|
1
|
De Rudder M, Manco R, Coubeau L, Fontaine A, Bertrand C, Leclercq IA, Dili A. Vascular damage and excessive proliferation compromise liver function after extended hepatectomy in mice. Hepatology 2025; 81:1468-1484. [PMID: 38661628 DOI: 10.1097/hep.0000000000000900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 03/27/2024] [Indexed: 04/26/2024]
Abstract
BACKGROUND AND AIMS Surgical resection remains the gold standard for liver tumor treatment, yet the emergence of postoperative liver failure, known as the small-for-size syndrome (SFSS), poses a significant challenge. The activation of hypoxia sensors in an SFSS liver remnant initiated early angiogenesis, improving the vascular architecture, safeguarding against liver failure, and reducing mortality. The study aimed to elucidate vascular remodeling mechanisms in SFSS and their impact on hepatocyte function and subsequent liver failure. APPROACH AND RESULTS Mice underwent extended partial hepatectomy to induce SFSS, with a subset exposed to hypoxia immediately after surgery. Hypoxia bolstered posthepatectomy survival rates. The early proliferation of liver sinusoidal cells, coupled with recruitment of putative endothelial progenitor cells, increased vascular density, improved lobular perfusion, and limited hemorrhagic events in the regenerating liver under hypoxia. Administration of granulocyte colony-stimulating factor in hepatectomized mice mimicked the effects of hypoxia on vascular remodeling and endothelial progenitor cell recruitment but failed to rescue survival. Compared to normoxia, hypoxia favored hepatocyte function over proliferation, promoting functional preservation in the regenerating remnant. Injection of Adeno-associated virus serotype 8-thyroxine-binding globulin-hepatocyte nuclear factor 4 alpha virus for hepatocyte-specific overexpression of hepatocyte nuclear factor 4 alpha, the master regulator of hepatocyte function, enforced functionality in proliferating hepatocytes but did not rescue survival. The combination of hepatocyte nuclear factor 4 alpha overexpression and granulocyte colony-stimulating factor treatment rescued survival after SFSS-setting hepatectomy. CONCLUSIONS In summary, SFSS arises from an imbalance and desynchronized interplay between functional regeneration and vascular restructuring. To improve survival following SFSS hepatectomy, it is essential to adopt a 2-pronged strategy aimed at preserving the function of proliferating parenchymal cells and simultaneously attenuating vascular damage.
Collapse
Affiliation(s)
- Maxime De Rudder
- Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Rita Manco
- Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Laurent Coubeau
- Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain (UCLouvain), Brussels, Belgium
- Department of Surgery, University Clinics of St Luc, UCLouvain, Brussels, Belgium
| | - Alix Fontaine
- Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Claude Bertrand
- Department of Surgery, University Hospital of UCLouvain-Namur, Site of Godinne, Yvoir, Belgium
| | - Isabelle A Leclercq
- Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Alexandra Dili
- Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain (UCLouvain), Brussels, Belgium
- Department of Surgery, University Hospital of UCLouvain-Namur, Site of Godinne, Yvoir, Belgium
| |
Collapse
|
|
2
|
Follert P, Große‐Segerath L, Lammert E. Blood flow-induced angiocrine signals promote organ growth and regeneration. Bioessays 2025; 47:e2400207. [PMID: 39529434 PMCID: PMC11755702 DOI: 10.1002/bies.202400207] [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: 08/29/2024] [Revised: 10/15/2024] [Accepted: 10/23/2024] [Indexed: 11/16/2024]
Abstract
Recently, we identified myeloid-derived growth factor (MYDGF) as a blood flow-induced angiocrine signal that promotes human and mouse hepatocyte proliferation and survival. Here, we review literature reporting changes in blood flow after partial organ resection in the liver, lung, and kidney, and we describe the angiocrine signals released by endothelial cells (ECs) upon blood flow alterations in these organs. While hepatocyte growth factor (HGF) and MYDGF are important angiocrine signals for liver regeneration, by now, angiocrine signals have also been reported to stimulate hyperplasia and/or hypertrophy during the regeneration of lungs and kidneys. In addition, angiocrine signals play a critical role in tumor growth. Understanding the mechano-elastic properties and flow-mediated alterations in the organ-specific microvasculature is crucial for therapeutic approaches to maintain organ health and initiate organ renewal.
Collapse
Affiliation(s)
- Paula Follert
- Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural SciencesInstitute of Metabolic PhysiologyDüsseldorfGermany
| | - Linda Große‐Segerath
- Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural SciencesInstitute of Metabolic PhysiologyDüsseldorfGermany
- German Diabetes Center (DDZ)Leibniz Center for Diabetes Research at Heinrich Heine University DüsseldorfDüsseldorfGermany
- German Center for Diabetes Research (DZD e.V.)NeuherbergGermany
| | - Eckhard Lammert
- Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural SciencesInstitute of Metabolic PhysiologyDüsseldorfGermany
- German Diabetes Center (DDZ)Leibniz Center for Diabetes Research at Heinrich Heine University DüsseldorfDüsseldorfGermany
- German Center for Diabetes Research (DZD e.V.)NeuherbergGermany
| |
Collapse
|
|
3
|
Yousefi Z, Nourbakhsh M, Sahebghadam Lotfi A. Pirfenidone Downregulates eIF6, P311, and TGF-β Expression and Improves Liver Fibrosis Induced by Bile Duct Ligation in Wistar Rats: Evidence for Liver Regeneration. DNA Cell Biol 2025; 44:109-124. [PMID: 39681345 DOI: 10.1089/dna.2024.0194] [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: 12/18/2024] Open
Abstract
Liver fibrosis (LF) is a clinical disorder characterized by inflammation and excessive accumulation of extracellular matrix (ECM). This study investigates the effects of the antifibrotic compound pirfenidone (PFD) on improving LF through histological changes and modulation of eukaryotic translation initiation factor 6 (eIF6), P311, and transforming growth factor beta (TGF-β) in rats with bile duct ligation (BDL)-induced LF. Rats received daily doses of PFD (200 and 500 mg/kg) for 4 weeks. The study encompassed biochemical, pathological, and immunohistochemical (IHC) analyses. mRNA levels of eIF6, P311, TGF-β, ECM deposition, hepatic stellate cell (HSC) activation, and inflammatory mediator genes were measured by RT-qPCR. Protein levels of eIF6, P311, and TGF-β were detected by western blotting. Compared with the BDL group, PFD dose-dependently reduced hydroxyproline content, liver index, biochemical parameters, fibrosis score, and fibrosis area. PFD also modulated BDL-induced hepatic inflammation, ECM accumulation, and HSC activation. IHC staining of Ki-67 and hepatocyte paraffin-1 revealed that PFD enhanced liver regeneration. The research confirmed that PFD gradually downregulated elevated eIF6, P311, and TGF-β levels in BDL-induced LF. These findings suggest that PFD could be a potential treatment for LF, as it may help attenuate fibrosis and enhance liver regeneration, possibly through the modulation of these specific markers.
Collapse
Affiliation(s)
- Zeynab Yousefi
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mitra Nourbakhsh
- Department of Clinical Biochemistry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Abbas Sahebghadam Lotfi
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| |
Collapse
|
|
4
|
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.
Collapse
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.
| |
Collapse
|
|
5
|
Hu S, Wu C, Li D, Jiang X, Wang P, Bi G, Ouyang H, Liang F, Zhou W, Yang X, Fang JH, Bi H. Pregnane X receptor activation promotes hematopoiesis during liver regeneration by inducing proliferation of hematopoietic stem and progenitor cells in mice. Pharmacol Res 2024; 210:107504. [PMID: 39522624 DOI: 10.1016/j.phrs.2024.107504] [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: 08/06/2024] [Revised: 11/07/2024] [Accepted: 11/07/2024] [Indexed: 11/16/2024]
Abstract
Liver regeneration is a complex process that involves the recruitment of bone marrow (BM)-derived hematopoietic stem and progenitor cells (HSPCs). Pregnane X receptor (PXR), also known as NR1I2, is an important regulator for liver enlargement and regeneration. However, the role of PXR activation in hematopoiesis during liver regeneration remains unclear. This study investigates the effects of PXR activation on HSPCs and hematopoiesis during liver regeneration, as well as the underlying mechanisms involved. Using a 70 % partial hepatectomy (PHx) on C57BL/6 wild-type (WT) and Pxr-null mice, we observed a significant correlation between the changes in HSPCs numbers in BM and the process of liver regeneration. PXR activation significantly increased the population of Lineage- Sca-1+ c-Kit+ (LSK) cells in the BM, which are key HSPCs involved in hematopoiesis. Additionally, PXR activation increased serum levels of thrombopoietin (TPO) and erythropoietin (EPO), factors known to support HSPCs proliferation and hematopoiesis in the process of liver regeneration. PXR activation does not affect the hematopoietic function of normal mice. Furthermore, mice subjected to irradiation or busulfan-induced hematopoietic dysfunction exhibited impaired liver regeneration, which was alleviated by PXR activation. Importantly, in Pxr-null mice, the promotive effects of PXR activation on liver regeneration and increase of HSPCs were markedly diminished. Moreover, liver-specific Pxr silencing using AAV-Pxr shRNA attenuated the PXR activation-mediated liver regeneration and increase in BM LSK cells, confirming the critical role of hepatic PXR in hematopoiesis during liver regeneration. Collectively, these findings reveal that PXR activation promotes HSPCs proliferation and hematopoiesis during liver regeneration, providing new insights into the molecular mechanisms underlying the role of PXR in liver regeneration and hematopoiesis.
Collapse
Affiliation(s)
- Shuang Hu
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Chenghua Wu
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Dan Li
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Xiaowen Jiang
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Peng Wang
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Guofang Bi
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Hui Ouyang
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Fengting Liang
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Wenhong Zhou
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Xiao Yang
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China; The State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen, China
| | - Jian-Hong Fang
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.
| | - Huichang Bi
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China; The State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen, China.
| |
Collapse
|
|
6
|
Ma J, Zhang L, Zhang X, Zhang L, Zhang H, Zhu Y, Huang X, Zhang T, Tang X, Wang Y, Chen L, Pu Q, Yang L, Cao Z, Ding BS. Inhibiting endothelial Rhoj blocks profibrotic vascular intussusception and angiocrine factors to sustain lung regeneration. Sci Transl Med 2024; 16:eado5266. [PMID: 39196961 DOI: 10.1126/scitranslmed.ado5266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 08/07/2024] [Indexed: 08/30/2024]
Abstract
Lung regeneration after fibrosis requires formation of functional new vasculature, which is essential for gas exchange and cellular cross-talk with other lung cells. It remains unknown how the lung vasculature can be regenerated without fibrosis. Here, we tested the role of N6-methyladenosine (m6A) modification of forkhead box protein O1 (Foxo1) mRNA in lung regeneration after pneumonectomy (PNX) in mice, a model for lung regrowth after surgical resection. Endothelial cell (EC)-specific knockout of methyltransferase-like 3 (Mettl3) and Foxo1 caused nonproductive intussusceptive angiogenesis (IA), which impaired regeneration and enhanced fibrosis. This nonproductive IA was characterized by enhanced endothelial proliferation and increased vascular splitting with increased numbers of pillar ECs. Endothelial-selective knockout of Mettl3 in mice stimulated nonproductive IA and up-regulation of profibrotic factors after PNX, promoting regeneration to fibrotic transition. EC-specific mutation of m6A modification sites in the Foxo1 gene in mice revealed that endothelial Mettl3 modified A504 and A2035 sites in the Foxo1 mRNA to maintain pro-regenerative endothelial glycolysis, ensuring productive IA and lung regeneration without fibrosis. Suppression of Mettl3-Foxo1 signaling stimulated a subset of hyperglycolytic and hyperproliferative 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (Pfkfb3)+, Ras homolog family member J (Rhoj)+, and platelet-derived growth factor subunit B (Pdgfb)+ ECs in both human and mouse lungs with fibrosis. Inhibiting this Pfkfb3+Rhoj+Pdgfb+ EC subset normalized IA, alleviated fibrosis, and restored regeneration in bleomycin (BLM)-injured mouse lungs. We found that m6A modification of Foxo1 in the mouse vasculature promoted lung regeneration over fibrosis after PNX and BLM injury.
