cancer Research, Medical University of Vienna, Vienna, Austria
| | - Alice Assinger
- Department of Vascular Biology and Thrombosis Research, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Patrick Starlinger
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
- Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, Mayo Clinic, Rochester, MN, USA
- Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
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Bishop D, Schwarz Q, Wiszniak S. Endothelial-derived angiocrine factors as instructors of embryonic development. Front Cell Dev Biol 2023; 11:1172114. [PMID: 37457293 PMCID: PMC10339107 DOI: 10.3389/fcell.2023.1172114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 06/19/2023] [Indexed: 07/18/2023] Open
Abstract
Blood vessels are well-known to play roles in organ development and repair, primarily owing to their fundamental function in delivering oxygen and nutrients to tissues to promote their growth and homeostasis. Endothelial cells however are not merely passive conduits for carrying blood. There is now evidence that endothelial cells of the vasculature actively regulate tissue-specific development, morphogenesis and organ function, as well as playing roles in disease and cancer. Angiocrine factors are growth factors, cytokines, signaling molecules or other regulators produced directly from endothelial cells to instruct a diverse range of signaling outcomes in the cellular microenvironment, and are critical mediators of the vascular control of organ function. The roles of angiocrine signaling are only beginning to be uncovered in diverse fields such as homeostasis, regeneration, organogenesis, stem-cell maintenance, cell differentiation and tumour growth. While in some cases the specific angiocrine factor involved in these processes has been identified, in many cases the molecular identity of the angiocrine factor(s) remain to be discovered, even though the importance of angiocrine signaling has been implicated. In this review, we will specifically focus on roles for endothelial-derived angiocrine signaling in instructing tissue morphogenesis and organogenesis during embryonic and perinatal development.
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24
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Deng W, Hu T, Xiong W, Jiang X, Cao Y, Li Z, Jiang H, Wang X. Soluble epoxide hydrolase deficiency promotes liver regeneration and ameliorates liver injury in mice by regulating angiocrine factors and angiogenesis. Biochim Biophys Acta Gen Subj 2023:130394. [PMID: 37315719 DOI: 10.1016/j.bbagen.2023.130394] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 05/21/2023] [Accepted: 05/24/2023] [Indexed: 06/16/2023]
Abstract
BACKGROUND Soluble epoxide hydrolase (sEH) is a key enzyme for the hydrolysis of epoxyeicosatrienoic acids (EETs) and has been implicated in the pathogenesis of hepatic inflammation, fibrosis, cancer, and nonalcoholic fatty liver disease. However, the role of sEH in liver regeneration and injury remains unclear. METHODS This study used sEH-deficient (sEH-/-) mice and wild-type (WT) mice. Hepatocyte proliferation was assessed by immunohistochemical (IHC) staining for Ki67. Liver injury was evaluated by histological staining with hematoxylin and eosin (H&E), Masson's trichrome, and Sirius red, as well as IHC staining for α-SMA. Hepatic macrophage infiltration and angiogenesis were reflected by IHC staining for CD68 and CD31. Liver angiocrine levels were detected by ELISA. The mRNA levels of angiocrine or cell cycle-related genes were measured by quantitative real-time RT-PCR (qPCR). The protein levels of cell proliferation-related protein and phosphorylated signal transducer and activator of transcription 3 (STAT3) were detected by western blotting. RESULTS sEH mRNA and protein levels were significantly upregulated in mice after 2/3 partial hepatectomy (PHx). Compared with WT mice, sEH-/- mice exhibited a higher liver/body weight ratio and more Ki67-positive cells on days 2 and 3 after PHx. The accelerated liver regeneration in sEH-/- mice was attributed to angiogenesis and endothelial-derived angiocrine (HGF) production. Subsequently, hepatic protein expression of cyclinD1 (CYCD1) and the downstream direct targets of the STAT3 pathway, such as c-fos, c-jun, and c-myc, were also suppressed post-PHx in sEH-/- compared to WT mice. Furthermore, sEH deficiency attenuated CCl4-induced acute liver injury and reduced fibrosis in both CCl4 and bile duct ligation (BDL)-induced liver fibrosis rodent models. Compared with WT mice, sEH-/- mice had slightly decreased hepatic macrophage infiltration and angiogenesis. Meanwhile, sEH-/- BDL mice had more Ki67-positive cells in the liver than WT BDL mice. CONCLUSIONS sEH deficiency alters the angiocrine profile of liver endothelial to accelerate hepatocyte proliferation and liver regeneration, and blunts acute liver injury and fibrosis by inhibiting inflammation and angiogenesis. sEH inhibition is a promising target for liver diseases to improve liver regeneration and damage.
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Affiliation(s)
- Wensheng Deng
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 33006, China; Laboratory of Digestive Surgery, Nanchang University, Nanchang 33006, China
| | - Tengcheng Hu
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 33006, China; Laboratory of Digestive Surgery, Nanchang University, Nanchang 33006, China
| | - Weixin Xiong
- Department of Cardiology, The Second Affiliated Hospital of Nanchang University, Nanchang 33006, China
| | - Xiaohua Jiang
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 33006, China; Laboratory of Digestive Surgery, Nanchang University, Nanchang 33006, China
| | - Yi Cao
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 33006, China; Laboratory of Digestive Surgery, Nanchang University, Nanchang 33006, China
| | - Zhengrong Li
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 33006, China; Laboratory of Digestive Surgery, Nanchang University, Nanchang 33006, China
| | - Hai Jiang
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 33006, China; Laboratory of Digestive Surgery, Nanchang University, Nanchang 33006, China.
| | - Xinxin Wang
- Department of Radiotherapy, The Third Hospital of Nanchang, Nanchang 330002, China.
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25
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Chen C, Liu X, Chang CY, Wang HY, Wang RF. The Interplay between T Cells and Cancer: The Basis of Immunotherapy. Genes (Basel) 2023; 14:genes14051008. [PMID: 37239368 DOI: 10.3390/genes14051008] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 04/17/2023] [Accepted: 04/24/2023] [Indexed: 05/28/2023] Open
Abstract
Over the past decade, immunotherapy has emerged as one of the most promising approaches to cancer treatment. The use of immune checkpoint inhibitors has resulted in impressive and durable clinical responses in the treatment of various cancers. Additionally, immunotherapy utilizing chimeric antigen receptor (CAR)-engineered T cells has produced robust responses in blood cancers, and T cell receptor (TCR)-engineered T cells are showing promising results in the treatment of solid cancers. Despite these noteworthy advancements in cancer immunotherapy, numerous challenges remain. Some patient populations are unresponsive to immune checkpoint inhibitor therapy, and CAR T cell therapy has yet to show efficacy against solid cancers. In this review, we first discuss the significant role that T cells play in the body's defense against cancer. We then delve into the mechanisms behind the current challenges facing immunotherapy, starting with T cell exhaustion due to immune checkpoint upregulation and changes in the transcriptional and epigenetic landscapes of dysfunctional T cells. We then discuss cancer-cell-intrinsic characteristics, including molecular alterations in cancer cells and the immunosuppressive nature of the tumor microenvironment (TME), which collectively facilitate tumor cell proliferation, survival, metastasis, and immune evasion. Finally, we examine recent advancements in cancer immunotherapy, with a specific emphasis on T-cell-based treatments.
