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Liu C, Zhu D, Xue J, Tulahong A, Aji T. Identifying KLF14 as a potential regulatory factor in liver regeneration trough transcriptomic and metabolomic. Sci Rep 2025; 15:7462. [PMID: 40032908 DOI: 10.1038/s41598-025-87614-3] [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: 10/08/2024] [Accepted: 01/21/2025] [Indexed: 03/05/2025] Open
Abstract
Liver regeneration is a complex process crucial for recovery after partial hepatectomy (PH) or ex-vivo liver resection and autotransplantation (ELRA). This study aimed to explore the molecular mechanisms involved in liver regeneration by analyzing peripheral blood samples from three patients with alveolar echinococcosis undergoing PH and ELRA. Peripheral blood samples were collected from three patients undergoing PH and three patients undergoing ELRA at three time points: pre-operation, postoperative day 1, and postoperative day 5, as well as three healthy controls. Transcriptomic analysis was performed to identify differentially expressed genes (DEGs) using RNA sequencing, while metabolomic analysis was conducted using untargeted liquid chromatography-mass spectrometry (LC-MS). Key findings were validated through real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis. Transcriptomic analysis revealed 3574 DEGs on post-operative day 1 compared to pre-operation in the ELRA group, and 3269 DEGs on post-operative day 5 compared to day 1. In the PH group, 1619 DEGs were identified on post-operative day 1 compared to pre-operation, and 896 DEGs were found on post-operative day 5 compared to day 1. Among these, 36 common genes were shared between both groups, primarily enriched in metabolic pathways. Integration of common genes, co-expression network analysis and Mfuzz clustering identified KLF14 as a gene correlated with liver regeneration processes, with its association with the PI3K-AKT pathway. Metabolomic analysis highlighted differentially expressed metabolites associated with lipid, amino acid, and energy metabolism. This study provides new insights into the molecular regulation of liver regeneration, identifying KLF14 and associated metabolic processes. These findings offer potential therapeutic targets for enhancing liver repair.
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Affiliation(s)
- Chang Liu
- The First Affiliated Hospital of Xinjiang Medical University, No. 137 Liyushan South Road, Urumqi, 830054, Xinjiang, China
| | - Dalong Zhu
- The First Affiliated Hospital of Xinjiang Medical University, No. 137 Liyushan South Road, Urumqi, 830054, Xinjiang, China
| | - Junlong Xue
- The First Affiliated Hospital of Xinjiang Medical University, No. 137 Liyushan South Road, Urumqi, 830054, Xinjiang, China
| | - Alimu Tulahong
- The First Affiliated Hospital of Xinjiang Medical University, No. 137 Liyushan South Road, Urumqi, 830054, Xinjiang, China
| | - Tuerganaili Aji
- Department of Hepatobiliary Hydatid Surgery, The First Affiliated Hospital of Xinjiang Medical University, No. 137 Liyushan South Road, Urumqi, 830054, Xinjiang, China.
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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.
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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
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Tsai YF, Fang MC, Chen CH, Yu IS, Shun CT, Tao MH, Sun CP, Lu J, Sheu JC, Hsu YC, Lin SW. Enhancement of adult liver regeneration in mice through the hepsin-mediated epidermal growth factor receptor signaling pathway. Commun Biol 2024; 7:1672. [PMID: 39702454 DOI: 10.1038/s42003-024-07357-1] [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: 04/04/2024] [Accepted: 12/03/2024] [Indexed: 12/21/2024] Open
Abstract
Given the widespread use of partial hepatectomy for treating various liver pathologies, understanding the mechanisms of liver regeneration is vital for enhancing liver resection and transplantation therapies. Here, we demonstrate the critical role of the serine protease Hepsin in promoting hepatocyte hypertrophy and proliferation. Under steady-state conditions, liver-specific overexpression of Hepsin in adult wild-type mice triggers hepatocyte hypertrophy and proliferation, significantly increasing liver size. This effect is predominantly driven by the catalytic activity of Hepsin, engaging the EGFR-Raf-MEK-ERK signaling pathway. Significantly, administering Hepsin substantially enhances hepatocyte proliferation and facilitates liver regeneration following a 70% partial hepatectomy. Crucially, the proliferation induced by Hepsin is a transient event, without leading to long-term adverse effects such as liver fibrosis or hepatocellular carcinoma, as evidenced by extensive observation. These results offer substantial potential for future clinical applications and translational research endeavors in the field of liver regeneration post-hepatectomy.