Collapse
Affiliation(s)
- Jie Ma
- Key Lab of Birth Defects and Related Diseases of Women and Children of MOE; State Key Lab of Biotherapy; State Key Laboratory of Respiratory Health and Multimorbidity; NHC Key Laboratory of Chronobiology; Sichuan-Chongqing Key Lab of Bio-Resource Research and Utilization; Development and Related Diseases of Women and Children Key Lab of Sichuan Province; West China Second University Hospital, College of Life Sciences, Sichuan University, Chengdu 610041, China
| | - Liyin Zhang
- Key Lab of Birth Defects and Related Diseases of Women and Children of MOE; State Key Lab of Biotherapy; State Key Laboratory of Respiratory Health and Multimorbidity; NHC Key Laboratory of Chronobiology; Sichuan-Chongqing Key Lab of Bio-Resource Research and Utilization; Development and Related Diseases of Women and Children Key Lab of Sichuan Province; West China Second University Hospital, College of Life Sciences, Sichuan University, Chengdu 610041, China
| | - Xu Zhang
- Department of Pathophysiology, Harbin Medical University, Harbin 150081, China
| | - Lanlan Zhang
- Key Lab of Birth Defects and Related Diseases of Women and Children of MOE; State Key Lab of Biotherapy; State Key Laboratory of Respiratory Health and Multimorbidity; NHC Key Laboratory of Chronobiology; Sichuan-Chongqing Key Lab of Bio-Resource Research and Utilization; Development and Related Diseases of Women and Children Key Lab of Sichuan Province; West China Second University Hospital, College of Life Sciences, Sichuan University, Chengdu 610041, China
- Department of Respiratory and Critical Care Medicine, Department of Thoracic Surgery and Institute of Thoracic Oncology, and Laboratory of Liver Transplantation, West China Hospital, Chengdu 610041, China
| | - Hua Zhang
- Key Lab of Birth Defects and Related Diseases of Women and Children of MOE; State Key Lab of Biotherapy; State Key Laboratory of Respiratory Health and Multimorbidity; NHC Key Laboratory of Chronobiology; Sichuan-Chongqing Key Lab of Bio-Resource Research and Utilization; Development and Related Diseases of Women and Children Key Lab of Sichuan Province; West China Second University Hospital, College of Life Sciences, Sichuan University, Chengdu 610041, China
| | - Yulei Zhu
- Key Lab of Birth Defects and Related Diseases of Women and Children of MOE; State Key Lab of Biotherapy; State Key Laboratory of Respiratory Health and Multimorbidity; NHC Key Laboratory of Chronobiology; Sichuan-Chongqing Key Lab of Bio-Resource Research and Utilization; Development and Related Diseases of Women and Children Key Lab of Sichuan Province; West China Second University Hospital, College of Life Sciences, Sichuan University, Chengdu 610041, China
| | - Xingming Huang
- Key Lab of Birth Defects and Related Diseases of Women and Children of MOE; State Key Lab of Biotherapy; State Key Laboratory of Respiratory Health and Multimorbidity; NHC Key Laboratory of Chronobiology; Sichuan-Chongqing Key Lab of Bio-Resource Research and Utilization; Development and Related Diseases of Women and Children Key Lab of Sichuan Province; West China Second University Hospital, College of Life Sciences, Sichuan University, Chengdu 610041, China
| | - Ting Zhang
- Department of Respiratory and Critical Care Medicine, Department of Thoracic Surgery and Institute of Thoracic Oncology, and Laboratory of Liver Transplantation, West China Hospital, Chengdu 610041, China
| | - Xiangdong Tang
- Department of Respiratory and Critical Care Medicine, Department of Thoracic Surgery and Institute of Thoracic Oncology, and Laboratory of Liver Transplantation, West China Hospital, Chengdu 610041, China
| | - Yuan Wang
- Key Lab of Birth Defects and Related Diseases of Women and Children of MOE; State Key Lab of Biotherapy; State Key Laboratory of Respiratory Health and Multimorbidity; NHC Key Laboratory of Chronobiology; Sichuan-Chongqing Key Lab of Bio-Resource Research and Utilization; Development and Related Diseases of Women and Children Key Lab of Sichuan Province; West China Second University Hospital, College of Life Sciences, Sichuan University, Chengdu 610041, China
| | - Lu Chen
- Key Lab of Birth Defects and Related Diseases of Women and Children of MOE; State Key Lab of Biotherapy; State Key Laboratory of Respiratory Health and Multimorbidity; NHC Key Laboratory of Chronobiology; Sichuan-Chongqing Key Lab of Bio-Resource Research and Utilization; Development and Related Diseases of Women and Children Key Lab of Sichuan Province; West China Second University Hospital, College of Life Sciences, Sichuan University, Chengdu 610041, China
| | - Qiang Pu
- Department of Respiratory and Critical Care Medicine, Department of Thoracic Surgery and Institute of Thoracic Oncology, and Laboratory of Liver Transplantation, West China Hospital, Chengdu 610041, China
| | - Liming Yang
- Department of Pathophysiology, Harbin Medical University, Harbin 150081, China
| | - Zhongwei Cao
- Key Lab of Birth Defects and Related Diseases of Women and Children of MOE; State Key Lab of Biotherapy; State Key Laboratory of Respiratory Health and Multimorbidity; NHC Key Laboratory of Chronobiology; Sichuan-Chongqing Key Lab of Bio-Resource Research and Utilization; Development and Related Diseases of Women and Children Key Lab of Sichuan Province; West China Second University Hospital, College of Life Sciences, Sichuan University, Chengdu 610041, China
| | - Bi-Sen Ding
- Key Lab of Birth Defects and Related Diseases of Women and Children of MOE; State Key Lab of Biotherapy; State Key Laboratory of Respiratory Health and Multimorbidity; NHC Key Laboratory of Chronobiology; Sichuan-Chongqing Key Lab of Bio-Resource Research and Utilization; Development and Related Diseases of Women and Children Key Lab of Sichuan Province; West China Second University Hospital, College of Life Sciences, Sichuan University, Chengdu 610041, China
| |
Collapse
|
|
7
|
Mishra F, Yuan Y, Yang JJ, Li B, Chan P, Liu Z. Depletion of Activated Hepatic Stellate Cells and Capillarized Liver Sinusoidal Endothelial Cells Using a Rationally Designed Protein for Nonalcoholic Steatohepatitis and Alcoholic Hepatitis Treatment. Int J Mol Sci 2024; 25:7447. [PMID: 39000553 PMCID: PMC11242029 DOI: 10.3390/ijms25137447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Revised: 06/28/2024] [Accepted: 07/01/2024] [Indexed: 07/16/2024] Open
Abstract
Nonalcoholic steatohepatitis (NASH) and alcoholic hepatitis (AH) affect a large part of the general population worldwide. Dysregulation of lipid metabolism and alcohol toxicity drive disease progression by the activation of hepatic stellate cells and the capillarization of liver sinusoidal endothelial cells. Collagen deposition, along with sinusoidal remodeling, alters sinusoid structure, resulting in hepatic inflammation, portal hypertension, liver failure, and other complications. Efforts were made to develop treatments for NASH and AH. However, the success of such treatments is limited and unpredictable. We report a strategy for NASH and AH treatment involving the induction of integrin αvβ3-mediated cell apoptosis using a rationally designed protein (ProAgio). Integrin αvβ3 is highly expressed in activated hepatic stellate cells (αHSCs), the angiogenic endothelium, and capillarized liver sinusoidal endothelial cells (caLSECs). ProAgio induces the apoptosis of these disease-driving cells, therefore decreasing collagen fibril, reversing sinusoid remodeling, and reducing immune cell infiltration. The reversal of sinusoid remodeling reduces the expression of leukocyte adhesion molecules on LSECs, thus decreasing leukocyte infiltration/activation in the diseased liver. Our studies present a novel and effective approach for NASH and AH treatment.
Collapse
Affiliation(s)
- Falguni Mishra
- Department of Biology, Georgia State University, Atlanta, GA 30303, USA
| | - Yi Yuan
- Department of Biology, Georgia State University, Atlanta, GA 30303, USA
| | - Jenny J Yang
- Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA
| | - Bin Li
- Department of Biology, Georgia State University, Atlanta, GA 30303, USA
| | - Payton Chan
- Department of Biology, Georgia State University, Atlanta, GA 30303, USA
| | - Zhiren Liu
- Department of Biology, Georgia State University, Atlanta, GA 30303, USA
| |
Collapse
|
|
8
|
He S, Luo Y, Ma W, Wang X, Yan C, Hao W, Fang Y, Su H, Lai B, Liu J, Xiong Y, Bai T, Ren X, Liu E, Han H, Wu Y, Yuan Z, Wang Y. Endothelial POFUT1 controls injury-induced liver fibrosis by repressing fibrinogen synthesis. J Hepatol 2024; 81:135-148. [PMID: 38460791 DOI: 10.1016/j.jhep.2024.02.032] [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: 07/20/2023] [Revised: 02/19/2024] [Accepted: 02/27/2024] [Indexed: 03/11/2024]
Abstract
BACKGROUND & AIMS NOTCH signaling in liver sinusoidal endothelial cells (LSECs) regulates liver fibrosis, a pathological feature of chronic liver diseases. POFUT1 is an essential regulator of NOTCH signaling. Here, we investigated the role of LSEC-expressed POFUT1 in liver fibrosis. METHODS Endothelial-specific Pofut1 knockout mice were generated and experimental liver fibrosis was induced by chronic carbon tetrachloride exposure or common bile duct ligation. Liver samples were assessed by ELISA, histology, electron microscopy, immunostaining and RNA in situ hybridization. LSECs and hepatic stellate cells (HSCs) were isolated for gene expression analysis by RNA sequencing, qPCR, and western blotting. Signaling crosstalk between LSECs and HSCs was investigated by treating HSCs with supernatant from LSEC cultures. Liver single-cell RNA sequencing datasets from patients with cirrhosis and healthy individuals were analyzed to evaluate the clinical relevance of gene expression changes observed in mouse studies. RESULTS POFUT1 loss promoted injury-induced LSEC capillarization and HSC activation, leading to aggravated liver fibrosis. RNA sequencing analysis revealed that POFUT1 deficiency upregulated fibrinogen expression in LSECs. Consistently, fibrinogen was elevated in LSECs of patients with cirrhosis. HSCs treated with supernatant from LSECs of Pofut1 null mice showed exacerbated activation compared to those treated with supernatant from control LSECs, and this effect was attenuated by knockdown of fibrinogen or by pharmacological inhibition of fibrinogen receptor signaling, altogether suggesting that LSEC-derived fibrinogen induced the activation of HSCs. Mechanistically, POFUT1 loss augmented fibrinogen expression by enhancing NOTCH/HES1/STAT3 signaling. CONCLUSIONS Endothelial POFUT1 prevents injury-induced liver fibrosis by repressing the expression of fibrinogen, which functions as a profibrotic paracrine signal to activate HSCs. Therapies targeting the POFUT1/fibrinogen axis offer a promising strategy for the prevention and treatment of fibrotic liver diseases. IMPACT AND IMPLICATIONS Paracrine signals produced by liver vasculature play a major role in the development of liver fibrosis, which is a pathological hallmark of most liver diseases. Identifying those paracrine signals is clinically relevant in that they may serve as therapeutic targets. In this study, we discovered that genetic deletion of Pofut1 aggravated experimental liver fibrosis in mouse models. Moreover, fibrinogen was identified as a downstream target repressed by Pofut1 in liver endothelial cells and functioned as a novel paracrine signal that drove liver fibrosis. In addition, fibrinogen was found to be relevant to cirrhosis and may serve as a potential therapeutic target for this devastating human disease.
Collapse
Affiliation(s)
- Shan He
- The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Department of Stomatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Yuru Luo
- The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Wangge Ma
- Cardiovascular Department, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Xiaoke Wang
- Cardiovascular Department, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Chengrong Yan
- The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Wenyang Hao
- The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Yuan Fang
- The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Hongyu Su
- The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Baochang Lai
- The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Junhui Liu
- Clinical Laboratory, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Ying Xiong
- Cardiovascular Department, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Ting Bai
- Cardiovascular Department, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Xiaoyong Ren
- Department of Stomatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Enqi Liu
- Department of Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Hua Han
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancer and Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Yue Wu
- Cardiovascular Department, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Cardiometabolic Innovation Center, Ministry of Education, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
| | - Zuyi Yuan
- Cardiovascular Department, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Cardiometabolic Innovation Center, Ministry of Education, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
| | - Yidong Wang
- The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Cardiovascular Department, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Cardiometabolic Innovation Center, Ministry of Education, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Department of Cardiology, Wenling First People's Hospital, The Affiliated Hospital of Wenzhou Medical University, Wenling, Zhejiang, China.
| |
Collapse
|
|
9
|
Liang M, Lyu ZS, Zhang YY, Tang SQ, Xing T, Chen YH, Wang Y, Jiang Q, Xu LP, Zhang XH, Huang XJ, Kong Y. Activation of PPARδ in bone marrow endothelial progenitor cells improves their hematopoiesis-supporting ability after myelosuppressive injury. Cancer Lett 2024; 592:216937. [PMID: 38704134 DOI: 10.1016/j.canlet.2024.216937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 04/30/2024] [Accepted: 04/30/2024] [Indexed: 05/06/2024]
Abstract
Dysfunctional bone marrow (BM) endothelial progenitor cells (EPCs) with high levels of reactive oxygen species (ROS) are responsible for defective hematopoiesis in poor graft function (PGF) patients with acute leukemia or myelodysplastic neoplasms post-allotransplant. However, the underlying mechanism by which BM EPCs regulate their intracellular ROS levels and the capacity to support hematopoiesis have not been well clarified. Herein, we demonstrated decreased levels of peroxisome proliferator-activated receptor delta (PPARδ), a lipid-activated nuclear receptor, in BM EPCs of PGF patients compared with those with good graft function (GGF). In vitro assays further identified that PPARδ knockdown contributed to reduced and dysfunctional BM EPCs, characterized by the impaired ability to support hematopoiesis, which were restored by PPARδ overexpression. Moreover, GW501516, an agonist of PPARδ, repaired the damaged BM EPCs triggered by 5-fluorouracil (5FU) in vitro and in vivo. Clinically, activation of PPARδ by GW501516 benefited the damaged BM EPCs from PGF patients or acute leukemia patients in complete remission (CR) post-chemotherapy. Mechanistically, we found that increased expression of NADPH oxidases (NOXs), the main ROS-generating enzymes, may lead to elevated ROS level in BM EPCs, and insufficient PPARδ may trigger BM EPC damage via ROS/p53 pathway. Collectively, we found that defective PPARδ contributes to BM EPC dysfunction, whereas activation of PPARδ in BM EPCs improves their hematopoiesis-supporting ability after myelosuppressive therapy, which may provide a potential therapeutic target not only for patients with leukemia but also for those with other cancers.