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Affiliation(s)
- Christina Chen
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Xin Liu
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Che-Yu Chang
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Helen Y Wang
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Rong-Fu Wang
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- Department of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
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Rizvi F, Lee YR, Diaz-Aragon R, So J, Florentino RM, Smith AR, Everton E, Ostrowska A, Jung K, Tam Y, Muramatsu H, Pardi N, Weissman D, Soto-Gutierrez A, Shin D, Gouon-Evans V. VEGFA mRNA-LNP promotes biliary epithelial cell-to-hepatocyte conversion in acute and chronic liver diseases and reverses steatosis and fibrosis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.04.17.537186. [PMID: 37131823 PMCID: PMC10153196 DOI: 10.1101/2023.04.17.537186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
The liver is known for its remarkable regenerative ability through proliferation of hepatocytes. Yet, during chronic injury or severe hepatocyte death, proliferation of hepatocytes is exhausted. To overcome this hurdle, we propose vascular-endothelial-growth-factor A (VEGFA) as a therapeutic means to accelerate biliary epithelial cell (BEC)-to-hepatocyte conversion. Investigation in zebrafish establishes that blocking VEGF receptors abrogates BEC-driven liver repair, while VEGFA overexpression promotes it. Delivery of VEGFA via non-integrative and safe nucleoside-modified mRNA encapsulated into lipid-nanoparticles (mRNA-LNP) in acutely or chronically injured mouse livers induces robust BEC-to-hepatocyte conversion and reversion of steatosis and fibrosis. In human and murine diseased livers, we further identified VEGFA-receptor KDR-expressing BECs associated with KDR-expressing cell-derived hepatocytes. This defines KDR-expressing cells, most likely being BECs, as facultative progenitors. This study reveals novel therapeutic benefits of VEGFA delivered via nucleoside-modified mRNA-LNP, whose safety is widely validated with COVID-19 vaccines, for harnessing BEC-driven repair to potentially treat liver diseases. Highlights Complementary mouse and zebrafish models of liver injury demonstrate the therapeutic impact of VEGFA-KDR axis activation to harness BEC-driven liver regeneration.VEGFA mRNA LNPs restore two key features of the chronic liver disease in humans such as steatosis and fibrosis.Identification in human cirrhotic ESLD livers of KDR-expressing BECs adjacent to clusters of KDR+ hepatocytes suggesting their BEC origin.KDR-expressing BECs may represent facultative adult progenitor cells, a unique BEC population that has yet been uncovered.
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27
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Ribatti D. Liver angiocrine factors. Tissue Cell 2023; 81:102027. [PMID: 36657255 DOI: 10.1016/j.tice.2023.102027] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 01/12/2023] [Accepted: 01/13/2023] [Indexed: 01/15/2023]
Abstract
Endothelial cells secrete growth factors, chemokines, and extracellular matrix components, including angiocrine factors or angiokines, involved in the regulation of organ morphogenesis, homeostasis, and regeneration. The concepts of angiocrine signaling have been demonstrated in the liver, pancreas, brain, lung, heart, kidney, skin, bone marrow, as well as in pathological conditions, including cancer. The aim of this review article is to analyze the role of angiocrine factors in the liver in physiological as well as in pathological conditions.
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Affiliation(s)
- Domenico Ribatti
- Department of Translational Biomedicine and Neurosciences,University of Bari Medical School, Piazza Giulio Cesare, 11, Policlinico, 70124 Bari, Italy.
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28
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Otsuka H. Nanofabrication Technologies to Control Cell and Tissue Function in Three-Dimension. Gels 2023; 9:gels9030203. [PMID: 36975652 PMCID: PMC10048556 DOI: 10.3390/gels9030203] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 02/14/2023] [Accepted: 02/24/2023] [Indexed: 03/29/2023] Open
Abstract
In the 2000s, advances in cellular micropatterning using microfabrication contributed to the development of cell-based biosensors for the functional evaluation of newly synthesized drugs, resulting in a revolutionary evolution in drug screening. To this end, it is essential to utilize cell patterning to control the morphology of adherent cells and to understand contact and paracrine-mediated interactions between heterogeneous cells. This suggests that the regulation of the cellular environment by means of microfabricated synthetic surfaces is not only a valuable endeavor for basic research in biology and histology, but is also highly useful to engineer artificial cell scaffolds for tissue regeneration. This review particularly focuses on surface engineering techniques for the cellular micropatterning of three-dimensional (3D) spheroids. To establish cell microarrays, composed of a cell adhesive region surrounded by a cell non-adherent surface, it is quite important to control a protein-repellent surface in the micro-scale. Thus, this review is focused on the surface chemistries of the biologically inspired micropatterning of two-dimensional non-fouling characters. As cells are formed into spheroids, their survival, functions, and engraftment in the transplanted site are significantly improved compared to single-cell transplantation. To improve the therapeutic effect of cell spheroids even further, various biomaterials (e.g., fibers and hydrogels) have been developed for spheroid engineering. These biomaterials not only can control the overall spheroid formation (e.g., size, shape, aggregation speed, and degree of compaction), but also can regulate cell-to-cell and cell-to-matrix interactions in spheroids. These important approaches to cell engineering result in their applications to tissue regeneration, where the cell-biomaterial composite is injected into diseased area. This approach allows the operating surgeon to implant the cell and polymer combinations with minimum invasiveness. The polymers utilized in hydrogels are structurally similar to components of the extracellular matrix in vivo, and are considered biocompatible. This review will provide an overview of the critical design to make hydrogels when used as cell scaffolds for tissue engineering. In addition, the new strategy of injectable hydrogel will be discussed as future directions.
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Affiliation(s)
- Hidenori Otsuka
- Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
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Yazici SE, Gedik ME, Leblebici CB, Kosemehmetoglu K, Gunaydin G, Dogrul AB. Can endocan serve as a molecular "hepatostat" in liver regeneration? Mol Med 2023; 29:29. [PMID: 36849916 PMCID: PMC9972723 DOI: 10.1186/s10020-023-00622-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 02/13/2023] [Indexed: 03/01/2023] Open
Abstract
BACKGROUND Intriguingly, liver regeneration after injury does not induce uncontrolled growth and the underlying mechanisms of such a "hepatostat" are still not clear. Endocan, a proteoglycan, was implicated in liver regeneration. It can support the function of hepatocyte growth factor/scatter factor in tissue repair after injury. Endostatin, a 20 kDa C-terminal fragment of collagen XVIII, may modulate the cessation of liver regeneration. eEF2K, a protein kinase that regulates protein synthesis, can regulate angiogenesis. Thus, we investigated the role of endocan, endostatin and eEF2K during normal liver regeneration. METHODS Serum samples and regenerating remnant liver tissues were obtained on various days after partial hepatectomy in rats. mRNA expression levels of Vegf and Pcna were analyzed in addition to immunohistochemical evaluations. Liver tissue protein levels of endostatin, endocan and p-eEF2K/eEF2K were determined with Western blot. Serum levels of endostatin and endocan were assessed with ELISA. RESULTS Pcna expression level in residual liver tissues peaked on day-1, while Vegf expression reached its highest level on days 1-3 after partial hepatectomy (70%). Endocan activity declined gradually on days 1-7. The decrease in liver endocan expression was accompanied by an increase in serum endocan levels. Partial hepatectomy induced a rapid increase in liver endostatin levels. Following its surge on day-1, endostatin expression gradually declined, which was accompanied by a peak in serum endostatin. Finally, partial hepatectomy was shown to regulate eEF2K; thus, increasing protein translation. CONCLUSIONS We revealed possible mechanistic insights into liver regeneration by examining the associations of Pcna, Vegf, endocan, endostatin, eEF2K with hepatic regeneration after partial hepatectomy. Indeed, endocan might serve as a useful biomarker to monitor clinical prognosis in a plethora of conditions such as recovery of donor's remaining liver after living-donor liver transplant. Whether endocan might represent a strategy to optimize liver regeneration when given therapeutically needs to be investigated in future studies.
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Affiliation(s)
- Sinan Efe Yazici
- Department of General Surgery, Hacettepe University School of Medicine, Sihhiye, 06100, Ankara, Turkey
| | - Mustafa Emre Gedik
- Department of Basic Oncology, Hacettepe University Cancer Institute, Sihhiye, 06100, Ankara, Turkey
| | - Can Berk Leblebici
- Department of Pathology, Hacettepe University School of Medicine, Sihhiye, 06100, Ankara, Turkey
| | - Kemal Kosemehmetoglu
- Department of Pathology, Hacettepe University School of Medicine, Sihhiye, 06100, Ankara, Turkey
| | - Gurcan Gunaydin
- Department of Basic Oncology, Hacettepe University Cancer Institute, Sihhiye, 06100, Ankara, Turkey.
| | - Ahmet Bulent Dogrul
- Department of General Surgery, Hacettepe University School of Medicine, Sihhiye, 06100, Ankara, Turkey.