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Affiliation(s)
- Yu-Fei Tsai
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Mo-Chu Fang
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chien-Hung Chen
- Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
- Department of Medicine, National Taiwan University Cancer Center, Taipei, Taiwan
| | - I-Shing Yu
- Laboratory Animal Center, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chia-Tung Shun
- Department and Graduate Institute of Forensic Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
- Department of Pathology, Good Liver Clinic, Taipei, Taiwan
- Department of Pathology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Mi-Hua Tao
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan
- Biomedical Translation Research Center (BioTReC), Academia Sinica, Taipei, Taiwan
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Cheng-Pu Sun
- Biomedical Translation Research Center (BioTReC), Academia Sinica, Taipei, Taiwan
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Jean Lu
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Jin-Chuan Sheu
- Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
- Liver Disease Prevention and Treatment Research Foundation, Taipei, Taiwan
| | - Yu-Chen Hsu
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.
- Liver Disease Prevention and Treatment Research Foundation, Taipei, Taiwan.
| | - Shu-Wha Lin
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.
- Department of Laboratory Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
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Mo D, Lv M, Mao X. Using different zebrafish models to explore liver regeneration. Front Cell Dev Biol 2024; 12:1485773. [PMID: 39544362 PMCID: PMC11560876 DOI: 10.3389/fcell.2024.1485773] [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: 08/24/2024] [Accepted: 10/22/2024] [Indexed: 11/17/2024] Open
Abstract
The liver possesses an impressive capability to regenerate following various injuries. Given its profound implications for the treatment of liver diseases, which afflict millions globally, liver regeneration stands as a pivotal area of digestive organ research. Zebrafish (Danio rerio) has emerged as an ideal model organism in regenerative medicine, attributed to their remarkable ability to regenerate tissues and organs, including the liver. Many fantastic studies have been performed to explore the process of liver regeneration using zebrafish, especially the extreme hepatocyte injury model. Biliary-mediated liver regeneration was first discovered in the zebrafish model and then validated in mammalian models and human patients. Considering the notable expansion of biliary epithelial cells in many end-stage liver diseases, the promotion of biliary-mediated liver regeneration might be another way to treat these refractory liver diseases. To date, a comprehensive review discussing the current advancements in zebrafish liver regeneration models is lacking. Therefore, this review aims to investigate the utility of different zebrafish models in exploring liver regeneration, highlighting the genetic and cellular insights gained and discussing the potential translational impact on human health.
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Affiliation(s)
- Dashuang Mo
- Department of Immunology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, China
| | - Mengzhu Lv
- Department of Immunology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, China
| | - Xiaoyu Mao
- College of Language Intelligence, Sichuan International Studies University, Chongqing, China
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Faheem S, Hameed H, Paiva-Santos AC, Khan MA, Ghumman SA, Hameed A. The role of chondroitin sulphate as a potential biomaterial for hepatic tissue regeneration: A comprehensive review. Int J Biol Macromol 2024; 280:136332. [PMID: 39482129 DOI: 10.1016/j.ijbiomac.2024.136332] [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: 04/05/2024] [Revised: 08/26/2024] [Accepted: 10/03/2024] [Indexed: 11/03/2024]
Abstract
Chondroitin sulphate is an anionic hetero-polysaccharide, having numerous structural affinities for building the bio-active components. In addition to biodegradable/biocompatible activities, chondroitin sulphate also possesses anti-coagulant/anti-thrombogenic, anti-inflammatory, anti-oxidant as well as anti-tumor activities. Chondroitin sulphate has an inherited affinity for glycosylation enzymes and receptors, which are overexpressed over degenerated cells and organelles. Because of this affinity, chondroitin sulphate is nominated as an active cellular/subcellular targeted biological macromolecule to assist in site-specific delivery. Chondroitin sulphate is mainly considered a promising biomaterial for drug targeting and tissue engineering due to its specific physicochemical, mechanical, bio-degradation, and biological characteristics. In this review, the fundamental applications of chondroitin sulphate in hepatic tissue engineering are discussed. Chondroitin sulphate along with mesenchymal stem cells (MSCs) based scaffold and hydrogels for biopharmaceuticals' delivery in hepatic tissue engineering are critically discussed. In addition, the manuscript also describes leading features and markers involved in hepatic damage, and the potential role of chondroitin sulphate-based delivery systems in hepatic tissue engineering.