Collapse
Affiliation(s)
- Mi Liang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Zhong-Shi Lyu
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Yuan-Yuan Zhang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, China.
| | - Shu-Qian Tang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Tong Xing
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, China; Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Yu-Hong Chen
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Yu Wang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Qian Jiang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Lan-Ping Xu
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Xiao-Hui Zhang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Xiao-Jun Huang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, China; Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China; State Key Laboratory of Natural and Biomimetic Drugs, China.
| | - Yuan Kong
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, China.
| |
Collapse
|
|
10
|
Scheidecker B, Poulain S, Sugimoto M, Arakawa H, Kim SH, Kawanishi T, Kato Y, Danoy M, Nishikawa M, Sakai Y. Mechanobiological stimulation in organ-on-a-chip systems reduces hepatic drug metabolic capacity in favor of regenerative specialization. Biotechnol Bioeng 2024; 121:1435-1452. [PMID: 38184801 DOI: 10.1002/bit.28653] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 12/20/2023] [Accepted: 12/22/2023] [Indexed: 01/08/2024]
Abstract
Hepatic physiology depends on the liver's complex structural composition which among others, provides high oxygen supply rates, locally differential oxygen tension, endothelial paracrine signaling, as well as residual hemodynamic shear stress to resident hepatocytes. While functional improvements were shown by implementing these factors into hepatic culture systems, direct cause-effect relationships are often not well characterized-obfuscating their individual contribution in more complex microphysiological systems. By comparing increasingly complex hepatic in vitro culture systems that gradually implement these parameters, we investigate the influence of the cellular microenvironment to overall hepatic functionality in pharmacological applications. Here, hepatocytes were modulated in terms of oxygen tension and supplementation, endothelial coculture, and exposure to fluid shear stress delineated from oxygen influx. Results from transcriptomic and metabolomic evaluation indicate that particularly oxygen supply rates are critical to enhance cellular functionality-with cellular drug metabolism remaining comparable to physiological conditions after prolonged static culture. Endothelial signaling was found to be a major contributor to differential phenotype formation known as metabolic zonation, indicated by WNT pathway activity. Lastly, oxygen-delineated shear stress was identified to direct cellular fate towards increased hepatic plasticity and regenerative phenotypes at the cost of drug metabolic functionality - in line with regenerative effects observed in vivo. With these results, we provide a systematic evaluation of critical parameters and their impact in hepatic systems. Given their adherence to physiological effects in vivo, this highlights the importance of their implementation in biomimetic devices, such as organ-on-a-chip systems. Considering recent advances in basic liver biology, direct translation of physiological structures into in vitro models is a promising strategy to expand the capabilities of pharmacological models.
Collapse
Affiliation(s)
| | - Stéphane Poulain
- Institute of Industrial Science, University of Tokyo, Tokyo, Japan
| | - Masahiro Sugimoto
- Institute for Advanced Biosciences, Keio University, Yamagata, Japan
- Institute of Medical Science, Tokyo Medical University, Tokyo, Japan
| | - Hiroshi Arakawa
- Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
| | - Soo H Kim
- Institute of Industrial Science, University of Tokyo, Tokyo, Japan
| | - Takumi Kawanishi
- Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
| | - Yukio Kato
- Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
| | - Mathieu Danoy
- Department of Chemical System Engineering, University of Tokyo, Tokyo, Japan
| | - Masaki Nishikawa
- Department of Chemical System Engineering, University of Tokyo, Tokyo, Japan
| | - Yasuyuki Sakai
- Department of Chemical System Engineering, University of Tokyo, Tokyo, Japan
| |
Collapse
|
|
11
|
Crawford JM, Bioulac-Sage P, Hytiroglou P. Structure, Function and Responses to Injury. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:1-95. [DOI: 10.1016/b978-0-7020-8228-3.00001-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
12
|
Gerwing M, Schindler P, Katou S, Köhler M, Stamm AC, Schmidt VF, Heindel W, Struecker B, Morgul H, Pascher A, Wildgruber M, Masthoff M. Multi-organ Radiomics-Based Prediction of Future Remnant Liver Hypertrophy Following Portal Vein Embolization. Ann Surg Oncol 2023; 30:7976-7985. [PMID: 37670120 PMCID: PMC10625940 DOI: 10.1245/s10434-023-14241-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 07/24/2023] [Indexed: 09/07/2023]
Abstract
BACKGROUND Portal vein embolization (PVE) is used to induce remnant liver hypertrophy prior to major hepatectomy. The purpose of this study was to evaluate the predictive value of baseline computed tomography (CT) data for future remnant liver (FRL) hypertrophy after PVE. METHODS In this retrospective study, all consecutive patients undergoing right-sided PVE with or without hepatic vein embolization between 2018 and 2021 were included. CT volumetry was performed before and after PVE to assess standardized FRL volume (sFRLV). Radiomic features were extracted from baseline CT after segmenting liver (without tumor), spleen and bone marrow. For selecting features that allow classification of response (hypertrophy ≥ 1.33), a stepwise dimension reduction was performed. Logistic regression models were fitted and selected features were tested for their predictive value. Decision curve analysis was performed on the test dataset. RESULTS A total of 53 patients with liver tumor were included in this study. sFRLV increased significantly after PVE, with a mean hypertrophy of FRL of 1.5 ± 0.3-fold. sFRLV hypertrophy ≥ 1.33 was reached in 35 (66%) patients. Three independent radiomic features, i.e. liver-, spleen- and bone marrow-associated, differentiated well between responders and non-responders. A logistic regression model revealed the highest accuracy (area under the curve 0.875) for the prediction of response, with sensitivity of 1.0 and specificity of 0.5. Decision curve analysis revealed a positive net benefit when applying the model. CONCLUSIONS This proof-of-concept study provides first evidence of a potential predictive value of baseline multi-organ radiomics CT data for FRL hypertrophy after PVE.
Collapse
Affiliation(s)
- Mirjam Gerwing
- Clinic for Radiology, University Hospital Münster, Münster, Germany.
| | | | - Shadi Katou
- Department for General, Visceral and Transplant Surgery, University Hospital Münster, Münster, Germany
| | - Michael Köhler
- Clinic for Radiology, University Hospital Münster, Münster, Germany
| | | | | | - Walter Heindel
- Clinic for Radiology, University Hospital Münster, Münster, Germany
| | - Benjamin Struecker
- Department for General, Visceral and Transplant Surgery, University Hospital Münster, Münster, Germany
| | - Haluk Morgul
- Department for General, Visceral and Transplant Surgery, University Hospital Münster, Münster, Germany
| | - Andreas Pascher
- Department for General, Visceral and Transplant Surgery, University Hospital Münster, Münster, Germany
| | - Moritz Wildgruber
- Clinic for Radiology, University Hospital Münster, Münster, Germany
- Department for Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Max Masthoff
- Clinic for Radiology, University Hospital Münster, Münster, Germany
| |
Collapse
|
|
13
|
Lotto J, Stephan TL, Hoodless PA. Fetal liver development and implications for liver disease pathogenesis. Nat Rev Gastroenterol Hepatol 2023; 20:561-581. [PMID: 37208503 DOI: 10.1038/s41575-023-00775-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/30/2023] [Indexed: 05/21/2023]
Abstract
The metabolic, digestive and homeostatic roles of the liver are dependent on proper crosstalk and organization of hepatic cell lineages. These hepatic cell lineages are derived from their respective progenitors early in organogenesis in a spatiotemporally controlled manner, contributing to the liver's specialized and diverse microarchitecture. Advances in genomics, lineage tracing and microscopy have led to seminal discoveries in the past decade that have elucidated liver cell lineage hierarchies. In particular, single-cell genomics has enabled researchers to explore diversity within the liver, especially early in development when the application of bulk genomics was previously constrained due to the organ's small scale, resulting in low cell numbers. These discoveries have substantially advanced our understanding of cell differentiation trajectories, cell fate decisions, cell lineage plasticity and the signalling microenvironment underlying the formation of the liver. In addition, they have provided insights into the pathogenesis of liver disease and cancer, in which developmental processes participate in disease emergence and regeneration. Future work will focus on the translation of this knowledge to optimize in vitro models of liver development and fine-tune regenerative medicine strategies to treat liver disease. In this Review, we discuss the emergence of hepatic parenchymal and non-parenchymal cells, advances that have been made in in vitro modelling of liver development and draw parallels between developmental and pathological processes.
Collapse
Affiliation(s)
- Jeremy Lotto
- Terry Fox Laboratory, BC Cancer, Vancouver, BC, Canada
- Cell and Developmental Biology Program, University of British Columbia, Vancouver, BC, Canada
| | - Tabea L Stephan
- Terry Fox Laboratory, BC Cancer, Vancouver, BC, Canada
- Cell and Developmental Biology Program, University of British Columbia, Vancouver, BC, Canada
| | - Pamela A Hoodless
- Terry Fox Laboratory, BC Cancer, Vancouver, BC, Canada.
- Cell and Developmental Biology Program, University of British Columbia, Vancouver, BC, Canada.
| |
Collapse
|
|
14
|
McConnell MJ, Kostallari E, Ibrahim SH, Iwakiri Y. The evolving role of liver sinusoidal endothelial cells in liver health and disease. Hepatology 2023; 78:649-669. [PMID: 36626620 PMCID: PMC10315420 DOI: 10.1097/hep.0000000000000207] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 11/25/2022] [Indexed: 01/12/2023]
Abstract
LSECs are a unique population of endothelial cells within the liver and are recognized as key regulators of liver homeostasis. LSECs also play a key role in liver disease, as dysregulation of their quiescent phenotype promotes pathological processes within the liver including inflammation, microvascular thrombosis, fibrosis, and portal hypertension. Recent technical advances in single-cell analysis have characterized distinct subpopulations of the LSECs themselves with a high resolution and defined their gene expression profile and phenotype, broadening our understanding of their mechanistic role in liver biology. This article will review 4 broad advances in our understanding of LSEC biology in general: (1) LSEC heterogeneity, (2) LSEC aging and senescence, (3) LSEC role in liver regeneration, and (4) LSEC role in liver inflammation and will then review the role of LSECs in various liver pathologies including fibrosis, DILI, alcohol-associated liver disease, NASH, viral hepatitis, liver transplant rejection, and ischemia reperfusion injury. The review will conclude with a discussion of gaps in knowledge and areas for future research.
Collapse
Affiliation(s)
- Matthew J. McConnell
- Section of Digestive Disease, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut
| | | | - Samar H. Ibrahim
- Division of Gastroenterology, Mayo Clinic, Rochester, MN
- Division of Pediatric Gastroenterology, Mayo Clinic, Rochester, MN
| | - Yasuko Iwakiri
- Section of Digestive Disease, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut
| |
Collapse
|
|
15
|
Toya K, Tomimaru Y, Kobayashi S, Harada A, Sasaki K, Iwagami Y, Yamada D, Noda T, Takahashi H, Kado T, Imamura H, Takaichi S, Chijimatsu R, Asaoka T, Tanemura M, Miyagawa S, Doki Y, Eguchi H. Efficacy of Autologous Skeletal Myoblast Cell Sheet Transplantation for Liver Regeneration in Liver Failure. Transplantation 2023; 107:e190-e200. [PMID: 37046371 DOI: 10.1097/tp.0000000000004567] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/14/2023]
Abstract
BACKGROUND No effective therapies have yet been established for liver regeneration in liver failure. Autologous skeletal myoblast cell sheet transplantation has been proven to improve cardiac function in patients with heart failure, and one of the mechanisms has been reported to be a paracrine effect by various growth factors associated with liver regeneration. Therefore, the present study focused on the effect of myoblast cells on liver regeneration in vitro and in vivo. METHODS We assessed the effect of myoblast cells on the cells comprising the liver in vitro in association with liver regeneration. In addition, we examined in vivo effect of skeletal myoblast cell sheet transplantation in C57/BL/6 mouse models of liver failure, such as liver fibrosis induced by thioacetamide and hepatectomy. RESULTS In vitro, the myoblast cells exhibited a capacity to promote the proliferation of hepatic epithelial cells and the angiogenesis of liver sinusoidal endothelial cells, and suppress the activation of hepatic stellate cells. In vivo, sheet transplantation significantly suppressed liver fibrosis in the induced liver fibrosis model and accelerated liver regeneration in the hepatectomy model. CONCLUSIONS Autologous skeletal myoblast cell sheet transplantation significantly improved the liver failure in the in vitro and in vivo models. Sheet transplantation is expected to have the potential to be a clinically therapeutic option for liver regeneration in liver failure.