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Elchaninov A, Vishnyakova P, Menyailo E, Sukhikh G, Fatkhudinov T. An Eye on Kupffer Cells: Development, Phenotype and the Macrophage Niche. Int J Mol Sci 2022; 23:9868. [PMID: 36077265 PMCID: PMC9456487 DOI: 10.3390/ijms23179868] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/14/2022] [Accepted: 08/29/2022] [Indexed: 11/16/2022] Open
Abstract
Macrophages are key participants in the maintenance of tissue homeostasis under normal and pathological conditions, and implement a rich diversity of functions. The largest population of resident tissue macrophages is found in the liver. Hepatic macrophages, termed Kupffer cells, are involved in the regulation of multiple liver functionalities. Specific differentiation profiles and functional activities of tissue macrophages have been attributed to the shaping role of the so-called tissue niche microenvironments. The fundamental macrophage niche concept was lately shaken by a flood of new data, leading to a revision and substantial update of the concept, which constitutes the main focus of this review. The macrophage community discusses contemporary evidence on the developmental origins of resident macrophages, notably Kupffer cells and the issues of heterogeneity of the hepatic macrophage populations, as well as the roles of proliferation, cell death and migration processes in the maintenance of macrophage populations of the liver. Special consideration is given to interactions of Kupffer cells with other local cell lineages, including Ito cells, sinusoidal endothelium and hepatocytes, which participate in the maintenance of their phenotypical and functional identity.
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Affiliation(s)
- Andrey Elchaninov
- Laboratory of Regenerative Medicine, National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia
- Histology Department, Pirogov Russian National Research Medical University, 117997 Moscow, Russia
| | - Polina Vishnyakova
- Laboratory of Regenerative Medicine, National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia
- Histology Department, Medical Institute, Peoples’ Friendship University of Russia, 117198 Moscow, Russia
| | - Egor Menyailo
- Laboratory of Growth and Development, Avtsyn Research Institute of Human Morphology of FSBI “Petrovsky National Research Centre of Surgery”, 117418 Moscow, Russia
| | - Gennady Sukhikh
- Laboratory of Regenerative Medicine, National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia
| | - Timur Fatkhudinov
- Histology Department, Medical Institute, Peoples’ Friendship University of Russia, 117198 Moscow, Russia
- Laboratory of Growth and Development, Avtsyn Research Institute of Human Morphology of FSBI “Petrovsky National Research Centre of Surgery”, 117418 Moscow, Russia
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Zhu M, Niu Q, Zhang J, Yu Y, Wang H, Zhu T, Wang G, Yang L, Yin Y, Li P. Amorphous selenium nanodots alleviate non-alcoholic fatty liver disease via activating VEGF receptor 1 to further inhibit phosphorylation of JNK/p38 MAPK pathways. Eur J Pharmacol 2022; 932:175235. [PMID: 36049560 DOI: 10.1016/j.ejphar.2022.175235] [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: 07/12/2022] [Revised: 08/22/2022] [Accepted: 08/23/2022] [Indexed: 12/01/2022]
Abstract
In clinic, there is still no unified standard for the treatment of non-alcoholic fatty liver disease (NAFLD), and the development of effective novel drugs to alleviate NAFLD remains a challenge. This study aimed to explore the effect and mechanism of amorphous selenium nanodots (A SeNDs) in alleviating NAFLD. Model rats with NAFLD were induced by the high-fat diet (HFD). Histomorphology was used to observe liver tissue, automatic biochemical analyzer was used to analyze liver function indicators, and ELISA kit was used to detect the effect of A SeNDs on oxidative stress and inflammatory factors in NAFLD rats. The results exhibited that A SeNDs could reduce hepatocyte steatosis, liver index, blood lipid level, and transaminase level in NAFLD rats. Furthermore, A SeNDs could relieve the oxidative stress and inflammatory reaction and maintain liver tissue structure in NAFLD rats. Mechanistically, A SeNDs (0.3 mg/kg/day) inhibit the phosphorylation of JNK/p38 MAPK pathways after activating vascular endothelial growth factor receptor 1 (VEGFR1) in the liver of rats with NAFLD to allay oxidative stress and inflammatory response and improves hepatic structure and liver function. Therefore, it should be an important method to mitigate NAFLD by supplementing A SeNDs to normalize hepatic structure and liver function.
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Affiliation(s)
- Moli Zhu
- School of Pharmacy, Xinxiang Medical University, Xinxiang, 453000, China; Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, 453000, China
| | - Qianqian Niu
- School of Pharmacy, Xinxiang Medical University, Xinxiang, 453000, China
| | - Jie Zhang
- School of Pharmacy, Xinxiang Medical University, Xinxiang, 453000, China
| | - Yanan Yu
- School of Pharmacy, Xinxiang Medical University, Xinxiang, 453000, China
| | - Huanhuan Wang
- School of Pharmacy, Xinxiang Medical University, Xinxiang, 453000, China
| | - Tiantian Zhu
- School of Pharmacy, Xinxiang Medical University, Xinxiang, 453000, China
| | - Ge Wang
- Basic Medical College, Xinxiang Medical University, Xinxiang, 453000, China
| | - Lin Yang
- Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, 453000, China.
| | - Yaling Yin
- Basic Medical College, Xinxiang Medical University, Xinxiang, 453000, China.
| | - Peng Li
- School of Pharmacy, Xinxiang Medical University, Xinxiang, 453000, China.
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Akindona FA, Frederico SC, Hancock JC, Gilbert MR. Exploring the origin of the cancer stem cell niche and its role in anti-angiogenic treatment for glioblastoma. Front Oncol 2022; 12:947634. [PMID: 36091174 PMCID: PMC9454306 DOI: 10.3389/fonc.2022.947634] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 07/08/2022] [Indexed: 11/21/2022] Open
Abstract
Cancer stem cells are thought to be the main drivers of tumorigenesis for malignancies such as glioblastoma (GBM). They are maintained through a close relationship with the tumor vasculature. Previous literature has well-characterized the components and signaling pathways for maintenance of this stem cell niche, but details on how the niche initially forms are limited. This review discusses development of the nonmalignant neural and hematopoietic stem cell niches in order to draw important parallels to the malignant environment. We then discuss what is known about the cancer stem cell niche, its relationship with angiogenesis, and provide a hypothesis for its development in GBM. A better understanding of the mechanisms of development of the tumor stem cell niche may provide new insights to potentially therapeutically exploit.
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Affiliation(s)
- Funto A. Akindona
- Neuro-Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD, United States
| | - Stephen C. Frederico
- Neuro-Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD, United States
- University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - John C. Hancock
- Neuro-Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD, United States
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
- Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
| | - Mark R. Gilbert
- Neuro-Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD, United States
- *Correspondence: Mark R. Gilbert,
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Dehlke K, Krause L, Tyufekchieva S, Murtha-Lemekhova A, Mayer P, Vlasov A, Klingmüller U, Mueller NS, Hoffmann K. Predicting liver regeneration following major resection. Sci Rep 2022; 12:13396. [PMID: 35927556 PMCID: PMC9352754 DOI: 10.1038/s41598-022-16968-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 07/19/2022] [Indexed: 11/09/2022] Open
Abstract
Breakdown of synthesis, excretion and detoxification defines liver failure. Post-hepatectomy liver failure (PHLF) is specific for liver resection and a rightfully feared complication due to high lethality and limited therapeutic success. Individual cytokine and growth factor profiles may represent potent predictive markers for recovery of liver function. We aimed to investigate these profiles in post-hepatectomy regeneration. This study combined a time-dependent cytokine and growth factor profiling dataset of a training (30 patients) and a validation (14 patients) cohorts undergoing major liver resection with statistical and predictive models identifying individual pathway signatures. 2319 associations were tested. Primary hepatocytes isolated from patient tissue samples were stimulated and their proliferation was analysed through DNA content assay. Common expression trajectories of cytokines and growth factors with strong correlation to PHLF, morbidity and mortality were identified despite highly individual perioperative dynamics. Especially, dynamics of EGF, HGF, and PLGF were associated with mortality. PLGF was additionally associated with PHLF and complications. A global association-network was calculated and validated to investigate interdependence of cytokines and growth factors with clinical attributes. Preoperative cytokine and growth factor signatures were identified allowing prediction of mortality following major liver resection by regression modelling. Proliferation analysis of corresponding primary human hepatocytes showed associations of individual regenerative potential with clinical outcome. Prediction of PHLF was possible on as early as first postoperative day (POD1) with AUC above 0.75. Prediction of PHLF and mortality is possible on POD1 with liquid-biopsy based risk profiling. Further utilization of these models would allow tailoring of interventional strategies according to individual profiles.