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Affiliation(s)
- Saleha Faheem
- Faculty of Pharmaceutical Sciences, University of Central Punjab, Lahore 54000, Pakistan.
| | - Huma Hameed
- Faculty of Pharmaceutical Sciences, University of Central Punjab, Lahore 54000, Pakistan.
| | - Ana Cláudia Paiva-Santos
- Department of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, 3000-548 Coimbra, Portugal; REQUIMTE/LAQV, Group of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, 3000-548 Coimbra, Portugal.
| | - Mahtab Ahmad Khan
- Faculty of Pharmaceutical Sciences, University of Central Punjab, Lahore 54000, Pakistan.
| | | | - Anam Hameed
- Department of Human Nutrition and Dietetics, Faculty of Rehabilitation and Allied Health Sciences, Riphah International University, Gulberg III, Lahore 54000, Pakistan.
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Li A, Qin Y, Gong G. The Changes of Mitochondria during Aging and Regeneration. Adv Biol (Weinh) 2024; 8:e2300445. [PMID: 38979843 DOI: 10.1002/adbi.202300445] [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: 12/04/2023] [Revised: 05/30/2024] [Indexed: 07/10/2024]
Abstract
Aging and regeneration are opposite cellular processes. Aging refers to progressive dysfunction in most cells and tissues, and regeneration refers to the replacement of damaged or dysfunctional cells or tissues with existing adult or somatic stem cells. Various studies have shown that aging is accompanied by decreased regenerative abilities, indicating a link between them. The performance of any cellular process needs to be supported by the energy that is majorly produced by mitochondria. Thus, mitochondria may be a link between aging and regeneration. It should be interesting to discuss how mitochondria behave during aging and regeneration. The changes of mitochondria in aging and regeneration discussed in this review can provide a timely and necessary study of the causal roles of mitochondrial homeostasis in longevity and health.
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Affiliation(s)
- Anqi Li
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Yuan Qin
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Guohua Gong
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
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Martucci NJ, Stoops J, Bowen W, Orr A, Cotner MC, Michalopoulos GK, Bhushan B, Mars WM. A Novel Role for the Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Delta Isoform in Hepatocellular Proliferation. THE AMERICAN JOURNAL OF PATHOLOGY 2024; 194:1511-1527. [PMID: 38705383 PMCID: PMC11393825 DOI: 10.1016/j.ajpath.2024.03.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 02/09/2024] [Accepted: 03/22/2024] [Indexed: 05/07/2024]
Abstract
The phosphatidylinositol-4,5-bisphosphate 3-kinase delta isoform (Pik3cd), usually considered immune-specific, was unexpectedly identified as a gene potentially related to either regeneration and/or differentiation in animals lacking hepatocellular Integrin Linked Kinase (ILK). Since a specific inhibitor (Idelalisib, or CAL101) for the catalytic subunit encoded by Pik3cd (p110δ) has reported hepatotoxicity when used for treating chronic lymphocytic leukemia and other lymphomas, the authors aimed to elucidate whether there is a role for p110δ in normal liver function. To determine the effect on normal liver regeneration, partial hepatectomy (PHx) was performed using mice in which p110δ was first inhibited using CAL101. Inhibition led to over a 50% decrease in proliferating hepatocytes in the first 2 days after PHx. This difference correlated with phosphorylation changes in the HGF and EGF receptors (MET and EGFR, respectively) and NF-κB signaling. Ingenuity Pathway Analyses implicated C/EBPβ, HGF, and the EGFR heterodimeric partner, ERBB2, as three of the top 20 regulators downstream of p110δ signaling because their pathways were suppressed in the presence of CAL101 at 1 day post-PHx. A regulatory role for p110δ signaling in mouse and rat hepatocytes through MET and EGFR was further verified using hepatocyte primary cultures, in the presence or absence of CAL101. Combined, these data support a role for p110δ as a downstream regulator of normal hepatocytes when stimulated to proliferate.