Collapse
Affiliation(s)
- Keisuke Toya
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Yoshito Tomimaru
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Shogo Kobayashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Akima Harada
- Department of Cardiovascular Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Kazuki Sasaki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Yoshifumi Iwagami
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Daisaku Yamada
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Takehiro Noda
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Hidenori Takahashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Takeshi Kado
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Hiroki Imamura
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Shohei Takaichi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Ryota Chijimatsu
- Center for Comprehensive Genomic Medicine, Okayama University Hospital, Okayama, Japan
| | - Tadafumi Asaoka
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Masahiro Tanemura
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Shigeru Miyagawa
- Department of Cardiovascular Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| |
Collapse
|
|
16
|
Ito Y, Hosono K, Amano H. Responses of hepatic sinusoidal cells to liver ischemia–reperfusion injury. Front Cell Dev Biol 2023; 11:1171317. [PMID: 37082623 PMCID: PMC10112669 DOI: 10.3389/fcell.2023.1171317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 03/27/2023] [Indexed: 04/07/2023] Open
Abstract
The liver displays a remarkable regenerative capacity in response to acute liver injury. In addition to the proliferation of hepatocytes during liver regeneration, non-parenchymal cells, including liver macrophages, liver sinusoidal endothelial cells (LSECs), and hepatic stellate cells (HSCs) play critical roles in liver repair and regeneration. Liver ischemia–reperfusion injury (IRI) is a major cause of increased liver damage during liver resection, transplantation, and trauma. Impaired liver repair increases postoperative morbidity and mortality of patients who underwent liver surgery. Successful liver repair and regeneration after liver IRI requires coordinated interplay and synergic actions between hepatic resident cells and recruited cell components. However, the underlying mechanisms of liver repair after liver IRI are not well understood. Recent technological advances have revealed the heterogeneity of each liver cell component in the steady state and diseased livers. In this review, we describe the progress in the biology of liver non-parenchymal cells obtained from novel technological advances. We address the functional role of each cell component in response to liver IRI and the interactions between diverse immune repertoires and non-hematopoietic cell populations during the course of liver repair after liver IRI. We also discuss how these findings can help in the design of novel therapeutic approaches. Growing insights into the cellular interactions during liver IRI would enhance the pathology of liver IRI understanding comprehensively and further develop the strategies for improvement of liver repair.
Collapse
|
|
17
|
Cao Z, Ding BS. Aging breaks liver vascular 'zone defense'. NATURE AGING 2023; 3:242-243. [PMID: 37118427 DOI: 10.1038/s43587-023-00371-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/30/2023]
Affiliation(s)
- Zhongwei Cao
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, NHC Key Laboratory of Chronobiology, Development and Related Diseases of Women and Children, Key Laboratory of Sichuan Province, West China Second University Hospital, Sichuan University, Chengdu, China.
| | - Bi-Sen Ding
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, NHC Key Laboratory of Chronobiology, Development and Related Diseases of Women and Children, Key Laboratory of Sichuan Province, West China Second University Hospital, Sichuan University, Chengdu, China.
| |
Collapse
|
|
18
|
Metabolomic Analysis, Perfusate Composition, and Pseudo-physiology of the Isolated Liver During Ex Situ Normothermic Machine Perfusion. Transplantation 2023; 107:e125-e126. [PMID: 36857151 DOI: 10.1097/tp.0000000000004530] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/02/2023]
|
|
19
|
Li ZW, Wang L. The role of liver sinusoidal endothelial cells in liver remodeling after injury. Hepatobiliary Pancreat Dis Int 2023; 22:22-27. [PMID: 36182636 DOI: 10.1016/j.hbpd.2022.09.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 09/15/2022] [Indexed: 02/07/2023]
Abstract
Liver transplantation is the optimal treatment for patients with end-stage liver disease, metabolic liver diseases, and hepatic malignancies that are not amenable to resection. Hepatic ischemia-reperfusion injury (IRI) is the main problem in liver transplantation and liver resection, leading to parenchymal cell injury and organ dysfunction. The damage of liver sinusoidal endothelial cells (LSECs) is a critical event in IRI. LSECs work as an important regulating factor of liver regeneration after partial hepatectomy. This review primarily describes the mechanisms of LSECs injury in IRI and explores the roles of LSECs in liver regeneration, and briefly introduces the protective strategies targeting LSECs damaged in IRI.
Collapse
Affiliation(s)
- Zhi-Wen Li
- Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China
| | - Lin Wang
- Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
| |
Collapse
|
|
20
|
Role of Endothelial Progenitor Cells in Frailty. Int J Mol Sci 2023; 24:ijms24032139. [PMID: 36768461 PMCID: PMC9916666 DOI: 10.3390/ijms24032139] [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: 12/26/2022] [Revised: 01/16/2023] [Accepted: 01/18/2023] [Indexed: 01/25/2023] Open
Abstract
Frailty is a clinical condition closely related to aging which is characterized by a multidimensional decline in biological reserves, a failure of physiological mechanisms and vulnerability to minor stressors. Chronic inflammation, the impairment of endothelial function, age-related endocrine system modifications and immunosenescence are important mechanisms in the pathophysiology of frailty. Endothelial progenitor cells (EPCs) are considered important contributors of the endothelium homeostasis and turn-over. In the elderly, EPCs are impaired in terms of function, number and survival. In addition, the modification of EPCs' level and function has been widely demonstrated in atherosclerosis, hypertension and diabetes mellitus, which are the most common age-related diseases. The purpose of this review is to illustrate the role of EPCs in frailty. Initially, we describe the endothelial dysfunction in frailty, the response of EPCs to the endothelial dysfunction associated with frailty and, finally, interventions which may restore the EPCs expression and function in frail people.
Collapse
|
|
21
|
Lv W, Zhou H, Aazmi A, Yu M, Xu X, Yang H, Huang YYS, Ma L. Constructing biomimetic liver models through biomaterials and vasculature engineering. Regen Biomater 2022; 9:rbac079. [PMID: 36338176 PMCID: PMC9629974 DOI: 10.1093/rb/rbac079] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Revised: 09/19/2022] [Accepted: 10/08/2022] [Indexed: 04/04/2024] Open
Abstract
The occurrence of various liver diseases can lead to organ failure of the liver, which is one of the leading causes of mortality worldwide. Liver tissue engineering see the potential for replacing liver transplantation and drug toxicity studies facing donor shortages. The basic elements in liver tissue engineering are cells and biomaterials. Both mature hepatocytes and differentiated stem cells can be used as the main source of cells to construct spheroids and organoids, achieving improved cell function. To mimic the extracellular matrix (ECM) environment, biomaterials need to be biocompatible and bioactive, which also help support cell proliferation and differentiation and allow ECM deposition and vascularized structures formation. In addition, advanced manufacturing approaches are required to construct the extracellular microenvironment, and it has been proved that the structured three-dimensional culture system can help to improve the activity of hepatocytes and the characterization of specific proteins. In summary, we review biomaterials for liver tissue engineering, including natural hydrogels and synthetic polymers, and advanced processing techniques for building vascularized microenvironments, including bioassembly, bioprinting and microfluidic methods. We then summarize the application fields including transplant and regeneration, disease models and drug cytotoxicity analysis. In the end, we put the challenges and prospects of vascularized liver tissue engineering.
Collapse
Affiliation(s)
- Weikang Lv
- State Key Laboratory of Fluid Power and Mechatronic Systems, Zhejiang University, Hangzhou 310058, China
- School of Mechanical Engineering, Zhejiang University, Hangzhou 310058, China
| | - Hongzhao Zhou
- State Key Laboratory of Fluid Power and Mechatronic Systems, Zhejiang University, Hangzhou 310058, China
- School of Mechanical Engineering, Zhejiang University, Hangzhou 310058, China
| | - Abdellah Aazmi
- State Key Laboratory of Fluid Power and Mechatronic Systems, Zhejiang University, Hangzhou 310058, China
- School of Mechanical Engineering, Zhejiang University, Hangzhou 310058, China
| | - Mengfei Yu
- The Affiliated Stomatologic Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Xiaobin Xu
- School of Materials Science and Engineering, Tongji University, Shanghai 201804, China
| | - Huayong Yang
- State Key Laboratory of Fluid Power and Mechatronic Systems, Zhejiang University, Hangzhou 310058, China
- School of Mechanical Engineering, Zhejiang University, Hangzhou 310058, China
| | | | - Liang Ma
- State Key Laboratory of Fluid Power and Mechatronic Systems, Zhejiang University, Hangzhou 310058, China
- School of Mechanical Engineering, Zhejiang University, Hangzhou 310058, China
| |
Collapse
|
|
22
|
Lyu ZS, Tang SQ, Xing T, Zhou Y, Lv M, Fu HX, Wang Y, Xu LP, Zhang XH, Lee HY, Kong Y, Huang XJ. The glycolytic enzyme PFKFB3 determines bone marrow endothelial progenitor cell damage after chemotherapy and irradiation. Haematologica 2022; 107:2365-2380. [PMID: 35354250 PMCID: PMC9521251 DOI: 10.3324/haematol.2021.279756] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 03/24/2022] [Indexed: 11/09/2022] Open
Abstract
Bone marrow (BM) endothelial progenitor cell (EPC) damage of unknown mechanism delays the repair of endothelial cells (EC) and recovery of hematopoiesis after chemo-radiotherapy. We found increased levels of the glycolytic enzyme PFKFB3 in the damaged BM EPC of patients with poor graft function, a clinical model of EPC damage-associated poor hematopoiesis after allogeneic hematopoietic stem cell transplantation. Moreover, in vitro the glycolysis inhibitor 3-(3-pyridinyl)- 1-(4-pyridinyl)-2-propen-1-one (3PO) alleviated the damaged BM EPC from patients with poor graft function. Consistently, PFKFB3 overexpression triggered BM EPC damage after 5-fluorouracil treatment and impaired hematopoiesis-supporting ability in vitro. Mechanistically, PFKFB3 facilitated pro-apoptotic transcription factor FOXO3A and expression of its downstream genes, including p21, p27, and FAS, after 5-fluorouracil treatment in vitro. Moreover, PFKFB3 induced activation of NF-κB and expression of its downstream adhesion molecule E-selectin, while it reduced hematopoietic factor SDF-1 expression, which could be rescued by FOXO3A silencing. High expression of PFKFB3 was found in damaged BM EC of murine models of chemo-radiotherapy-induced myelosuppression. Furthermore, a murine model of BM EC-specific PFKFB3 overexpression demonstrated that PFKFB3 aggravated BM EC damage, and impaired the recovery of hematopoiesis after chemotherapy in vivo, effects which could be mitigated by 3PO, indicating a critical role of PFKFB3 in regulating BM EC damage. Clinically, PFKFB3-induced FOXO3A expression and NF-κB activation were confirmed to contribute to the damaged BM EPC of patients with acute leukemia after chemotherapy. 3PO repaired the damaged BM EPC by reducing FOXO3A expression and phospho-NF-κB p65 in patients after chemotherapy. In summary, our results reveal a critical role of PFKFB3 in triggering BM EPC damage and indicate that endothelial-PFKFB3 may be a potential therapeutic target for myelosuppressive injury.
Collapse
Affiliation(s)
- Zhong-Shi Lyu
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, China; Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing
| | - Shu-Qian Tang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing
| | - Tong Xing
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, China; Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing
| | - Yang Zhou
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing
| | - Meng Lv
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing
| | - Hai-Xia Fu
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing
| | - Yu Wang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing
| | - Lan-Ping Xu
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing
| | - Xiao-Hui Zhang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing
| | - Hsiang-Ying Lee
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China; School of Life Sciences, Peking University, Beijing
| | - Yuan Kong
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing.
| | - Xiao-Jun Huang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, China; Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing.
| |
Collapse
|
|
23
|
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:ijms23179868. [PMID: 36077265 PMCID: PMC9456487 DOI: 10.3390/ijms23179868] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 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.
Collapse
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
- Correspondence:
| | - 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
| |
Collapse
|
|
24
|
Fan Z, Kong M, Dong W, Dong C, Miao X, Guo Y, Liu X, Miao S, Li L, Chen T, Qu Y, Yu F, Duan Y, Lu Y, Zou X. Trans-activation of eotaxin-1 by Brg1 contributes to liver regeneration. Cell Death Dis 2022; 13:495. [PMID: 35614068 PMCID: PMC9132924 DOI: 10.1038/s41419-022-04944-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 05/10/2022] [Accepted: 05/12/2022] [Indexed: 12/14/2022]
Abstract
Infiltration of eosinophils is associated with and contributes to liver regeneration. Chemotaxis of eosinophils is orchestrated by the eotaxin family of chemoattractants. We report here that expression of eotaxin-1 (referred to as eotaxin hereafter), but not that of either eotaxin-2 or eotaxin-3, were elevated, as measured by quantitative PCR and ELISA, in the proliferating murine livers compared to the quiescent livers. Similarly, exposure of primary murine hepatocytes to hepatocyte growth factor (HGF) stimulated eotaxin expression. Liver specific deletion of Brahma-related gene 1 (Brg1), a chromatin remodeling protein, attenuated eosinophil infiltration and down-regulated eotaxin expression in mice. Brg1 deficiency also blocked HGF-induced eotaxin expression in cultured hepatocytes. Further analysis revealed that Brg1 could directly bind to the proximal eotaxin promoter to activate its transcription. Mechanistically, Brg1 interacted with nuclear factor kappa B (NF-κB)/RelA to activate eotaxin transcription. NF-κB knockdown or pharmaceutical inhibition disrupted Brg1 recruitment to the eotaxin promoter and blocked eotaxin induction in hepatocytes. Adenoviral mediated over-expression of eotaxin overcame Brg1 deficiency caused delay in liver regeneration in mice. On the contrary, eotaxin depletion with RNAi or neutralizing antibodies retarded liver regeneration in mice. More important, Brg1 expression was detected to be correlated with eotaxin expression and eosinophil infiltration in human liver specimens. In conclusion, our data unveil a novel role of Brg1 as a regulator of eosinophil trafficking by activating eotaxin transcription.