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Affiliation(s)
- Karolin Dehlke
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany
| | - Linda Krause
- Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Silvana Tyufekchieva
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany
| | - Anastasia Murtha-Lemekhova
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany
| | - Philipp Mayer
- Department of Diagnostic and Interventional Radiology, Ruprecht Karls University, 69120, Heidelberg, Germany
| | - Artyom Vlasov
- Division of Systems Biology of Signal Transduction, German Cancer Research Center, 69120, Heidelberg, Germany
| | - Ursula Klingmüller
- Division of Systems Biology of Signal Transduction, German Cancer Research Center, 69120, Heidelberg, Germany
| | - Nikola S Mueller
- Institute of Computational Biology, Helmholtz Center Munich, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.
| | - Katrin Hoffmann
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
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Guo L, Zhu Z, Gao C, Chen K, Lu S, Yan H, Liu W, Wang M, Ding Y, Huang L, Wang X. Development of Biomimetic Hepatic Lobule-Like Constructs on Silk-Collagen Composite Scaffolds for Liver Tissue Engineering. Front Bioeng Biotechnol 2022; 10:940634. [PMID: 35814001 PMCID: PMC9260023 DOI: 10.3389/fbioe.2022.940634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 05/31/2022] [Indexed: 11/13/2022] Open
Abstract
Constructing an engineered hepatic lobule-mimetic model is challenging owing to complicated lobular architecture and crucial hepatic functionality. Our previous study has demonstrated the feasibility of using silk fibroin (SF) scaffolds as functional templates for engineering hepatic lobule-like constructs. But the unsatisfactory chemical and physical performances of the SF-only scaffold and the inherent defect in the functional activity of the carcinoma-derived seeding cells remain to be addressed to satisfy the downstream application demand. In this study, SF-collagen I (SFC) composite scaffolds with improved physical and chemical properties were fabricated, and their utilization for bioengineering a more hepatic lobule-like construct was explored using the immortalized human hepatocyte-derived liver progenitor-like cells (iHepLPCs) and endothelial cells incorporated in the dynamic culture system. The SFC scaffolds prepared through the directional lyophilization process showed radially aligned porous structures with increased swelling ratio and porosity, ameliorative mechanical stiffness that resembled the normal liver matrix more closely, and improved biocompatibility. The iHepLPCs displayed a hepatic plate-like distribution and differentiated into matured hepatocytes with improved hepatic function in vitro and in vivo. Moreover, hepatocyte–endothelial cell interphase arrangement was generated in the co-culture compartment with improved polarity, bile capillary formation, and enhanced liver functions compared with the monocultures. Thus, a more biomimetic hepatic lobule-like model was established and could provide a valuable and robust platform for various applications, including bioartificial liver and drug screening.
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Affiliation(s)
- Lina Guo
- College of Basic Medical Science, Dalian Medical University, Dalian, China
| | - Ziqing Zhu
- National Engineering Laboratory for Modern Silk, College of Textile and Clothing Engineering, Soochow University, Suzhou, China
| | - Chuanzhou Gao
- College of Basic Medical Science, Dalian Medical University, Dalian, China
| | - Kaiwen Chen
- School of Bioengineering, State Key Laboratory of Fine Chemistry, Dalian University of Technology, Dalian, China
| | - Shenzhou Lu
- National Engineering Laboratory for Modern Silk, College of Textile and Clothing Engineering, Soochow University, Suzhou, China
| | - Hexin Yan
- Department of Anesthesiology and Critical Care Medicine, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Shanghai Engineering Research Center of Peri-operative Organ Support and Function Preservation, Shanghai, China
| | - Wenming Liu
- Department of Anesthesiology and Critical Care Medicine, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Shanghai Engineering Research Center of Peri-operative Organ Support and Function Preservation, Shanghai, China
| | - Mingqi Wang
- College of Basic Medical Science, Dalian Medical University, Dalian, China
| | - Yanfang Ding
- College of Basic Medical Science, Dalian Medical University, Dalian, China
| | - Lin Huang
- College of Basic Medical Science, Dalian Medical University, Dalian, China
- *Correspondence: Lin Huang, ; Xiuli Wang,
| | - Xiuli Wang
- College of Basic Medical Science, Dalian Medical University, Dalian, China
- General Surgery Center, Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University, Guangzhou, China
- *Correspondence: Lin Huang, ; Xiuli Wang,
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Abstract
Karaman et al. (2022. J. Exp. Med.https://doi.org/10.1084/jem.20210565) examined the differential effects of the conditional deletion of genes encoding each VEGF receptor, VEGFR1, VEGFR2 and VEGFR 3, as well as combinations thereof in mice. The results highlight the crosstalk between receptors in different organs and emphasize the importance of VEGF receptor expression and interplay in vascular heterogeneity.
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Affiliation(s)
- Pin Li
- Department of Pathology, University of California, San Diego, La Jolla, CA
- Moores Cancer Center, University of California, San Diego, La Jolla, CA
| | - Napoleone Ferrara
- Department of Pathology, University of California, San Diego, La Jolla, CA
- Moores Cancer Center, University of California, San Diego, La Jolla, CA
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Duan JL, Zhou ZY, Ruan B, Fang ZQ, Ding J, Liu JJ, Song P, Xu H, Xu C, Yue ZS, Han H, Dou GR, Wang L. Notch-Regulated c-Kit-Positive Liver Sinusoidal Endothelial Cells Contribute to Liver Zonation and Regeneration. Cell Mol Gastroenterol Hepatol 2022; 13:1741-1756. [PMID: 35114417 PMCID: PMC9046233 DOI: 10.1016/j.jcmgh.2022.01.019] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 01/20/2022] [Accepted: 01/21/2022] [Indexed: 01/20/2023]
Abstract
BACKGROUND & AIMS Liver sinusoidal endothelial cells (SECs) promote the proliferation of hepatocytes during liver regeneration. However, the specific subset of SECs and its mechanisms during the process remain unclear. In this study, we investigated the potential role of c-kit+ SECs, a newly identified subset of SECs in liver regeneration. METHODS Partial hepatectomy mice models were established to induce liver regeneration. Hepatic c-kit expression was detected by quantitative reverse-transcription polymerase chain reaction, immunofluorescent staining, and fluorescence-activated cell sorting. VE-cadherin-cyclization recombinase-estrogen receptor (Cdh5-Cre-ERT) Notch intracellular domain and Cdh5-Cre recombination signal binding protein Jκfloxp mice were introduced to mutate Notch signaling. c-Kit+ SECs were isolated by magnetic beads. Single-cell RNA sequencing was performed on isolated SECs. Liver injuries were induced by CCl4 or quantitative polymerase chain reaction injection. RESULTS Hepatic c-kit is expressed predominantly in SECs. Liver resident SECs contribute to the increase of c-kit during partial hepatectomy-induced liver regeneration. Isolated c-kit+ SECs promote hepatocyte proliferation in vivo and in vitro by facilitating angiocrine. The distribution of c-kit shows distinct spatial differences that are highly coincident with the liver zonation marker wingless-type MMTV integration site family, member2 (Wnt2). Notch mutation reshapes the c-kit distribution and liver zonation, resulting in altered hepatocyte proliferation. c-Kit+ SECs were shown to regulate hepatocyte regeneration through angiocrine in a Wnt2-dependent manner. Activation of the Notch signaling pathway weakens liver regeneration by inhibiting positive regulatory effects of c-kit+ SECs on hepatocytes. Furthermore, c-kit+ SEC infusion attenuates toxin-induced liver injuries in mice. CONCLUSIONS Our results suggest that c-kit+ SECs contributes to liver zonation and regeneration through Wnt2 and is regulated by Notch signaling, providing opportunities for novel therapeutic approaches to liver injury in the future. Transcript profiling: GEO (accession number: GSE134037).