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Affiliation(s)
- Nicole J Martucci
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - John Stoops
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - William Bowen
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Anne Orr
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Mary-Claire Cotner
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | | | - Bharat Bhushan
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Wendy M Mars
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.
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Alqabandi W, Dhaunsi GS. L-Glutamine mitigates bile acid-induced inhibition of growth factor activity in rat hepatocyte cultures. Growth Factors 2024; 42:120-127. [PMID: 39320940 DOI: 10.1080/08977194.2024.2407566] [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: 09/19/2023] [Accepted: 09/17/2024] [Indexed: 09/26/2024]
Abstract
Bile acid-induced hepatotoxicity is inevitable in Cholestasis pathogenesis and L-Glutamine (L-Gln) has been reported to prevent total parenteral nutrition (TPN)-induced cholestasis in premature neonates. While mechanisms remain unknown, we hypothesize that bile acids impair growth factor (GF) function in hepatocytes which L-glutamine prevents through NAPDH oxidase (NOX) modulation. Glycochenodeoxycholic acid (GCDC, 0-100 µM) when added to primary hepatocyte cultures significantly (p < 0.01) decreased the FBS-induced BrdU incorporation, however inhibition of Fibroblast Growth factor (FGF)- or Hepatocyte growth factor (HGF)-induced DNA synthesis was more pronounced (p < 0.001). L-Gln markedly attenuated GCDC-mediated inhibition of DNA synthesis in both FBS and GF-treated cells. GCDC significantly increased the NADPH oxidase activity and NOX-1 protein expression that were markedly reduced by L-Gln and protein kinase c (PKC) inhibitor, LY-333531. Apocynin (APCN) and diphenyliodonium (DPI) significantly blocked the GCDC-mediated inhibition of GF-induced DNA synthesis. This study demonstrates that bile acid-induced hepatotoxicity involves dysfunction of certain growth factors via protein kinase c (PKC)- mediated NOX modulation which can be corrected, at least partly, by L-glutamine.
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Kavak N, Akcan G, Balcı N, Süer AA, Güler İ, Kavak RP. The impact of augmenter of liver regeneration in blunt liver trauma: An experimental model analysis. ULUS TRAVMA ACIL CER 2024; 30:472-479. [PMID: 38967532 PMCID: PMC11331352 DOI: 10.14744/tjtes.2024.92575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Revised: 05/23/2024] [Accepted: 06/15/2024] [Indexed: 07/06/2024]
Abstract
BACKGROUND Traumatic liver injury is an acute event that triggers liver repair. The augmenter of liver regeneration (ALR) has been identified as a growth factor involved in this process. This study evaluates the impact of ALR on isolated liver blunt trauma and examines its relationship with various time intervals. METHODS Forty healthy female Wistar albino rats were divided into five groups (n=8 each). Isolated blunt liver trauma was induced using a custom-designed trauma platform in all groups except for Group 1. The groups were categorized by the timing of euthanasia post-trauma: 2nd (15 minutes), 3rd (30 minutes), 4th (45 minutes), and 5th (60 minutes). Assessments included plasma ALR levels, liver tissue ALR levels (both intact and lacerated), biochemical indices, and liver histological analysis. RESULTS Plasma ALR levels in Group 4 were higher than in Groups 1 and 2 (p<0.01). Intact liver ALR levels in Groups 3 and 4 exceeded those in Group 1 (p<0.05, p<0.01, respectively). Intact liver tissue ALR levels in Group 5 were lower than in Groups 3 and 4 (p<0.05, p<0.01, respectively). Lacerated liver tissue ALR levels in Group 5 were higher than those in Groups 2 and 3. In Group 1, the plasma ALR level was higher than the intact liver tissue ALR level (p<0.05). In Group 2, plasma ALR levels exceeded those in intact liver tissue ALR levels (p<0.01). In Group 3, plasma ALR levels surpassed both lacerated and intact liver tissue ALR levels (p<0.05, p<0.001, respectively). In Group 4, the plasma ALR level was higher than the intact liver tissue ALR level (p<0.01), and the lacerated liver tissue level was higher than the intact liver ALR level (p<0.001). Additionally, inflammation scores were higher in Groups 3, 4, and 5 compared to Group 2 (p<0.05, p<0.01, p<0.01, respectively). CONCLUSION This study is the first to explore the role of ALR in isolated blunt liver trauma. Following blunt liver trauma, both plasma and liver tissue ALR levels change within minutes.