Collapse
Affiliation(s)
- Zhiwen Fan
- grid.428392.60000 0004 1800 1685Department of Pathology, Nanjing Drum Tower Hospital Affiliated with Nanjing University School of Medicine, Nanjing, China ,grid.428392.60000 0004 1800 1685Department of Gastroenterology, Nanjing Drum Tower Hospital Affiliated with Nanjing University School of Medicine, Nanjing, China
| | - Ming Kong
- grid.89957.3a0000 0000 9255 8984Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | - Wenhui Dong
- grid.89957.3a0000 0000 9255 8984Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | - Chunlong Dong
- grid.410745.30000 0004 1765 1045Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital, Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xiulian Miao
- grid.411351.30000 0001 1119 5892College of Life Sciences and Institute of Biomedical Research, Liaocheng University, Liaocheng, China
| | - Yan Guo
- grid.411351.30000 0001 1119 5892College of Life Sciences and Institute of Biomedical Research, Liaocheng University, Liaocheng, China
| | - Xingyu Liu
- grid.411351.30000 0001 1119 5892College of Life Sciences and Institute of Biomedical Research, Liaocheng University, Liaocheng, China
| | - Shuying Miao
- grid.428392.60000 0004 1800 1685Department of Pathology, Nanjing Drum Tower Hospital Affiliated with Nanjing University School of Medicine, Nanjing, China
| | - Lin Li
- grid.428392.60000 0004 1800 1685Department of Pathology, Nanjing Drum Tower Hospital Affiliated with Nanjing University School of Medicine, Nanjing, China
| | - Tingting Chen
- grid.428392.60000 0004 1800 1685Department of Pathology, Nanjing Drum Tower Hospital Affiliated with Nanjing University School of Medicine, Nanjing, China
| | - Yeqing Qu
- grid.428392.60000 0004 1800 1685Experimental Animal Center, Nanjing Drum Tower Hospital Affiliated with Nanjing University School of Medicine, Nanjing, China
| | - Fei Yu
- grid.428392.60000 0004 1800 1685Experimental Animal Center, Nanjing Drum Tower Hospital Affiliated with Nanjing University School of Medicine, Nanjing, China
| | - Yunfei Duan
- grid.490563.d0000000417578685Department of Hepatobiliary Surgery, the First People’s Hospital of Changzhou, the Third Hospital Affiliated with Soochow University, Changzhou, China
| | - Yunjie Lu
- grid.490563.d0000000417578685Department of Hepatobiliary Surgery, the First People’s Hospital of Changzhou, the Third Hospital Affiliated with Soochow University, Changzhou, China
| | - Xiaoping Zou
- grid.428392.60000 0004 1800 1685Department of Gastroenterology, Nanjing Drum Tower Hospital Affiliated with Nanjing University School of Medicine, Nanjing, China
| |
Collapse
|
|
25
|
Mooli RGR, Mukhi D, Ramakrishnan SK. Oxidative Stress and Redox Signaling in the Pathophysiology of Liver Diseases. Compr Physiol 2022; 12:3167-3192. [PMID: 35578969 PMCID: PMC10074426 DOI: 10.1002/cphy.c200021] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The increased production of derivatives of molecular oxygen and nitrogen in the form of reactive oxygen species (ROS) and reactive nitrogen species (RNS) lead to molecular damage called oxidative stress. Under normal physiological conditions, the ROS generation is tightly regulated in different cells and cellular compartments. Any disturbance in the balance between the cellular generation of ROS and antioxidant balance leads to oxidative stress. In this article, we discuss the sources of ROS (endogenous and exogenous) and antioxidant mechanisms. We also focus on the pathophysiological significance of oxidative stress in various cell types of the liver. Oxidative stress is implicated in the development and progression of various liver diseases. We narrate the master regulators of ROS-mediated signaling and their contribution to liver diseases. Nonalcoholic fatty liver diseases (NAFLD) are influenced by a "multiple parallel-hit model" in which oxidative stress plays a central role. We highlight the recent findings on the role of oxidative stress in the spectrum of NAFLD, including fibrosis and liver cancer. Finally, we provide a brief overview of oxidative stress biomarkers and their therapeutic applications in various liver-related disorders. Overall, the article sheds light on the significance of oxidative stress in the pathophysiology of the liver. © 2022 American Physiological Society. Compr Physiol 12:3167-3192, 2022.
Collapse
Affiliation(s)
- Raja Gopal Reddy Mooli
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Dhanunjay Mukhi
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Sadeesh K Ramakrishnan
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| |
Collapse
|
|
26
|
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.
Collapse
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
| |
Collapse
|
|
27
|
Abstract
Non-alcoholic fatty liver disease is comprised of either simple steatosis (non-alcoholic fatty liver) or a more advanced inflammatory and fibrogenic stage (non-alcoholic steatohepatitis [NASH]). NASH affects a growing proportion of the global adult and pediatric population, leading to rising rates of liver fibrosis and hepatocellular carcinoma. NASH is a multifactorial disease that is part of a systemic metabolic disorder. Here, we provide an overview of the metabolic underpinnings of NASH pathogenesis and established drivers of inflammation and fibrosis. Clarification of underlying fibrogenic and inflammatory mechanisms will advance the development of novel treatment strategies as there are no approved therapies at present. We discuss emerging experimental approaches and potential novel investigational strategies derived from animal models including the inflammasome, epigenetic reprogramming, Hippo signaling, Notch signaling, engineered T cells to remove fibrogenic HSCs, and HSC-specific targeting therapies. Recently completed and ongoing clinical trials and antifibrotics are discussed, illuminating the growing expectation that one or more therapies will yield clinical benefit in NASH in the coming years.
Collapse
Affiliation(s)
- Youngmin A. Lee
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Scott L. Friedman
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| |
Collapse
|
|
28
|
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.
Collapse
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
| |
Collapse
|
|
29
|
Ghanim AMH, Younis NS, Metwaly HA. Vanillin augments liver regeneration effectively in Thioacetamide induced liver fibrosis rat model. Life Sci 2021; 286:120036. [PMID: 34637793 DOI: 10.1016/j.lfs.2021.120036] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 07/05/2021] [Accepted: 10/04/2021] [Indexed: 12/12/2022]
Abstract
AIMS This study has been designed to investigate the role of vanillin either as prophylaxis or treatment in liver regeneration augmentation and liver fibrosis regression in thioacetamide (TAA) induced liver damage. MATERIALS AND METHODS Animals were injected with TAA to induce liver injury (200mg/kg twice weekly) for 8 weeks. In vanillin prophylaxis group; rats were administered vanillin (100 mg/Kg; IP, daily) from day 1 of TAA injection for 8 weeks. In vanillin treatment group; rats were confronted with the same dose of TAA injection for 8 weeks then treated with vanillin (100 mg/Kg, IP, daily) for 4 weeks. ALT, AST activities, serum albumin, hepatic GSH, MDA, HGF, VEGF, IL-6 and TNF-α levels were measured and also, MMP-2, TIMP-1 and cyclin D gene expression were determined. Liver sections were stained with H&E and Sirius red and immunostained for Ki-67 and α-SMA for histological and immunohistological changes analysis. KEY FINDINGS Vanillin improved liver function and histology. Also, showed a remarkable increase in hepatic HGF and VEGF level, and up-regulation of cyclin D1 expression accompanied by a significant up-regulation of MMP-2 and down- regulation of TIMP-1. All these effects were accompanied by TNF-α, IL-6 and oxidative stress significant attenuation. SIGNIFICANCE In conclusion, vanillin enhanced liver regeneration in TAA induced liver damage model; targeting growth factors (HGF, VEGF) and cellular proliferation marker cyclin D1. As well as stimulating fibrosis regression by inhibition of ECM accumulation and enhancing its degradation.
Collapse
Affiliation(s)
- Amal M H Ghanim
- Department of Biochemistry, Faculty of Pharmacy, Fayoum University, Fayoum 63514, Egypt.
| | - Nancy S Younis
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, Saudi Arabia; Department of Pharmacology, Zagazig University, Zagazig, Egypt.
| | - Heba A Metwaly
- Department of Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21500, Egypt.
| |
Collapse
|
|
30
|
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: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
[Figure: see text].
Collapse
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
| |
Collapse
|
|
31
|
Turaga RC, Satyanarayana G, Sharma M, Yang JJ, Wang S, Liu C, Li S, Yang H, Grossniklaus H, Farris AB, Gracia-Sancho J, Liu ZR. Targeting integrin αvβ3 by a rationally designed protein for chronic liver disease treatment. Commun Biol 2021; 4:1087. [PMID: 34531529 PMCID: PMC8445973 DOI: 10.1038/s42003-021-02611-2] [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: 06/04/2020] [Accepted: 08/26/2021] [Indexed: 12/22/2022] Open
Abstract
Chronic Liver Diseases (CLD) are characterized by abnormal accumulation of collagen fibrils, neo-angiogenesis, and sinusoidal remodeling. Collagen deposition along with intrahepatic angiogenesis and sinusoidal remodeling alters sinusoid structure resulting in portal hypertension, liver failure, and other complications. Efforts were made to develop treatments for CLDs. However, the success of such treatments is limited and unpredictable. We report a strategy for CLD treatment by induction of integrin αvβ3 mediated cell apoptosis using a rationally designed protein (ProAgio). ProAgio is designed to target integrin αvβ3 at a novel site. Integrin αvβ3 is highly expressed in activated Hepatic Stellate Cells (HSC), angiogenic endothelium, and capillarized Liver Sinusoidal Endothelial Cells (LSEC). ProAgio induces apoptosis of these disease causative cells. Tests with liver fibrosis mouse models demonstrate that ProAgio reverses liver fibrosis and relieves blood flow resistance by depleting activated HSC and capillarized LSEC. Our studies demonstrate an effective approach for CLD treatment.
Collapse
Affiliation(s)
- Ravi Chakra Turaga
- Department of Biology, Georgia State University, Atlanta, GA, 30324, USA
| | | | - Malvika Sharma
- Department of Biology, Georgia State University, Atlanta, GA, 30324, USA
| | - Jenny J Yang
- Department of Chemistry, Georgia State University, Atlanta, USA
| | | | | | - Sun Li
- Department of Chemistry, Georgia State University, Atlanta, USA
| | - Hua Yang
- Department Ophthalmology, Emory University, Atlanta, GA, 30322, USA
| | | | | | | | - Zhi-Ren Liu
- Department of Biology, Georgia State University, Atlanta, GA, 30324, USA.
| |
Collapse
|
|
32
|
Große-Segerath L, Lammert E. Role of vasodilation in liver regeneration and health. Biol Chem 2021; 402:1009-1019. [PMID: 33908220 DOI: 10.1515/hsz-2021-0155] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 04/12/2021] [Indexed: 12/14/2022]
Abstract
Recently, we have shown that an enhanced blood flow through the liver triggers hepatocyte proliferation and thereby liver growth. In this review, we first explain the literature on hepatic blood flow and its changes after partial hepatectomy (PHx), before we present the different steps of liver regeneration that take place right after the initial hemodynamic changes induced by PHx. Those parts of the molecular mechanisms governing liver regeneration, which are directly associated with the hepatic vascular system, are subsequently reviewed. These include β1 integrin-dependent mechanotransduction in liver sinusoidal endothelial cells (LSECs), triggering mechanically-induced activation of the vascular endothelial growth factor receptor-3 (VEGFR3) and matrix metalloproteinase-9 (MMP9) as well as release of growth-promoting angiocrine signals. Finally, we speculate how advanced age and obesity negatively affect the hepatic vasculature and thus liver regeneration and health, and we conclude our review with some recent technical progress in the clinic that employs liver perfusion. In sum, the mechano-elastic properties and alterations of the hepatic vasculature are key to better understand and influence liver health, regeneration, and disease.
Collapse
Affiliation(s)
- Linda Große-Segerath
- Institute of Metabolic Physiology, Heinrich Heine University, D-40225 Düsseldorf, Germany
- Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, D-40225 Düsseldorf, Germany
- German Center for Diabetes Research (DZD e.V.), Helmholtz Zentrum München, D-85764 Neuherberg, Germany
| | - Eckhard Lammert
- Institute of Metabolic Physiology, Heinrich Heine University, D-40225 Düsseldorf, Germany
- Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, D-40225 Düsseldorf, Germany
- German Center for Diabetes Research (DZD e.V.), Helmholtz Zentrum München, D-85764 Neuherberg, Germany
| |
Collapse
|
|
33
|
De Rudder M, Dili A, Stärkel P, Leclercq IA. Critical Role of LSEC in Post-Hepatectomy Liver Regeneration and Failure. Int J Mol Sci 2021; 22:8053. [PMID: 34360818 PMCID: PMC8347197 DOI: 10.3390/ijms22158053] [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: 06/04/2021] [Revised: 07/20/2021] [Accepted: 07/24/2021] [Indexed: 02/07/2023] Open
Abstract
Liver sinusoids are lined by liver sinusoidal endothelial cells (LSEC), which represent approximately 15 to 20% of the liver cells, but only 3% of the total liver volume. LSEC have unique functions, such as fluid filtration, blood vessel tone modulation, blood clotting, inflammatory cell recruitment, and metabolite and hormone trafficking. Different subtypes of liver endothelial cells are also known to control liver zonation and hepatocyte function. Here, we have reviewed the origin of LSEC, the different subtypes identified in the liver, as well as their renewal during homeostasis. The liver has the exceptional ability to regenerate from small remnants. The past decades have seen increasing awareness in the role of non-parenchymal cells in liver regeneration despite not being the most represented population. While a lot of knowledge has emerged, clarification is needed regarding the role of LSEC in sensing shear stress and on their participation in the inductive phase of regeneration by priming the hepatocytes and delivering mitogenic factors. It is also unclear if bone marrow-derived LSEC participate in the proliferative phase of liver regeneration. Similarly, data are scarce as to LSEC having a role in the termination phase of the regeneration process. Here, we review what is known about the interaction between LSEC and other liver cells during the different phases of liver regeneration. We next explain extended hepatectomy and small liver transplantation, which lead to "small for size syndrome" (SFSS), a lethal liver failure. SFSS is linked to endothelial denudation, necrosis, and lobular disturbance. Using the knowledge learned from partial hepatectomy studies on LSEC, we expose several techniques that are, or could be, used to avoid the "small for size syndrome" after extended hepatectomy or small liver transplantation.