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Affiliation(s)
- Juan-Li Duan
- Department of Hepatobiliary Surgery, Xi'an, China
| | - Zi-Yi Zhou
- Department of Ophthalmology, Xi-Jing Hospital, Xi'an, China
| | - Bai Ruan
- Department of Hepatobiliary Surgery, Xi'an, China; State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Xi'an, China; Center of Clinical Aerospace Medicine, Department of Aviation Medicine, Fourth Military Medical University, Xi'an, China
| | | | - Jian Ding
- Department of Hepatobiliary Surgery, Xi'an, China
| | | | - Ping Song
- Department of Hepatobiliary Surgery, Xi'an, China
| | - Hao Xu
- Department of Hepatobiliary Surgery, Xi'an, China
| | - Chen Xu
- Department of Hepatobiliary Surgery, Xi'an, China
| | - Zhen-Sheng Yue
- Department of Hepatobiliary Surgery, Xi'an, China; Department of Ophthalmology, Xi-Jing Hospital, Xi'an, China
| | - Hua Han
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Xi'an, China.
| | - Guo-Rui Dou
- Department of Ophthalmology, Xi-Jing Hospital, Xi'an, China.
| | - Lin Wang
- Department of Hepatobiliary Surgery, Xi'an, China; State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Xi'an, China.
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37
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Eckstrum K, Striz A, Ferguson M, Zhao Y, Sprando R. Evaluation of the utility of the Beta Human Liver Emulation System (BHLES) for CFSAN's regulatory toxicology program. Food Chem Toxicol 2022; 161:112828. [PMID: 35066125 DOI: 10.1016/j.fct.2022.112828] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 01/10/2022] [Accepted: 01/17/2022] [Indexed: 12/27/2022]
Abstract
Microphysiological systems (MPS), such as organ-on-a-chip platforms, are an emerging alternative model that may be useful for predicting human physiology and/or toxicity. Due to the interest in these platforms, the Center for Food Safety and Applied Nutrition partnered with Emulate to evaluate the utility of the Beta Human Liver Emulation System (BHLES) for its regulatory science program. Using known hepatotoxic compounds (usnic acid, benzbromarone, tamoxifen, and acetaminophen) and compounds that have no reported human cases of liver toxicity (dimethyl sulfoxide, theophylline, and aminohippurate) the platforms' performance was evaluated. Chemical toxicity was assessed by albumin secretion, urea and LDH release, nuclei number, mitochondrial membrane potential, and apoptosis. System/platform performance was evaluated in terms of sensitivity and specificity, power, and variability and repeatability. Chemical interactions with the Chip material were also assessed. Preliminary findings suggested that for the model test compounds selected, the BHLES was able to accurately predict toxicity, demonstrated high sensitivity and specificity, high power, and low variability. However, some compounds interacted with the Chip material indicating variable exposure levels that should be accounted for when planning experimentation. The details of the evaluation are presented herein.
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Affiliation(s)
- Kirsten Eckstrum
- Office of Applied Research and Safety Assessment, Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, Laurel, MD, 20708, USA.
| | - Anneliese Striz
- Office of Applied Research and Safety Assessment, Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, Laurel, MD, 20708, USA
| | - Martine Ferguson
- Office of Analytics and Outreach, Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, College Park, MD, 20740, USA
| | - Yang Zhao
- Office of Applied Research and Safety Assessment, Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, Laurel, MD, 20708, USA
| | - Robert Sprando
- Office of Applied Research and Safety Assessment, Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, Laurel, MD, 20708, USA
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38
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Karaman S, Paavonsalo S, Heinolainen K, Lackman MH, Ranta A, Hemanthakumar KA, Kubota Y, Alitalo K. Interplay of vascular endothelial growth factor receptors in organ-specific vessel maintenance. J Exp Med 2022; 219:212969. [PMID: 35050301 PMCID: PMC8785977 DOI: 10.1084/jem.20210565] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 10/31/2021] [Accepted: 12/22/2021] [Indexed: 12/13/2022] Open
Abstract
Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are quintessential for the development and maintenance of blood and lymphatic vessels. However, genetic interactions between the VEGFRs are poorly understood. VEGFR2 is the dominant receptor that is required for the growth and survival of the endothelium, whereas deletion of VEGFR1 or VEGFR3 was reported to induce vasculature overgrowth. Here we show that vascular regression induced by VEGFR2 deletion in postnatal and adult mice is aggravated by additional deletion of VEGFR1 or VEGFR3 in the intestine, kidney, and pancreas, but not in the liver or kidney glomeruli. In the adult mice, hepatic and intestinal vessels regressed within a few days after gene deletion, whereas vessels in skin and retina remained stable for at least four weeks. Our results show changes in endothelial transcriptomes and organ-specific vessel maintenance mechanisms that are dependent on VEGFR signaling pathways and reveal previously unknown functions of VEGFR1 and VEGFR3 in endothelial cells.
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Affiliation(s)
- Sinem Karaman
- Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland
- Translational Cancer Medicine Research Program, Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland
- Individualized Drug Therapy Research Program, Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland
| | - Satu Paavonsalo
- Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland
- Translational Cancer Medicine Research Program, Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland
- Individualized Drug Therapy Research Program, Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland
| | - Krista Heinolainen
- Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland
- Translational Cancer Medicine Research Program, Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland
| | - Madeleine H. Lackman
- Individualized Drug Therapy Research Program, Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland
| | - Amanda Ranta
- Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland
- Translational Cancer Medicine Research Program, Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland
| | | | - Yoshiaki Kubota
- Department of Anatomy, Keio University School of Medicine, Tokyo, Japan
| | - Kari Alitalo
- Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland
- Translational Cancer Medicine Research Program, Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland
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Aboismail A, El-Shazly M, Abdallah N, Elsayed E, Abo-Yossef R. Study of the effect of vascular endothelial growth factor (VEGF) C(+405)G (rs2010963) single nucleotide polymorphism on the development of esophageal and gastric varices and risk of variceal bleeding in cirrhotic hepatitis C virus (HCV) patients (VEGF) C(+405)G IN esophageal and gastric varices. EGYPTIAN LIVER JOURNAL 2022. [DOI: 10.1186/s43066-021-00160-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Abstract
Background
HCV infection is a major worldwide cause of chronic liver diseases. Esophageal and gastric varices are common in cirrhotic patients due to concomitant portal hypertension. Variceal hemorrhage is a major decompensating event with high morbidity and mortality. Endothelial dysfunction, occurring in cirrhosis, facilitates the development of liver cirrhosis, portal hypertension and contributes to increased intrahepatic vascular resistance..VEGF family members are major regulators of blood vessel development and function.
Results
The study was conducted on 90 subjects admitted to Tropical Medicine Department, Alexandria Main University Hospital: 30 cirrhotic patients with endoscopically proven varices (group A), 30 cirrhotic patients without varices (group B), and 30 healthy controls (group C). All patients was subjected to detailed history taking and thorough clinical examination, laboratory investigations, ultrasound abdomen, upper gastrointestinal endoscopy, and genotyping for VEGF C(+405)G (rs2010963) by 5′ nuclease assay. The VEGF C(+405)G (rs2010963) GG genotype was associated with higher prevalence of esophageal and gastric varices and higher bleeding risk.
Conclusion
VEGF C(+405)G (rs2010963) is an important genetic determinant of esophageal varices, gastric varices, and correlates with variceal bleeding risk. Genetic testing of this SNP would be useful in prediction of esophageal and gastric varices and bleeding risk.
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40
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Li P, Li Q, Biswas N, Xin H, Diemer T, Liu L, Perez Gutierrez L, Paternostro G, Piermarocchi C, Domanskyi S, Wang RK, Ferrara N. LIF, a mitogen for choroidal endothelial cells, protects the choriocapillaris: implications for prevention of geographic atrophy. EMBO Mol Med 2022; 14:e14511. [PMID: 34779136 PMCID: PMC8749470 DOI: 10.15252/emmm.202114511] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 10/21/2021] [Accepted: 10/25/2021] [Indexed: 12/18/2022] Open
Abstract
In the course of our studies aiming to discover vascular bed-specific endothelial cell (EC) mitogens, we identified leukemia inhibitory factor (LIF) as a mitogen for bovine choroidal EC (BCE), although LIF has been mainly characterized as an EC growth inhibitor and an anti-angiogenic molecule. LIF stimulated growth of BCE while it inhibited, as previously reported, bovine aortic EC (BAE) growth. The JAK-STAT3 pathway mediated LIF actions in both BCE and BAE cells, but a caspase-independent proapoptotic signal mediated by cathepsins was triggered in BAE but not in BCE. LIF administration directly promoted activation of STAT3 and increased blood vessel density in mouse eyes. LIF also had protective effects on the choriocapillaris in a model of oxidative retinal injury. Analysis of available single-cell transcriptomic datasets shows strong expression of the specific LIF receptor in mouse and human choroidal EC. Our data suggest that LIF administration may be an innovative approach to prevent atrophy associated with AMD, through protection of the choriocapillaris.