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Affiliation(s)
- Nezih Kavak
- Department of Emergency, Etlik City Hospital, Ankara-Türkiye
| | - Gülben Akcan
- Department of Histology and Embryology, Karatay University, Konya-Türkiye
| | - Nurgül Balcı
- Republic of Türkiye, Ministry of Health, Family Medicine, General Directorate of Public Hospitals, Family Medicine, Ankara-Türkiye
| | - Aziz Ahmet Süer
- Coordinator Head Physician of Turkish Ministry of Health, Ankara City Hospital, General Surgery, Ankara-Türkiye
| | - İlkay Güler
- The Republic of Türkiye, Ministry of Health, Directorate of Public Hospitals, General Surgery, Ankara-Türkiye
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Barcena AJR, Owens TC, Melancon S, Workeneh I, Tran Cao HS, Vauthey JN, Huang SY. Current Perspectives and Progress in Preoperative Portal Vein Embolization with Stem Cell Augmentation (PVESA). Stem Cell Rev Rep 2024; 20:1236-1251. [PMID: 38613627 PMCID: PMC11222268 DOI: 10.1007/s12015-024-10719-1] [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] [Accepted: 04/03/2024] [Indexed: 04/15/2024]
Abstract
Portal vein embolization with stem cell augmentation (PVESA) is an emerging approach for enhancing the growth of the liver segment that will remain after surgery (i.e., future liver remnant, FLR) in patients with liver cancer. Conventional portal vein embolization (PVE) aims to induce preoperative FLR growth, but it has a risk of failure in patients with underlying liver dysfunction and comorbid illnesses. PVESA combines PVE with stem cell therapy to potentially improve FLR size and function more effectively and efficiently. Various types of stem cells can help improve liver growth by secreting paracrine signals for hepatocyte growth or by transforming into hepatocytes. Mesenchymal stem cells (MSCs), unrestricted somatic stem cells, and small hepatocyte-like progenitor cells have been used to augment liver growth in preclinical animal models, while clinical studies have demonstrated the benefit of CD133 + bone marrow-derived MSCs and hematopoietic stem cells. These investigations have shown that PVESA is generally safe and enhances liver growth after PVE. However, optimizing the selection, collection, and application of stem cells remains crucial to maximize benefits and minimize risks. Additionally, advanced stem cell technologies, such as priming, genetic modification, and extracellular vesicle-based therapy, that could further enhance efficacy outcomes should be evaluated. Despite its potential, PVESA requires more investigations, particularly mechanistic studies that involve orthotopic animal models of liver cancer with concomitant liver injury as well as larger human trials.
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Affiliation(s)
- Allan John R Barcena
- Department of Interventional Radiology, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Unit, Houston, TX, 1471, 77030, United States
- College of Medicine, University of the Philippines Manila, Manila, NCR, 1000, Philippines
| | - Tyler C Owens
- Department of Interventional Radiology, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Unit, Houston, TX, 1471, 77030, United States
| | - Sophie Melancon
- Department of Interventional Radiology, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Unit, Houston, TX, 1471, 77030, United States
| | - Isias Workeneh
- Department of Interventional Radiology, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Unit, Houston, TX, 1471, 77030, United States
| | - Hop S Tran Cao
- Department of Surgical Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, United States
| | - Jean-Nicolas Vauthey
- Department of Surgical Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, United States
| | - Steven Y Huang
- Department of Interventional Radiology, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Unit, Houston, TX, 1471, 77030, United States.