Collapse
Affiliation(s)
- Maxime De Rudder
- Laboratory of Hepato-Gastroenterology, Institute of Experimental and Clinical Research, UCLouvain, 1200 Brussels, Belgium; (M.D.R.); (A.D.); (P.S.)
| | - Alexandra Dili
- Laboratory of Hepato-Gastroenterology, Institute of Experimental and Clinical Research, UCLouvain, 1200 Brussels, Belgium; (M.D.R.); (A.D.); (P.S.)
- HPB Surgery Unit, Centre Hospitalier Universitaire UCL Namur, Site Mont-Godinne, 5530 Yvoir, Belgium
| | - Peter Stärkel
- Laboratory of Hepato-Gastroenterology, Institute of Experimental and Clinical Research, UCLouvain, 1200 Brussels, Belgium; (M.D.R.); (A.D.); (P.S.)
- Department of Hepato-Gastroenterology, Cliniques Universitaires Saint-Luc, 1200 Brussels, Belgium
| | - Isabelle A. Leclercq
- Laboratory of Hepato-Gastroenterology, Institute of Experimental and Clinical Research, UCLouvain, 1200 Brussels, Belgium; (M.D.R.); (A.D.); (P.S.)
| |
Collapse
|
|
34
|
Akın E, Sarıbeyoğlu K, Esen E, Aytaç E, Özbay G, Uzun H, Pekmezci S. Does taurolidine have any effect on liver regeneration and oxidation in the experimental hepatectomy model? Turk J Surg 2021. [DOI: 10.47717/turkjsurg.2021.4690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Objective: Taurolidine is a bicyclic molecule produced by the natural amino acid taurine. Antibacterial, antiendotoxic and cytoprotective effects of taurolidine have been shown experimentally. Data on the effects of taurolidine on oxidative stress and hepatic regeneration are limited. The aim of the study was to evaluate the effect of taurolidine on hepatic regeneration and oxidative stress in rats undergoing partial hepatectomy.
Material and Methods: Forty adult, male Wistar Albino rats were randomly divided into four equal groups: sham (S) group (n= 10), post-sham opera- tion taurolidine administered (ST) group (n= 10), partial hepatectomy (H) group (n= 10) and post-partial hepatectomy taurolidine administered (HT) group (n= 10). 100 mg/kg/day taurolidine was administered for seven days. Blood and liver tissue samples were collected on postoperative day seven. Liver tissue malondialdehyde, glutathione and Cu-Zn superoxide dismutase activity (SOD) were measured to assess oxidative stress. Binuclear hepato- cyte and Ki-67 antigen levels were measured to evaluate hepatic regeneration.
Results: There was no difference between the groups for malondialdehyde, Cu-Zn superoxide dismutase and glutathione levels (p> 0.05). Binuclear nuclei levels were comparable between the H and HT groups (p= 0.06), while taurolidine decreased binuclear hepatocyte levels in the sham operated groups (p= 0.02). Taurolidine application decreased Ki-67 levels after partial hepatectomy (p= 0.001).
Conclusion: Taurolidine may cause anti-regenerative effects after partial hepatectomy without causing oxidative damage.
Collapse
|
|
35
|
Lee AR, Baek SM, Lee SW, Kim TU, Han JE, Bae S, Park SJ, Kim TH, Jeong KS, Choi SK, Park JK. Nuclear VEGFR-2 Expression of Hepatocytes Is Involved in Hepatocyte Proliferation and Liver Regeneration During Chronic Liver Injury. In Vivo 2021; 35:1473-1483. [PMID: 33910825 DOI: 10.21873/invivo.12400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/06/2021] [Accepted: 03/12/2021] [Indexed: 11/10/2022]
Abstract
BACKGROUND/AIM The pathological role of vascular endothelial growth factor receptor 2 (VEGFR-2) in chronic liver injury and liver regeneration is not fully understood. This study analysed the role of VEGFR-2 in liver fibrosis and its regeneration process. MATERIALS AND METHODS We administered intraperitoneally 50 mg/kg to 300 mg/kg thioacetamide (TAA) to 9-week-old male mice for 17 weeks. We measured levels of VEGFR-2 protein and identified the location of cells that specifically express VEGFR-2. RESULTS VEGFR-2 is rarely expressed in normal hepatocytes. However, high VEGFR-2 expression in liver sinusoidal endothelial cells was noted in the TAA group. Conversely, the group that experienced regeneration from liver fibrosis showed significantly higher VEGFR-2 expression in the nucleus of hepatocytes compared to the other groups. CONCLUSION VEGFR-2 plays a pivotal role in the nucleus of hepatocytes during liver regeneration and VEGFR-2 may be closely related to cell division. Therefore, VEGFR-2 may be a new therapeutic target for liver regeneration.
Collapse
Affiliation(s)
- A-Rang Lee
- Department of Veterinary Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Su-Min Baek
- Department of Veterinary Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Seoung-Woo Lee
- Department of Veterinary Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Tae-Un Kim
- Department of Veterinary Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Jee Eun Han
- College of Veterinary Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Seulgi Bae
- College of Veterinary Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Sang-Joon Park
- College of Veterinary Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Tae-Hwan Kim
- Department of Veterinary Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Kyu-Shik Jeong
- Department of Veterinary Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Republic of Korea.,Stem Cell Therapeutic Research Institute, Kyungpook National University, Daegu, Republic of Korea
| | - Seong-Kyoon Choi
- Core Protein Resources Center, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, Republic of Korea
| | - Jin-Kyu Park
- Department of Veterinary Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Republic of Korea; .,Stem Cell Therapeutic Research Institute, Kyungpook National University, Daegu, Republic of Korea
| |
Collapse
|
|
36
|
Abstract
Liver sinusoidal endothelial cells (LSECs) form the wall of the hepatic sinusoids. Unlike other capillaries, they lack an organized basement membrane and have cytoplasm that is penetrated by open fenestrae, making the hepatic microvascular endothelium discontinuous. LSECs have essential roles in the maintenance of hepatic homeostasis, including regulation of the vascular tone, inflammation and thrombosis, and they are essential for control of the hepatic immune response. On a background of acute or chronic liver injury, LSECs modify their phenotype and negatively affect neighbouring cells and liver disease pathophysiology. This Review describes the main functions and phenotypic dysregulations of LSECs in liver diseases, specifically in the context of acute injury (ischaemia-reperfusion injury, drug-induced liver injury and bacterial and viral infection), chronic liver disease (metabolism-associated liver disease, alcoholic steatohepatitis and chronic hepatotoxic injury) and hepatocellular carcinoma, and provides a comprehensive update of the role of LSECs as therapeutic targets for liver disease. Finally, we discuss the open questions in the field of LSEC pathobiology and future avenues of research.
Collapse
|
|
37
|
Yang M, Zhang C. The role of liver sinusoidal endothelial cells in cancer liver metastasis. Am J Cancer Res 2021; 11:1845-1860. [PMID: 34094657 PMCID: PMC8167702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Accepted: 03/03/2021] [Indexed: 06/12/2023] Open
Abstract
Liver sinusoidal endothelial cells (LSECs) are the gatekeeper cells in the liver, contributing critical roles in liver physiological and pathological changes. Factors such as dietary macronutrients, toxins, and aging impact LSEC fenestration. Defenestration of LSECs changes their phenotype and function. Under liver injury, capillarized LSECs promote hepatic stellate cells (HSCs) activation and fibrogenesis, while decapillarized LSECs protect the activation of HSCs and liver injury. The expression of chemokines, such as CXCL9 and CXCL16, changes and impacts the infiltration of immune cells in the liver during disease progression, including hepatocellular carcinoma (HCC). As the largest solid organ, liver is one of the most favorable organs into where tumor cells metastasize. The increased interaction and adhesion of circulating tumor cells (CTCs) with LSECs in the local microenvironment and LSEC-induced tolerance of immunity promote cancer liver metastasis. Several strategies can be applied to target LSEC to modulate their function to prevent cancer liver metastasis, including gut microbiota modulation, microRNA therapy, and medical treatment. Delivery of different treatment agents with nanoparticles may promote precise target treatment. Overall, targeting LSECs is a potential strategy for treatment of early liver diseases and prevention of cancer liver metastasis.
Collapse
Affiliation(s)
- Ming Yang
- Department of Surgery, University of MissouriColumbia, Missouri, USA
| | - Chunye Zhang
- Department of Veterinary Pathobiology, University of MissouriColumbia, Missouri, USA
| |
Collapse
|
|
38
|
Kovač Peić A, Šrajer Gajdošik M, Brilliant K, Callanan H, Hixson DC, Begić M, Josić D. Changes in the proteome of extracellular vesicles shed by rat liver after subtoxic exposure to acetaminophen. Electrophoresis 2021; 42:1388-1398. [PMID: 33837589 DOI: 10.1002/elps.202100020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 03/18/2021] [Accepted: 03/20/2021] [Indexed: 01/16/2023]
Abstract
To identify changes in extracellular vesicles (EVs) secreted by the liver following drug-induced liver injury (DILI), rats were treated with a subtoxic dose (500 mg/kg) of the analgesic drug, acetaminophen (APAP). EVs were collected by liver perfusion of sham and APAP-treated rats. Changes in EVs morphology were examined by transmission electron microscopic analysis of negatively stained vesicles. Results from morphometric analysis of EVs revealed striking differences in their size and distribution. Proteome composition of EVs collected by liver perfusion was determined by mass spectrometry using methods of sample preparation that enabled better detection of both highly hydrophobic proteins and proteins with complex post-translational modifications. The collection of EVs after liver perfusion is an approach that enables the isolation of EVs shed not only by isolated hepatocytes, but also by the entire complement of hepatic cells. EVs derived after DILI had a lower content of alpha-1-macroglobulin, ferritin, and members of cytochrome 450 family. Fibronectin, aminopeptidase N, metalloreductase STEAP4, integrin beta, and members of the annexin family were detected only in APAP-treated samples of EVs. These results show that the present approach can provide valuable insights into the response of the liver following drug-induced liver injury.
Collapse
Affiliation(s)
| | | | - Kate Brilliant
- Proteomics Core, COBRE CCRD, Rhode Island Hospital, Providence, RI, USA
| | - Helen Callanan
- Proteomics Core, COBRE CCRD, Rhode Island Hospital, Providence, RI, USA
| | - Douglas C Hixson
- Proteomics Core, COBRE CCRD, Rhode Island Hospital, Providence, RI, USA.,Warren Alpert Medical School, Brown University, Providence, RI, USA
| | - Marija Begić
- Faculty of Medicine, Juraj Dobrila University of Pula, Pula, Croatia
| | - Djuro Josić
- Proteomics Core, COBRE CCRD, Rhode Island Hospital, Providence, RI, USA.,Warren Alpert Medical School, Brown University, Providence, RI, USA
| |
Collapse
|
|
39
|
Angiodiversity and organotypic functions of sinusoidal endothelial cells. Angiogenesis 2021; 24:289-310. [PMID: 33745018 PMCID: PMC7982081 DOI: 10.1007/s10456-021-09780-y] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Accepted: 03/04/2021] [Indexed: 02/08/2023]
Abstract
‘Angiodiversity’ refers to the structural and functional heterogeneity of endothelial cells (EC) along the segments of the vascular tree and especially within the microvascular beds of different organs. Organotypically differentiated EC ranging from continuous, barrier-forming endothelium to discontinuous, fenestrated endothelium perform organ-specific functions such as the maintenance of the tightly sealed blood–brain barrier or the clearance of macromolecular waste products from the peripheral blood by liver EC-expressed scavenger receptors. The microvascular bed of the liver, composed of discontinuous, fenestrated liver sinusoidal endothelial cells (LSEC), is a prime example of organ-specific angiodiversity. Anatomy and development of LSEC have been extensively studied by electron microscopy as well as linage-tracing experiments. Recent advances in cell isolation and bulk transcriptomics or single-cell RNA sequencing techniques allowed the identification of distinct LSEC molecular programs and have led to the identification of LSEC subpopulations. LSEC execute homeostatic functions such as fine tuning the vascular tone, clearing noxious substances from the circulation, and modulating immunoregulatory mechanisms. In recent years, the identification and functional analysis of LSEC-derived angiocrine signals, which control liver homeostasis and disease pathogenesis in an instructive manner, marks a major change of paradigm in the understanding of liver function in health and disease. This review summarizes recent advances in the understanding of liver vascular angiodiversity and the functional consequences resulting thereof.