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Affiliation(s)
- Pin Li
- Department of PathologyUniversity of California San DiegoLa JollaCAUSA
| | - Qin Li
- Department of OphthalmologyUniversity of California San DiegoLa JollaCAUSA
| | - Nilima Biswas
- Department of PathologyUniversity of California San DiegoLa JollaCAUSA
| | - Hong Xin
- Department of PathologyUniversity of California San DiegoLa JollaCAUSA
| | - Tanja Diemer
- Department of PathologyUniversity of California San DiegoLa JollaCAUSA
| | - Lixian Liu
- Department of PathologyUniversity of California San DiegoLa JollaCAUSA
| | | | | | - Carlo Piermarocchi
- Department of Physics and AstronomyMichigan State UniversityEast LansingMIUSA
| | - Sergii Domanskyi
- Department of Physics and AstronomyMichigan State UniversityEast LansingMIUSA
| | - Ruikang K Wang
- Department of BioengineeringUniversity of WashingtonSeattleWAUSA
| | - Napoleone Ferrara
- Department of PathologyUniversity of California San DiegoLa JollaCAUSA
- Department of OphthalmologyUniversity of California San DiegoLa JollaCAUSA
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Hadjittofi C, Feretis M, Martin J, Harper S, Huguet E. Liver regeneration biology: Implications for liver tumour therapies. World J Clin Oncol 2021; 12:1101-1156. [PMID: 35070734 PMCID: PMC8716989 DOI: 10.5306/wjco.v12.i12.1101] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 06/22/2021] [Accepted: 11/28/2021] [Indexed: 02/06/2023] Open
Abstract
The liver has remarkable regenerative potential, with the capacity to regenerate after 75% hepatectomy in humans and up to 90% hepatectomy in some rodent models, enabling it to meet the challenge of diverse injury types, including physical trauma, infection, inflammatory processes, direct toxicity, and immunological insults. Current understanding of liver regeneration is based largely on animal research, historically in large animals, and more recently in rodents and zebrafish, which provide powerful genetic manipulation experimental tools. Whilst immensely valuable, these models have limitations in extrapolation to the human situation. In vitro models have evolved from 2-dimensional culture to complex 3 dimensional organoids, but also have shortcomings in replicating the complex hepatic micro-anatomical and physiological milieu. The process of liver regeneration is only partially understood and characterized by layers of complexity. Liver regeneration is triggered and controlled by a multitude of mitogens acting in autocrine, paracrine, and endocrine ways, with much redundancy and cross-talk between biochemical pathways. The regenerative response is variable, involving both hypertrophy and true proliferative hyperplasia, which is itself variable, including both cellular phenotypic fidelity and cellular trans-differentiation, according to the type of injury. Complex interactions occur between parenchymal and non-parenchymal cells, and regeneration is affected by the status of the liver parenchyma, with differences between healthy and diseased liver. Finally, the process of termination of liver regeneration is even less well understood than its triggers. The complexity of liver regeneration biology combined with limited understanding has restricted specific clinical interventions to enhance liver regeneration. Moreover, manipulating the fundamental biochemical pathways involved would require cautious assessment, for fear of unintended consequences. Nevertheless, current knowledge provides guiding principles for strategies to optimise liver regeneration potential.
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Affiliation(s)
- Christopher Hadjittofi
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Michael Feretis
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Jack Martin
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Simon Harper
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Emmanuel Huguet
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
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Developmental angiocrine diversification of endothelial cells for organotypic regeneration. Dev Cell 2021; 56:3042-3051. [PMID: 34813766 DOI: 10.1016/j.devcel.2021.10.020] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 10/17/2021] [Accepted: 10/26/2021] [Indexed: 02/08/2023]
Abstract
Adult organs are vascularized by specialized blood vessels. In addition to inter-organ vascular heterogeneity, each organ is arborized by structurally and functionally diversified populations of endothelial cells (ECs). The molecular pathways that are induced to orchestrate inter- and intra- organ vascular heterogeneity and zonation are shaped during development and fully specified postnatally. Notably, intra-organ specialization of ECs is associated with induction of angiocrine factors that guide cross-talk between ECs and parenchymal cells, establishing co-zonated vascular regions within each organ. In this review, we describe how microenvironmental tissue-specific biophysical, biochemical, immune, and inflammatory cues dictate the specialization of ECs with zonated functions. We delineate how physiological and biophysical stressors in the developing liver, lung, and kidney vasculature induce specialization of capillary beds. Deciphering mechanisms by which vascular microvasculature diversity is attained could set the stage for treating regenerative disorders and promote healing of organs without provoking fibrosis.
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The Hepatic Sinusoid in Chronic Liver Disease: The Optimal Milieu for Cancer. Cancers (Basel) 2021; 13:cancers13225719. [PMID: 34830874 PMCID: PMC8616349 DOI: 10.3390/cancers13225719] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 11/08/2021] [Accepted: 11/11/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary During the development of chronic liver disease, the hepatic sinusoid undergoes major changes that further compromise the hepatic function, inducing persistent inflammation and the formation of scar tissue, together with alterations in liver hemodynamics. This diseased background may induce the formation and development of hepatocellular carcinoma (HCC), which is the most common form of primary liver cancer and a major cause of mortality. In this review, we describe the ways in which the dysregulation of hepatic sinusoidal cells—including liver sinusoidal cells, Kupffer cells, and hepatic stellate cells—may have an important role in the development of HCC. Our review summarizes all of the known sinusoidal processes in both health and disease, and possible treatments focusing on the dysregulation of the sinusoid; finally, we discuss how some of these alterations occurring during chronic injury are shared with the pathology of HCC and may contribute to its development. Abstract The liver sinusoids are a unique type of microvascular beds. The specialized phenotype of sinusoidal cells is essential for their communication, and for the function of all hepatic cell types, including hepatocytes. Liver sinusoidal endothelial cells (LSECs) conform the inner layer of the sinusoids, which is permeable due to the fenestrae across the cytoplasm; hepatic stellate cells (HSCs) surround LSECs, regulate the vascular tone, and synthetize the extracellular matrix, and Kupffer cells (KCs) are the liver-resident macrophages. Upon injury, the harmonic equilibrium in sinusoidal communication is disrupted, leading to phenotypic alterations that may affect the function of the whole liver if the damage persists. Understanding how the specialized sinusoidal cells work in coordination with each other in healthy livers and chronic liver disease is of the utmost importance for the discovery of new therapeutic targets and the design of novel pharmacological strategies. In this manuscript, we summarize the current knowledge on the role of sinusoidal cells and their communication both in health and chronic liver diseases, and their potential pharmacologic modulation. Finally, we discuss how alterations occurring during chronic injury may contribute to the development of hepatocellular carcinoma, which is usually developed in the background of chronic liver disease.
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Zhang H, Ma Y, Cheng X, Wu D, Huang X, Chen B, Ren Y, Jiang W, Tang X, Bai T, Chen Y, Zhao Y, Zhang C, Xiao X, Liu J, Deng Y, Ye T, Chen L, Liu HM, Friedman SL, Chen L, Ding BS, Cao Z. Targeting epigenetically maladapted vascular niche alleviates liver fibrosis in nonalcoholic steatohepatitis. Sci Transl Med 2021; 13:eabd1206. [PMID: 34613814 DOI: 10.1126/scitranslmed.abd1206] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
[Figure: see text].