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Salerno D, Peruzzi G, Giuseppe Rubens Pascucci, Levrero M, Belloni L, Pediconi N. miRNA-27a-3p is involved in the plasticity of differentiated hepatocytes. Gene 2024; 913:148387. [PMID: 38499211 DOI: 10.1016/j.gene.2024.148387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 02/01/2024] [Accepted: 03/15/2024] [Indexed: 03/20/2024]
Abstract
BACKGROUND Epigenetic mechanisms, including DNA methylation, histone modifications, and chromatin remodeling, are highly involved in the regulation of hepatocyte viability, proliferation, and plasticity. We have previously demonstrated that repression of H3K27 methylation in differentiated hepatic HepaRG cells by treatment with GSK-J4, an inhibitor of JMJD3 and UTX H3K27 demethylase activity, changed their phenotype, inducing differentiated hepatocytes to proliferate. In addition to the epigenetic enzymatic role in the regulation of the retro-differentiation process, emerging evidence indicate that microRNAs (miRNAs) are involved in controlling hepatocyte proliferation during liver regeneration. Hence, the aim of this work is to investigate the impact of H3K27 methylation on miRNAs expression profile and its role in the regulation of the differentiation status of human hepatic progenitors HepaRG cells. METHODS A miRNA-sequencing was carried out in differentiated HepaRG cells treated or not with GSK-J4. Target searching and Gene Ontology analysis were performed to identify the molecular processes modulated by differentially expressed miRNAs. The biological functions of selected miRNAs was further investigated by transfection of miRNAs inhibitors or mimics in differentiated HepaRG cells followed by qPCR analysis, albumin ELISA assay, CD49a FACS analysis and EdU staining. RESULTS We identified 12 miRNAs modulated by GSK-J4; among these, miR-27a-3p and miR- 423-5p influenced the expression of several proliferation genes in differentiated HepaRG cells. MiR-27a-3p overexpression increased the number of hepatic cells reentering proliferation. Interestingly, both miR-27a-3p and miR-423-5p did not affect the expression levels of genes involved in the differentiation of progenitors HepaRG cells. CONCLUSIONS Modulation of H3K27me3 methylation in differentiated HepaRG cells, by GSK-J4 treatment, influenced miRNA' s expression profile pushing liver cells towards a proliferating phenotype. We demonstrated the involvement of miR-27a-3p in reinducing proliferation of differentiated hepatocytes suggesting a potential role in liver plasticity.
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Affiliation(s)
- Debora Salerno
- Dept. of Molecular Medicine, Sapienza University of Rome, Italy; Center for Life Nano & Neuro Science, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161 Rome, Italy
| | - Giovanna Peruzzi
- Center for Life Nano & Neuro Science, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161 Rome, Italy
| | - Giuseppe Rubens Pascucci
- Research Unit of Clinical Immunology and Vaccinology, Academic Department of Pediatrics, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy; Department of Systems Medicine, University of Rome "Tor Vergata", Italy
| | - Massimo Levrero
- Cancer Research Center of Lyon (CRCL), INSERM U1052, CNRS UMR5286, Lyon, France
| | - Laura Belloni
- Center for Life Nano & Neuro Science, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161 Rome, Italy; Dept. of Medical and Surgical Sciences and Translational Medicine, Sapienza University of Rome, Via Giorgio Nicola Papanicolau, 00189 Rome, Italy.
| | - Natalia Pediconi
- Center for Life Nano & Neuro Science, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161 Rome, Italy; Dept. of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy.