Collapse
|
|
40
|
Lu J, Zhao YL, Zhang XQ, Li LJ. The vascular endothelial growth factor signaling pathway regulates liver sinusoidal endothelial cells during liver regeneration after partial hepatectomy. Expert Rev Gastroenterol Hepatol 2021; 15:139-147. [PMID: 32902336 DOI: 10.1080/17474124.2020.1815532] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Liver regeneration after partial hepatectomy is a very complex and well-regulated procedure. It utilizes all liver cell types, which are associated with signaling pathways involving growth factors, cytokines, and stimulatory and inhibitory feedback of several growth-related signals. Liver sinusoidal endothelial cells (LSECs) contribute to liver regeneration after partial hepatectomy. Vascular endothelial growth factor (VEGF) has various functions in LSECs. In this review, we summarize the relationship between VEGF and LSECs involving VEGF regulatory activity in the vascular endothelium. AREAS COVERED Maintenance of the fenestrated LSEC phenotype requires two VEGF pathways: VEGF stimulated-NO acting through the cGMP pathway and VEGF independent of nitric oxide (NO). The results suggest that VEGF is a key regenerating mediator of LSECs in the partial hepatectomy model. NO-independent pathway was also essential to the maintenance of the LSEC in liver regeneration. EXPERT OPINION Liver regeneration remains a fascinating and significative research field in recent years. The liver involved of molecular pathways except for LSEC-VEGF pathways that make the field of liver further depth studies should be put into effect to elaborate the undetermined confusions, which will be better to understand liver regeneration.
Collapse
Affiliation(s)
- Juan Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital of Medicine School, Zhejiang University , Hangzhou, China
| | - Ya-Lei Zhao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital of Medicine School, Zhejiang University , Hangzhou, China
| | - Xiao-Qian Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital of Medicine School, Zhejiang University , Hangzhou, China
| | - Lan-Juan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital of Medicine School, Zhejiang University , Hangzhou, China
| |
Collapse
|
|
41
|
Zhang J, Chan HF, Wang H, Shao D, Tao Y, Li M. Stem cell therapy and tissue engineering strategies using cell aggregates and decellularized scaffolds for the rescue of liver failure. J Tissue Eng 2021; 12:2041731420986711. [PMID: 35003615 PMCID: PMC8733710 DOI: 10.1177/2041731420986711] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 12/18/2020] [Indexed: 12/11/2022] Open
Abstract
Liver failure is a lethal condition with hepatocellular dysfunction, and liver transplantation is presently the only effective treatment. However, due to the limited availability of donors and the potential immune rejection, novel therapeutic strategies are actively sought to restore the normal hepatic architectures and functions, especially for livers with inherited metabolic dysfunctions or chronic diseases. Although the conventional cell therapy has shown promising results, the direct infusion of hepatocytes is hampered by limited hepatocyte sources, poor cell viability, and engraftment. Hence, this review mainly highlights the role of stem cells and progenitors as the alternative cell source and summarizes the potential approaches based on tissue engineering to improve the delivery efficiency of cells. Particularly, the underlying mechanisms for cell therapy using stem cells and progenitors are discussed in two main aspects: paracrine effect and cell differentiation. Moreover, tissue-engineering approaches using cell aggregates and decellularized liver scaffolds for bioengineering of functional hepatic constructs are discussed and compared in terms of the potential to replicate liver physiological structures. In the end, a potentially effective strategy combining the premium advantages of stem cell aggregates and decellularized liver scaffolds is proposed as the future direction of liver tissue engineering and regeneration.
Collapse
Affiliation(s)
- Jiabin Zhang
- Laboratory of Biomaterials and Translational Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Liver Disease, Guangzhou, China
| | - Hon Fai Chan
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong, China
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Haixia Wang
- Laboratory of Biomaterials and Translational Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Dan Shao
- Institutes of Life Sciences, School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou, China
| | - Yu Tao
- Laboratory of Biomaterials and Translational Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Mingqiang Li
- Laboratory of Biomaterials and Translational Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Liver Disease, Guangzhou, China
| |
Collapse
|
|
42
|
Hypoxia maintains the fenestration of liver sinusoidal endothelial cells and promotes their proliferation through the SENP1/HIF-1α/VEGF signaling axis. Biochem Biophys Res Commun 2021; 540:42-50. [PMID: 33445109 DOI: 10.1016/j.bbrc.2020.12.104] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Accepted: 12/29/2020] [Indexed: 02/09/2023]
Abstract
Liver sinusoidal endothelial cells (LSECs), which play a very critical role in liver regeneration, function in hypoxic environments, but few studies have elucidated the specific mechanism. As a hypoxia-sensitive gene, Sentrin/SUMO-specific protease 1(SENP1) is upregulated in solid tumors due to hypoxia and promotes tumor proliferation. We speculate that LSECs may upregulate SENP1 in hypoxic environments and that SENP1 may act on downstream genes to allow the cells to adapt to the hypoxic environment. To elucidate the reasons for the survival of LSECs under hypoxia, we designed experiments to explore the possible mechanism. First, we cultured murine LSECs in hypoxic conditions for a certain time (24 h and 72 h), and then, we observed that the proliferation ability of the hypoxia group was higher than that of the normoxia group, and the number of unique fenestrae of the LSECs in the hypoxia group was more than that of the LSECs in the normoxia group. Then, we divided the LSECs into several groups for hypoxic culture for time points (6 h, 12 h, 24 h, 36 h, and 72 h), and we found that the expression of SENP1, HIF-1α and VEGF was significantly upregulated. Then, we silenced SENP1 and HIF-1α with si-SENP1 and si-HIF-1α, respectively. SENP1, HIF-1α and VEGF were significantly downregulated, as determined by RT-PCR, WB and ELISA. Unexpectedly, the proliferation activity of the LSECs decreased and the fenestrae disappeared more in the si-SENP1 and si-HIF-1α groups than in the control group. It is concluded that LSECs cultured under hypoxic conditions may maintain fenestrae and promote proliferation through the SENP1/HIF-1α/VEGF signaling axis, thereby adapting to the hypoxic environment.
Collapse
|
|
43
|
Liver regeneration: biological and pathological mechanisms and implications. Nat Rev Gastroenterol Hepatol 2021; 18:40-55. [PMID: 32764740 DOI: 10.1038/s41575-020-0342-4] [Citation(s) in RCA: 522] [Impact Index Per Article: 130.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/24/2020] [Indexed: 02/08/2023]
Abstract
The liver is the only solid organ that uses regenerative mechanisms to ensure that the liver-to-bodyweight ratio is always at 100% of what is required for body homeostasis. Other solid organs (such as the lungs, kidneys and pancreas) adjust to tissue loss but do not return to 100% of normal. The current state of knowledge of the regenerative pathways that underlie this 'hepatostat' will be presented in this Review. Liver regeneration from acute injury is always beneficial and has been extensively studied. Experimental models that involve partial hepatectomy or chemical injury have revealed extracellular and intracellular signalling pathways that are used to return the liver to equivalent size and weight to those prior to injury. On the other hand, chronic loss of hepatocytes, which can occur in chronic liver disease of any aetiology, often has adverse consequences, including fibrosis, cirrhosis and liver neoplasia. The regenerative activities of hepatocytes and cholangiocytes are typically characterized by phenotypic fidelity. However, when regeneration of one of the two cell types fails, hepatocytes and cholangiocytes function as facultative stem cells and transdifferentiate into each other to restore normal liver structure. Liver recolonization models have demonstrated that hepatocytes have an unlimited regenerative capacity. However, in normal liver, cell turnover is very slow. All zones of the resting liver lobules have been equally implicated in the maintenance of hepatocyte and cholangiocyte populations in normal liver.
Collapse
|
|
44
|
Shang H, Bai T, Zhu S, Yang X, Liu C, Xu D, Zhuge Y, Song Y, Hou X. Prognostic factors for pyrrolizidine alkaloid-induced hepatic sinusoidal obstruction syndrome: a multicenter study in China. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:11. [PMID: 33553304 PMCID: PMC7859749 DOI: 10.21037/atm-20-731] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Background In China, one of the major causes of hepatic sinusoidal obstruction syndrome (HSOS) is the intake of herbals containing pyrrolizidine alkaloid (PA). However, prognostic factors for PA-induced HSOS are poorly understood. The aim of this study was to identify the independent prognostic factors for PA-induced HSOS using a multi-center study. Methods A total of 117 PA-induced HSOS patients were enrolled for data collection in three university hospitals from November 2003 to September 2018. Univariate and multivariate Cox proportional hazards analysis were used to determine prognostic factors for PA-induced HSOS. Results The median age of the PA-induced HSOS patients was 61 years (range, 21–88 years), and 64% of them were male. The survival rates at 1, 3, and 36 months were 89.71%, 72.60%, and 69.19%, respectively. Significant differences in prothrombin time (PT), international normalized ratio, total bilirubin, severity grading [new criteria for severity grading of hematopoietic stem cell transplantation (HSCT)-related HSOS in adults] were found between patients who survived and those who died. Univariate and multivariate survival analysis using Cox’s regression model demonstrated low serum albumin (<35 g/L), elevated serum urea (>8.2 mmol/L) and severe or very severe HSOS (European Society for Blood and Marrow Transplantation 2016 criteria) were independent prognostic factors of survival. Conclusions Serum albumin, serum urea, and severity grading were independent prognostic factors for patients with PA-induced HSOS, and can contribute to identifying potentially high-risk patients for early effective intervention. Trial registration ChiCTR-DRD-17010709 (www.chictr.org.cn).
Collapse
Affiliation(s)
- Haitao Shang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tao Bai
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shenghua Zhu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoqian Yang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chang Liu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dong Xu
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuzheng Zhuge
- Department of Gastroenterology, Drum Tower Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Yuhu Song
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaohua Hou
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
|
45
|
Terkelsen MK, Bendixen SM, Hansen D, Scott EA, Moeller AF, Nielsen R, Mandrup S, Schlosser A, Andersen TL, Sorensen GL, Krag A, Natarajan KN, Detlefsen S, Dimke H, Ravnskjaer K. Transcriptional Dynamics of Hepatic Sinusoid-Associated Cells After Liver Injury. Hepatology 2020; 72:2119-2133. [PMID: 32145072 PMCID: PMC7820956 DOI: 10.1002/hep.31215] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Revised: 01/29/2020] [Accepted: 02/21/2020] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIMS Hepatic sinusoidal cells are known actors in the fibrogenic response to injury. Activated hepatic stellate cells (HSCs), liver sinusoidal endothelial cells, and Kupffer cells are responsible for sinusoidal capillarization and perisinusoidal matrix deposition, impairing vascular exchange and heightening the risk of advanced fibrosis. While the overall pathogenesis is well understood, functional relations between cellular transitions during fibrogenesis are only beginning to be resolved. At single-cell resolution, we here explored the heterogeneity of individual cell types and dissected their transitions and crosstalk during fibrogenesis. APPROACH AND RESULTS We applied single-cell transcriptomics to map the heterogeneity of sinusoid-associated cells in healthy and injured livers and reconstructed the single-lineage HSC trajectory from pericyte to myofibroblast. Stratifying each sinusoidal cell population by activation state, we projected shifts in sinusoidal communication upon injury. Weighted gene correlation network analysis of the HSC trajectory led to the identification of core genes whose expression proved highly predictive of advanced fibrosis in patients with nonalcoholic steatohepatitis (NASH). Among the core members of the injury-repressed gene module, we identified plasmalemma vesicle-associated protein (PLVAP) as a protein amply expressed by mouse and human HSCs. PLVAP expression was suppressed in activated HSCs upon injury and may hence define hitherto unknown roles for HSCs in the regulation of microcirculatory exchange and its breakdown in chronic liver disease. CONCLUSIONS Our study offers a single-cell resolved account of drug-induced injury of the mammalian liver and identifies key genes that may serve important roles in sinusoidal integrity and as markers of advanced fibrosis in human NASH.