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Affiliation(s)
- Hua Zhang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Yongyuan Ma
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Xinying Cheng
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Dongbo Wu
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xingming Huang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Bin Chen
- Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yafeng Ren
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Wei Jiang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xiaoqiang Tang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Ting Bai
- Department of Cardiology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China
| | - Yutian Chen
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Yilin Zhao
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Chunxue Zhang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Xia Xiao
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Jing Liu
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Yue Deng
- Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China
| | - Tinghong Ye
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Lu Chen
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Han-Min Liu
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Scott L Friedman
- Fibrosis Research Program, Division of Pulmonary and Critical Care Medicine, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Liping Chen
- Department of Biliary Surgery, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Bi-Sen Ding
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China.,Fibrosis Research Program, Division of Pulmonary and Critical Care Medicine, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.,Division of Regenerative Medicine, Weill Cornell Medicine, New York, NY 10065, USA
| | - Zhongwei Cao
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China.,Fibrosis Research Program, Division of Pulmonary and Critical Care Medicine, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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Murtha-Lemekhova A, Fuchs J, Ghamarnejad O, Nikdad M, Probst P, Hoffmann K. Influence of cytokines, circulating markers and growth factors on liver regeneration and post-hepatectomy liver failure: a systematic review and meta-analysis. Sci Rep 2021; 11:13739. [PMID: 34215781 PMCID: PMC8253792 DOI: 10.1038/s41598-021-92888-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 06/07/2021] [Indexed: 02/07/2023] Open
Abstract
The pathophysiology of post-hepatectomy liver failure is not entirely understood but is rooted in the disruption of normal hepatocyte regeneration and homeostasis. Current investigations of post-hepatectomy liver failure and regeneration are focused on evaluation of circulating hepatic function parameters (transaminases, cholestasis, and coagulation parameters), volumetry and hepatic hemodynamics. However, identification of biochemical factors associated with regeneration and post hepatectomy liver failure is crucial for understanding the pathophysiology and identification of patients at risk. The objective of the present systematic review was to identify circulating factors associated with liver regeneration and post hepatectomy liver failure in patients undergoing hepatectomy. The quantitative analysis was intended if studies provided sufficient data. Electronic databases (MEDLINE via PubMed, Web of Knowledge, Cochrane Library and WHO International Clinical Trials Registry Platform) were searched for publications on cell signaling factors in liver regeneration and post-hepatectomy liver failure following liver resection in clinical setting. No date restriction was given. No language restriction was used. Studies were assessed using MINORS. This study was registered at PROSPERO (CRD42020165384) prior to data extraction. In total 1953 publications were evaluated for titles and abstracts after exclusion of duplicates. Full texts of 167 studies were further evaluated for inclusion. 26 articles were included in the review and 6 publications were included in the meta-analyses. High levels of serum hyaluronic acid even preoperatively are associated with PHLF but especially increased levels early after resection are predictive of PHLF with high sensitivity and specificity. Postoperative elevation of HA to levels between 100 and 500 ng/ml is increased the risk for PHLF ([OR] = 246.28, 95% [CI]: 11.82 to 5131.83; p = 0.0004) Inteleukin-6 levels show contradicting result in association with organ dysfunction. HGF positively correlates with liver regeneration. Overall, due to heterogeneity, scarcity, observational study design and largely retrospective analysis, the certainty of evidence, assessed with GRADE, is very low. High levels of serum hyaluronic acid show a strong association with PHLF and increased levels after resection are predictive of PHLF with high sensitivity and specificity, even on POD1. Interleukin-6 levels need to be studied further due to contradictive results in association with organ dysfunction. For HGF, no quantitative analysis could be made. Yet, most studies find positive correlation between high HGF levels and regeneration. Prospective studies investigating HGF and other growth factors, hyaluronic acid and interleukins 1 and 6 in correlation with liver regeneration measured sequentially through e.g. volumetry, and liver function parameters, preferably expanding the analysis to include dynamic liver function tests, are needed to sufficiently illustrate the connection between biomolecule levels and clinical outcomes.
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Affiliation(s)
- Anastasia Murtha-Lemekhova
- Department of General, Visceral, and Transplantation Surgery, Ruprecht Karl University, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany
| | - Juri Fuchs
- Department of General, Visceral, and Transplantation Surgery, Ruprecht Karl University, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany
| | - Omid Ghamarnejad
- Department of General, Visceral, and Transplantation Surgery, Ruprecht Karl University, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany
| | - Mohammedsadegh Nikdad
- Department of General, Visceral, and Transplantation Surgery, Ruprecht Karl University, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany
| | - Pascal Probst
- Department of General, Visceral, and Transplantation Surgery, Ruprecht Karl University, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany
- Study Center of the German Surgical Society (SDGC), Heidelberg University Hospital, Heidelberg, Germany
| | - Katrin Hoffmann
- Department of General, Visceral, and Transplantation Surgery, Ruprecht Karl University, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
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Engineering the Vasculature of Stem-Cell-Derived Liver Organoids. Biomolecules 2021; 11:biom11070966. [PMID: 34208902 PMCID: PMC8301828 DOI: 10.3390/biom11070966] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 06/23/2021] [Accepted: 06/28/2021] [Indexed: 12/28/2022] Open
Abstract
The vasculature of stem-cell-derived liver organoids can be engineered using methods that recapitulate embryonic liver development. Hepatic organoids with a vascular network offer great application prospects for drug screening, disease modeling, and therapeutics. However, the application of stem cell-derived organoids is hindered by insufficient vascularization and maturation. Here, we review different theories about the origin of hepatic cells and the morphogenesis of hepatic vessels to provide potential approaches for organoid generation. We also review the main protocols for generating vascularized liver organoids from stem cells and consider their potential and limitations in the generation of vascularized liver organoids.
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Danoy M, Tauran Y, Poulain S, Jellali R, Bruce J, Leduc M, Le Gall M, Koui Y, Arakawa H, Gilard F, Gakiere B, Kato Y, Plessy C, Kido T, Miyajima A, Sakai Y, Leclerc E. Investigation of the hepatic development in the coculture of hiPSCs-derived LSECs and HLCs in a fluidic microenvironment. APL Bioeng 2021; 5:026104. [PMID: 34027283 PMCID: PMC8116060 DOI: 10.1063/5.0041227] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 04/02/2021] [Indexed: 12/29/2022] Open
Abstract
Interactions between the different liver cell types are critical to the maintenance or induction of their function in vitro. In this work, human-induced Pluripotent Stem Cells (hiPSCs)-derived Liver Sinusoidal Endothelial Cells (LSECs) and Hepatocytes-Like Cells (HLCs) were cultured and matured in a microfluidic environment. Both cell populations were differentiated in Petri dishes, detached, and inoculated in microfluidic biochips. In cocultures of both cell types, the tissue has exhibited a higher production of albumin (3.19 vs 5.31 μg/mL/106 cells in monocultures and cocultures) as well as a higher inducibility CYP450 over monocultures of HLCs. Tubular-like structures composed of LSECs and positive for the endothelial marker PECAM1, as well as a tissue more largely expressing Stabilin-2 were detected in cocultures only. In contrast, monocultures exhibited no network and less specific endothelial markers. The transcriptomic analysis did not reveal a marked difference between the profiles of both culture conditions. Nevertheless, the analysis allowed us to highlight different upstream regulators in cocultures (SP1, EBF1, and GATA3) and monocultures (PML, MECP2, and NRF1). In cocultures, the multi-omics dataset after 14 days of maturation in biochips has shown the activation of signaling related to hepatic maturation, angiogenesis, and tissue repair. In this condition, inflammatory signaling was also found to be reduced when compared to monocultures as illustrated by the activation of NFKB and by the detection of several cytokines involved in tissue injury in the latter. Finally, the extracted biological processes were discussed regarding the future development of a new generation of human in vitro hepatic models.