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Allahverdi H. Exploring the therapeutic potential of plasma from intermittent fasting and untreated rats on aging-induced liver damage. J Cell Mol Med 2024; 28:e18456. [PMID: 38923278 PMCID: PMC11199341 DOI: 10.1111/jcmm.18456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 04/21/2024] [Accepted: 05/16/2024] [Indexed: 06/28/2024] Open
Abstract
This research aims to investigate the effects of plasma from 12-month-old intermittently fasting rats (IFpls) and untreated rats (Npls) on the liver biomolecules and histological changes in 24-month-old male Sprague-Dawley rats. Fasting rats underwent an 18-h daily fasting period and a 6-h feeding window for 35 days. The plasma was administered bi-daily, and blood samples were examined for specific liver biomolecules. Fourier transform infrared (FTIR) spectroscopy and linear discriminant analysis (LDA) was used to identify molecular profiles. Liver sections were stained for histopathological evaluation, and the expression levels of Notch signalling pathway components were assessed. Distinct molecular profiles were identified across liver biomolecules, lipids, proteins and nucleic acids with high accuracy. Notably, IFpls was found to protect against hepatic instability, microvesicular steatosis and liver fibrosis by decreasing lymphatic infiltration density and Notch pathway expression levels. Both treatments reduced protein oxidation and carbonylation, with Npls showing a pronounced decrease in protein oxidation. Furthermore, Npls increased protein conformation and glycogen/phosphate content, while IFpls increased glucose/protein content. Both IFpls and Npls induce substantial and unique alterations in liver biomolecules. IFpls offers a protective effect on various liver conditions, while Npls exhibits promising results in reducing protein oxidation and altering biomolecule content. These findings offer valuable insights for future research and potential therapeutic approaches.
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Affiliation(s)
- Hüseyin Allahverdi
- Department of Molecular Biology and GeneticsMuş Alparslan UniversityMuşTurkey
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13
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de Haan LR, van Golen RF, Heger M. Molecular Pathways Governing the Termination of Liver Regeneration. Pharmacol Rev 2024; 76:500-558. [PMID: 38697856 DOI: 10.1124/pharmrev.123.000955] [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: 11/07/2023] [Revised: 01/24/2024] [Accepted: 02/08/2024] [Indexed: 05/05/2024] Open
Abstract
The liver has the unique capacity to regenerate, and up to 70% of the liver can be removed without detrimental consequences to the organism. Liver regeneration is a complex process involving multiple signaling networks and organs. Liver regeneration proceeds through three phases: the initiation phase, the growth phase, and the termination phase. Termination of liver regeneration occurs when the liver reaches a liver-to-body weight that is required for homeostasis, the so-called "hepatostat." The initiation and growth phases have been the subject of many studies. The molecular pathways that govern the termination phase, however, remain to be fully elucidated. This review summarizes the pathways and molecules that signal the cessation of liver regrowth after partial hepatectomy and answers the question, "What factors drive the hepatostat?" SIGNIFICANCE STATEMENT: Unraveling the pathways underlying the cessation of liver regeneration enables the identification of druggable targets that will allow us to gain pharmacological control over liver regeneration. For these purposes, it would be useful to understand why the regenerative capacity of the liver is hampered under certain pathological circumstances so as to artificially modulate the regenerative processes (e.g., by blocking the cessation pathways) to improve clinical outcomes and safeguard the patient's life.
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Affiliation(s)
- Lianne R de Haan
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
| | - Rowan F van Golen
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
| | - Michal Heger
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
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14
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Sun QJ, Liu T. Subcellular distribution of prohibitin 1 in rat liver during liver regeneration and its cellular implication. World J Hepatol 2024; 16:65-74. [PMID: 38313239 PMCID: PMC10835489 DOI: 10.4254/wjh.v16.i1.65] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 11/03/2023] [Accepted: 11/28/2023] [Indexed: 01/23/2024] Open
Abstract
BACKGROUND The function of prohibitin 1 (Phb1) during liver regeneration (LR) remains relatively unexplored. Our previous research identified downregulation of Phb1 in rat liver mitochondria 24 h after 70% partial hepatectomy (PHx), as determined by subcellular proteomic analysis. AIM To investigate the potential role of Phb1 during LR. METHODS We examined changes in Phb1 mRNA and protein levels, subcellular distribution, and abundance in rat liver during LR following 70% PHx. We also evaluated mitochondrial changes and apoptosis using electron microscopy and flow cytometry. RNA-interference-mediated knockdown of Phb1 (PHBi) was performed in BRL-3A cells. RESULTS Compared with sham-operation control groups, Phb1 mRNA and protein levels in 70% PHx test groups were downregulated at 24 h, then upregulated at 72 and 168 h. Phb1 was mainly located in mitochondria, showed a reduced abundance at 24 h, significantly increased at 72 h, and almost recovered to normal at 168 h. Phb1 was also present in nuclei, with continuous increase in abundance observed 72 and 168 h after 70% PHx. The altered ultrastructure and reduced mass of mitochondria during LR had almost completely recovered to normal at 168 h. PHBi in BRL-3A cells resulted in increased S-phase entry, a higher number of apoptotic cells, and disruption of mitochondrial membrane potential. CONCLUSION Phb1 may contribute to maintaining mitochondrial stability and could play a role in regulating cell proliferation and apoptosis of rat liver cells during LR.