Collapse
Affiliation(s)
- Mike K. Terkelsen
- Department of Biochemistry and Molecular BiologyUniversity of Southern DenmarkOdense MDenmark,Center for Functional Genomics and Tissue Plasticity (ATLAS)University of Southern DenmarkOdense MDenmark
| | - Sofie M. Bendixen
- Department of Biochemistry and Molecular BiologyUniversity of Southern DenmarkOdense MDenmark,Center for Functional Genomics and Tissue Plasticity (ATLAS)University of Southern DenmarkOdense MDenmark
| | - Daniel Hansen
- Department of Biochemistry and Molecular BiologyUniversity of Southern DenmarkOdense MDenmark
| | - Emma A.H. Scott
- Department of Biochemistry and Molecular BiologyUniversity of Southern DenmarkOdense MDenmark
| | - Andreas F. Moeller
- Department of Biochemistry and Molecular BiologyUniversity of Southern DenmarkOdense MDenmark
| | - Ronni Nielsen
- Department of Biochemistry and Molecular BiologyUniversity of Southern DenmarkOdense MDenmark,Center for Functional Genomics and Tissue Plasticity (ATLAS)University of Southern DenmarkOdense MDenmark
| | - Susanne Mandrup
- Department of Biochemistry and Molecular BiologyUniversity of Southern DenmarkOdense MDenmark,Center for Functional Genomics and Tissue Plasticity (ATLAS)University of Southern DenmarkOdense MDenmark
| | - Anders Schlosser
- Department of Molecular MedicineUniversity of Southern DenmarkOdense CDenmark
| | - Thomas L. Andersen
- Department of Molecular MedicineUniversity of Southern DenmarkOdense CDenmark,Department of Clinical ResearchUniversity of Southern DenmarkOdense CDenmark,Department of PathologyOdense University HospitalOdense CDenmark
| | - Grith L. Sorensen
- Department of Molecular MedicineUniversity of Southern DenmarkOdense CDenmark
| | - Aleksander Krag
- Center for Functional Genomics and Tissue Plasticity (ATLAS)University of Southern DenmarkOdense MDenmark,Department of Clinical ResearchUniversity of Southern DenmarkOdense CDenmark,Department of Gastroenterology and HepatologyOdense University HospitalOdense CDenmark,Department of NephrologyOdense University HospitalOdense CDenmark
| | - Kedar N. Natarajan
- Department of Biochemistry and Molecular BiologyUniversity of Southern DenmarkOdense MDenmark,Danish Institute for Advanced StudyUniversity of Southern DenmarkOdense MDenmark
| | - Sönke Detlefsen
- Department of PathologyOdense University HospitalOdense CDenmark
| | - Henrik Dimke
- Department of Molecular MedicineUniversity of Southern DenmarkOdense CDenmark,Department of NephrologyOdense University HospitalOdense CDenmark
| | - Kim Ravnskjaer
- Department of Biochemistry and Molecular BiologyUniversity of Southern DenmarkOdense MDenmark,Center for Functional Genomics and Tissue Plasticity (ATLAS)University of Southern DenmarkOdense MDenmark
| |
Collapse
|
|
46
|
Eckstrum K, Striz A, Ferguson M, Zhao Y, Welch B, Solomotis N, Olejnik N, Sprando R. Utilization of a model hepatotoxic compound, diglycolic acid, to evaluate liver Organ-Chip performance and in vitro to in vivo concordance. Food Chem Toxicol 2020; 146:111850. [DOI: 10.1016/j.fct.2020.111850] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 10/30/2020] [Accepted: 11/02/2020] [Indexed: 10/23/2022]
|
|
47
|
Sinusoidal Endothelial Cell Progenitor Cells Promote Tumour Progression in Patients with Hepatocellular Carcinoma. Stem Cells Int 2020; 2020:8819523. [PMID: 33312206 PMCID: PMC7719537 DOI: 10.1155/2020/8819523] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 10/20/2020] [Accepted: 10/31/2020] [Indexed: 12/13/2022] Open
Abstract
Objective As sinusoidal endothelial cell progenitor cells (SEPCs) play a significant role in liver regeneration, it is necessary to elucidate whether SEPCs participate in tumour progression of hepatocellular carcinoma (HCC). Methods A total of 45 patients with primary HCC who underwent liver resection were included in this study. The liver tumours were removed from the patients, and partial tissues were prepared to identify SEPCs through double staining of CD133/CD45 and CD133/CD31 at the same location. Blood samples were collected to examine liver function parameters and tumour markers. The demographics and clinicopathological characteristics of the patients were collected for correlation analysis with SEPCs. Results SEPCs were observed in several blood vessels within the HCC nodules of all 45 patients, but no SEPCs were detected in the tumour-adjacent tissues. The number of SEPCs was correlated with the expression levels of HCC tumour markers α-fetoprotein (AFP) and CA199. There was a positive correlation between the expression of SEPC markers and diameter of HCC tumours in differently differentiated specimens (P < 0.01). The expression levels of SEPC markers were significantly higher in patients with poorly differentiated HCC than in patients with moderately and highly differentiated HCC (P < 0.05). Conclusions SEPCs are closely associated with HCC progression; therefore, SEPCs may be considered potential prognostic and metastatic biomarkers and therapeutic candidates for HCC.
Collapse
|
|
48
|
Bhandari S, Li R, Simón-Santamaría J, McCourt P, Johansen SD, Smedsrød B, Martinez-Zubiaurre I, Sørensen KK. Transcriptome and proteome profiling reveal complementary scavenger and immune features of rat liver sinusoidal endothelial cells and liver macrophages. BMC Mol Cell Biol 2020; 21:85. [PMID: 33246411 PMCID: PMC7694354 DOI: 10.1186/s12860-020-00331-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Accepted: 11/18/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Liver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs; liver resident macrophages) form the body's most effective scavenger cell system for the removal of harmful blood-borne substances, ranging from modified self-proteins to pathogens and xenobiotics. Controversies in the literature regarding the LSEC phenotype pose a challenge when determining distinct functionalities of KCs and LSECs. This may be due to overlapping functions of the two cells, insufficient purification and/or identification of the cells, rapid dedifferentiation of LSECs in vitro, or species differences. We therefore characterized and quantitatively compared expressed gene products of freshly isolated, highly pure LSECs (fenestrated SE-1/FcγRIIb2+) and KCs (CD11b/c+) from Sprague Dawley, Crl:CD (SD), male rats using high throughput mRNA-sequencing and label-free proteomics. RESULTS We observed a robust correlation between the proteomes and transcriptomes of the two cell types. Integrative analysis of the global molecular profile demonstrated the immunological aspects of LSECs. The constitutive expression of several immune genes and corresponding proteins of LSECs bore some resemblance with the expression in macrophages. LSECs and KCs both expressed high levels of scavenger receptors (SR) and C-type lectins. Equivalent expression of SR-A1 (Msr1), mannose receptor (Mrc1), SR-B1 (Scarb1), and SR-B3 (Scarb2) suggested functional similarity between the two cell types, while functional distinction between the cells was evidenced by LSEC-specific expression of the SRs stabilin-1 (Stab1) and stabilin-2 (Stab2), and the C-type lectins LSECtin (Clec4g) and DC-SIGNR (Clec4m). Many immune regulatory factors were differentially expressed in LSECs and KCs, with one cell predominantly expressing a specific cytokine/chemokine and the other cell the cognate receptor, illustrating the complex cytokine milieu of the sinusoids. Both cells expressed genes and proteins involved in antigen processing and presentation, and lymphocyte co-stimulation. CONCLUSIONS Our findings support complementary and partly overlapping scavenging and immune functions of LSECs and KCs. This highlights the importance of including LSECs in studies of liver immunity, and liver clearance and toxicity of large molecule drugs and nano-formulations.
Collapse
Affiliation(s)
- Sabin Bhandari
- Department of Medical Biology, Vascular Biology Research Group, University of Tromsø (UiT) -The Arctic University of Norway, Hansine Hansens veg 18, N-9037, Tromsø, Norway
| | - Ruomei Li
- Department of Medical Biology, Vascular Biology Research Group, University of Tromsø (UiT) -The Arctic University of Norway, Hansine Hansens veg 18, N-9037, Tromsø, Norway
| | - Jaione Simón-Santamaría
- Department of Medical Biology, Vascular Biology Research Group, University of Tromsø (UiT) -The Arctic University of Norway, Hansine Hansens veg 18, N-9037, Tromsø, Norway
| | - Peter McCourt
- Department of Medical Biology, Vascular Biology Research Group, University of Tromsø (UiT) -The Arctic University of Norway, Hansine Hansens veg 18, N-9037, Tromsø, Norway
| | - Steinar Daae Johansen
- Department of Medical Biology, Vascular Biology Research Group, University of Tromsø (UiT) -The Arctic University of Norway, Hansine Hansens veg 18, N-9037, Tromsø, Norway.,Faculty of Biosciences and Aquaculture, Nord University, Bodø, Norway
| | - Bård Smedsrød
- Department of Medical Biology, Vascular Biology Research Group, University of Tromsø (UiT) -The Arctic University of Norway, Hansine Hansens veg 18, N-9037, Tromsø, Norway.
| | | | - Karen Kristine Sørensen
- Department of Medical Biology, Vascular Biology Research Group, University of Tromsø (UiT) -The Arctic University of Norway, Hansine Hansens veg 18, N-9037, Tromsø, Norway
| |
Collapse
|
|
49
|
Mak KM, Shin DW. Hepatic sinusoids versus central veins: Structures, markers, angiocrines, and roles in liver regeneration and homeostasis. Anat Rec (Hoboken) 2020; 304:1661-1691. [PMID: 33135318 DOI: 10.1002/ar.24560] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 10/14/2020] [Accepted: 10/22/2020] [Indexed: 01/20/2023]
Abstract
The blood circulates through the hepatic sinusoids delivering nutrients and oxygen to the liver parenchyma and drains into the hepatic central vein, yet the structures and phenotypes of these vessels are distinctively different. Sinusoidal endothelial cells are uniquely fenestrated, lack basal lamina and possess organelles involved in endocytosis, pinocytosis, degradation, synthesis and secretion. Hepatic central veins are nonfenestrated but are also active in synthesis and secretion. Endothelial cells of sinusoids and central veins secrete angiocrines that play respective roles in hepatic regeneration and metabolic homeostasis. The list of markers for identifying sinusoidal endothelial cells is long and their terminologies are complex. Further, their uses vary in different investigations and, in some instances, could be confusing. Central vein markers are fewer but more distinctive. Here we analyze and categorize the molecular pathways/modules associated with the sinusoid-mediated liver regeneration in response to partial hepatectomy and chemical-induced acute or chronic injury. Similarly, we highlight the findings that central vein-derived angiocrines interact with Wnt/β-catenin in perivenous hepatocytes to direct gene expression and maintain pericentral metabolic zonation. The proposal that perivenous hepatocytes behave as stem/progenitor cells to provoke hepatic homeostatic cell renewal is reevaluated and newer concepts of broad zonal distribution of hepatocyte proliferation in liver homeostasis and regeneration are updated. Thus, this review integrates the structures, biology and physiology of liver sinusoids and central veins in mediating hepatic regeneration and metabolic homeostasis.
Collapse
Affiliation(s)
- Ki M Mak
- Department of Medical Education and Center for Anatomy and Functional Morphology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Da Wi Shin
- Department of Medical Education and Center for Anatomy and Functional Morphology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| |
Collapse
|
|
50
|
Wang X, Walkey CJ, Maretti-Mira AC, Wang L, Johnson DL, DeLeve LD. Susceptibility of Rat Steatotic Liver to Ischemia-Reperfusion Is Treatable With Liver-Selective Matrix Metalloproteinase Inhibition. Hepatology 2020; 72:1771-1785. [PMID: 32060938 PMCID: PMC7523533 DOI: 10.1002/hep.31179] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 01/23/2020] [Indexed: 12/31/2022]
Abstract
BACKGROUND AND AIMS This study examined whether enhanced susceptibility of steatotic liver to ischemia-reperfusion (I/R) injury is due to impaired recruitment of bone marrow (BM) progenitors of liver sinusoidal endothelial cells (LSECs, also called sinusoidal endothelial cell progenitor cells [sprocs]) with diminished repair of injured LSECs and whether restoring signaling to recruit BM sprocs reduces I/R injury. APPROACH AND RESULTS Hepatic vessels were clamped for 1 hour in rats fed a high-fat, high-fructose (HFHF) diet for 5, 10, or 15 weeks. Matrix metalloproteinase 9 (MMP-9) antisense oligonucleotides (ASO) or an MMP inhibitor were used to induce liver-selective MMP-9 inhibition. HFHF rats had mild, moderate, and severe steatosis, respectively, at 5, 10, and 15 weeks. I/R injury was enhanced in HFHF rats; this was accompanied by complete absence of hepatic vascular endothelial growth factor (VEGF)-stromal cell-derived factor 1 (sdf1) signaling, leading to lack of BM sproc recruitment. Liver-selective MMP-9 inhibition to protect against proteolytic cleavage of hepatic VEGF using either MMP-9 ASO or intraportal MMP inhibitor in 5-week and 10-week HFHF rats enhanced hepatic VEGF-sdf1 signaling, increased BM sproc recruitment, and reduced alanine aminotransferase (ALT) by 92% and 77% at 5 weeks and by 80% and 64% at 10 weeks of the HFHF diet, respectively. After I/R injury in 15-week HFHF rats, the MMP inhibitor reduced active MMP-9 expression by 97%, ameliorated histologic evidence of injury, and reduced ALT by 58%, which is comparable to control rats sustaining I/R injury. Rescue therapy with intraportal MMP inhibitor, given after ischemia, in the 5-week HFHF rat reduced ALT by 71% and reduced necrosis. CONCLUSIONS Lack of signaling to recruit BM sprocs that repair injured LSECs renders steatotic liver more susceptible to I/R injury. Liver-selective MMP-9 inhibition enhances VEGF-sdf1 signaling and recruitment of BM sprocs, which markedly protects against I/R injury, even in severely steatotic rats.
Collapse
Affiliation(s)
- Xiangdong Wang
- USC Division of Gastrointestinal and Liver Disease and the USC Research Center for Liver Disease, Keck Medicine of USC Los Angeles CA
| | - Christopher J. Walkey
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston TX
| | - Ana C. Maretti-Mira
- USC Division of Gastrointestinal and Liver Disease and the USC Research Center for Liver Disease, Keck Medicine of USC Los Angeles CA
| | - Lei Wang
- USC Division of Gastrointestinal and Liver Disease and the USC Research Center for Liver Disease, Keck Medicine of USC Los Angeles CA
| | - Deborah L. Johnson
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston TX
| | - Laurie D. DeLeve
- USC Division of Gastrointestinal and Liver Disease and the USC Research Center for Liver Disease, Keck Medicine of USC Los Angeles CA
| |
Collapse
|