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Affiliation(s)
- Mathieu Danoy
- Authors to whom correspondence should be addressed: and
| | | | - Stephane Poulain
- RIKEN Center for Life Science Technologies, Division of Genomic Technologies, 1-7-22, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan
| | - Rachid Jellali
- Université de Technologie de Compiègne, CNRS, Biomechanics and Bioengineering, Centre de recherche Royallieu, CS 60319, 60203 Compiègne Cedex, Compiegne, France
| | - Johanna Bruce
- Plateforme protéomique 3P5, Université de Paris, Institut Cochin, INSERM, CNRS, F-75014 Paris, France
| | - Marjorie Leduc
- Plateforme protéomique 3P5, Université de Paris, Institut Cochin, INSERM, CNRS, F-75014 Paris, France
| | - Morgane Le Gall
- Plateforme protéomique 3P5, Université de Paris, Institut Cochin, INSERM, CNRS, F-75014 Paris, France
| | - Yuta Koui
- Laboratory of Stem Cell Therapy, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
| | - Hiroshi Arakawa
- Laboratory of Molecular Pharmacokinetics, Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa City, Ishikawa 920-1192, Japan
| | - Francoise Gilard
- Institute of Plant Sciences Paris-Saclay (IPS2), UMR 9213/UMR1403, CNRS, INRA, Université Paris-Sud, Université d'Evry, Université Paris-Diderot, Sorbonne Paris-Cité, Saclay Plant Sciences, Bâtiment 630, 91405 Orsay, France
| | - Bertrand Gakiere
- Institute of Plant Sciences Paris-Saclay (IPS2), UMR 9213/UMR1403, CNRS, INRA, Université Paris-Sud, Université d'Evry, Université Paris-Diderot, Sorbonne Paris-Cité, Saclay Plant Sciences, Bâtiment 630, 91405 Orsay, France
| | - Yukio Kato
- Laboratory of Molecular Pharmacokinetics, Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa City, Ishikawa 920-1192, Japan
| | - Charles Plessy
- RIKEN Center for Life Science Technologies, Division of Genomic Technologies, 1-7-22, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan
| | - Taketomo Kido
- Laboratory of Stem Cell Therapy, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
| | - Atsushi Miyajima
- Laboratory of Stem Cell Therapy, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
| | - Yasuyuki Sakai
- Department of Chemical System Engineering, graduate school of Engineering, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8656, Japan
| | - Eric Leclerc
- Authors to whom correspondence should be addressed: and
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Shono Y, Kushida Y, Wakao S, Kuroda Y, Unno M, Kamei T, Miyagi S, Dezawa M. Protection of liver sinusoids by intravenous administration of human Muse cells in a rat extra-small partial liver transplantation model. Am J Transplant 2021; 21:2025-2039. [PMID: 33350582 PMCID: PMC8248424 DOI: 10.1111/ajt.16461] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 11/22/2020] [Accepted: 12/11/2020] [Indexed: 01/25/2023]
Abstract
Small-for-size syndrome (SFSS) has a poor prognosis due to excessive shear stress and sinusoidal microcirculatory disturbances in the acute phase after living-donor liver transplantation (LDLT). Multilineage-differentiating stress enduring (Muse) cells are reparative stem cells found in various tissues and currently under clinical trials. These cells selectively home to damaged sites via the sphingosine-1-phosphate (S1P)-S1P receptor 2 system and repair damaged tissue by pleiotropic effects, including tissue protection and damaged/apoptotic cell replacement by differentiating into tissue-constituent cells. The effects of intravenously administered human bone marrow-Muse cells and -mesenchymal stem cells (MSCs) (4 × 105 ) on liver sinusoidal endothelial cells (LSECs) were examined in a rat SFSS model without immunosuppression. Compared with MSCs, Muse cells intensively homed to the grafted liver, distributed to the sinusoids and vessels, and delivered improved blood chemistry and Ki-67(+) proliferative hepatocytes and -LSECs within 3 days. Tissue clearing and three-dimensional imaging by multiphoton laser confocal microscopy revealed maintenance of the sinusoid continuity, organization, and surface area, as well as decreased sinusoid interruption in the Muse group. Small-interfering RNA-induced knockdown of hepatocyte growth factor and vascular endothelial growth factor-A impaired the protective effect of Muse cells on LSECs. Intravenous injection of Muse cells might be a feasible approach for LDLT with less recipient burden.
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Affiliation(s)
- Yoshihiro Shono
- Department of SurgeryTohoku University Graduate School of MedicineSendaiMiyagiJapan
| | - Yoshihiro Kushida
- Department of Stem Cell Biology and HistologyTohoku University Graduate School of MedicineSendaiMiyagiJapan
| | - Shohei Wakao
- Department of Stem Cell Biology and HistologyTohoku University Graduate School of MedicineSendaiMiyagiJapan
| | - Yasumasa Kuroda
- Department of Stem Cell Biology and HistologyTohoku University Graduate School of MedicineSendaiMiyagiJapan
| | - Michiaki Unno
- Department of SurgeryTohoku University Graduate School of MedicineSendaiMiyagiJapan
| | - Takashi Kamei
- Department of SurgeryTohoku University Graduate School of MedicineSendaiMiyagiJapan
| | - Shigehito Miyagi
- Department of SurgeryTohoku University Graduate School of MedicineSendaiMiyagiJapan
| | - Mari Dezawa
- Department of Stem Cell Biology and HistologyTohoku University Graduate School of MedicineSendaiMiyagiJapan
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49
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Riddiough GE, Jalal Q, Perini MV, Majeed AW. Liver regeneration and liver metastasis. Semin Cancer Biol 2021; 71:86-97. [PMID: 32532594 DOI: 10.1016/j.semcancer.2020.05.012] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 05/18/2020] [Accepted: 05/18/2020] [Indexed: 12/12/2022]
Abstract
Surgical resection for primary and secondary hepatic neoplasms provides the best chance of cure. Advanced surgical techniques such as portal vein embolisation, two-staged hepatectomy and associated liver partition and portal vein ligation for staged-hepatectomy (ALPPS) have facilitated hepatic resection in patients with previously unresectable, bi-lobar disease. These techniques are frequently employed to ensure favourable clinical outcomes and avoid potentially fatal post-operative complications such as small for size syndrome and post-hepatectomy liver failure. However, they rely on the innate ability of the liver to regenerate. As our knowledge of liver organogenesis, liver regeneration and hepatocarcinogenesis has expanded in recent decades it has come to light that liver regeneration may also drive tumour recurrence. Clinical studies in patients undergoing portal vein embolisation indicate that tumours may progress following the procedure in concordance with liver regeneration and hypertrophy, however overall survival in these patients has not been shown to be worse. In this article, we delve into the mechanisms underlying liver regeneration to better understand the complex ways in which this may affect tumour behaviour and ultimately inform clinical decisions.
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Affiliation(s)
- Georgina E Riddiough
- Department of Surgery at Austin Health, The University of Melbourne, Level 8, Lance Townsend Building, 145 Studley Road, Heidelberg, VIC 3084, Australia.
| | - Qaiser Jalal
- Sheffield Teaching Hospitals, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S10 2JF, United Kingdom.
| | - Marcos V Perini
- Department of Surgery at Austin Health, The University of Melbourne, Level 8, Lance Townsend Building, 145 Studley Road, Heidelberg, VIC 3084, Australia.
| | - Ali W Majeed
- Sheffield Teaching Hospitals, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S10 2JF, United Kingdom.
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50
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Yao T, Zhang Y, Lv M, Zang G, Ng SS, Chen X. Advances in 3D cell culture for liver preclinical studies. Acta Biochim Biophys Sin (Shanghai) 2021; 53:643-651. [PMID: 33973620 DOI: 10.1093/abbs/gmab046] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Indexed: 11/13/2022] Open
Abstract
The 3D cell culture model is an indispensable tool in the study of liver biology in the field of health and disease and the development of clinically relevant products for liver therapies. The 3D culture model captures critical factors of the microenvironmental niche required by hepatocytes for exhibiting optimal phenotypes, thus enabling the pursuit of a range of preclinical studies that are not entirely feasible in conventional 2D cell models. In this review, we highlight the major attributes associated with and the components needed for the development of a functional 3D liver culture model for a range of applications.
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Affiliation(s)
- Ting Yao
- Department of Infectious Diseases, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China
| | - Yi Zhang
- Department of Infectious Diseases, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China
| | - Mengjiao Lv
- Department of Infectious Diseases, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China
| | - Guoqing Zang
- Department of Infectious Diseases, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China
| | - Soon Seng Ng
- Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London W2 1PG, UK
| | - Xiaohua Chen
- Department of Infectious Diseases, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China
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