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Affiliation(s)
- Qing-Ju Sun
- Department of Clinical Laboratory, Navy No. 971 Hospital, Qingdao 266072, Shandong Province, China
| | - Tao Liu
- Department of Infectious Diseases, Navy No. 971 Hospital, Qingdao 266071, Shandong Province, China.
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15
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Hu Y, Wang R, An N, Li C, Wang Q, Cao Y, Li C, Liu J, Wang Y. Unveiling the power of microenvironment in liver regeneration: an in-depth overview. Front Genet 2023; 14:1332190. [PMID: 38152656 PMCID: PMC10751322 DOI: 10.3389/fgene.2023.1332190] [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: 11/02/2023] [Accepted: 11/29/2023] [Indexed: 12/29/2023] Open
Abstract
The liver serves as a vital regulatory hub for various physiological processes, including sugar, protein, and fat metabolism, coagulation regulation, immune system maintenance, hormone inactivation, urea metabolism, and water-electrolyte acid-base balance control. These functions rely on coordinated communication among different liver cell types, particularly within the liver's fundamental hepatic lobular structure. In the early stages of liver development, diverse liver cells differentiate from stem cells in a carefully orchestrated manner. Despite its susceptibility to damage, the liver possesses a remarkable regenerative capacity, with the hepatic lobule serving as a secure environment for cell division and proliferation during liver regeneration. This regenerative process depends on a complex microenvironment, involving liver resident cells, circulating cells, secreted cytokines, extracellular matrix, and biological forces. While hepatocytes proliferate under varying injury conditions, their sources may vary. It is well-established that hepatocytes with regenerative potential are distributed throughout the hepatic lobules. However, a comprehensive spatiotemporal model of liver regeneration remains elusive, despite recent advancements in genomics, lineage tracing, and microscopic imaging. This review summarizes the spatial distribution of cell gene expression within the regenerative microenvironment and its impact on liver regeneration patterns. It offers valuable insights into understanding the complex process of liver regeneration.
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Affiliation(s)
- Yuelei Hu
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Jilin University, Changchun, China
- Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Ruilin Wang
- Department of Cadre’s Wards Ultrasound Diagnostics, Ultrasound Diagnostic Center, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Ni An
- Clinical Translational Science Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Chen Li
- Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
- College of Life Science and Bioengineering, Faculty of Environmental and Life Sciences, Beijing University of Technology, Beijing, China
| | - Qi Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Jilin University, Changchun, China
- Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Yannan Cao
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Jilin University, Changchun, China
- Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Chao Li
- Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Juan Liu
- Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Yunfang Wang
- Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
- Clinical Translational Science Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
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16
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Eissa AM, Hassanin MH, Ibrahim IAAEH. Hepatic β-arrestins: potential roles in liver health and disease. Mol Biol Rep 2023; 50:10399-10407. [PMID: 37843713 PMCID: PMC10676313 DOI: 10.1007/s11033-023-08898-0] [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: 05/29/2023] [Accepted: 10/04/2023] [Indexed: 10/17/2023]
Abstract
Β-arrestins are intracellular scaffolding proteins that have multifaceted roles in different types of disorders. In this review article, we gave a summary about the discovery, characterization and classification of these proteins and their intracellular functions. Moreover, this review article focused on the hepatic expression of β-arrestins and their hepatocellular distribution and function in each liver cell type. Also, we showed that β-arrestins are key regulators of distinct types of hepatic disorders. On the other hand, we addressed some important points that have never been studied before regarding the role of β-arrestins in certain types of hepatic disorders which needs more research efforts to cover.
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Affiliation(s)
| | | | - Islam A A E H Ibrahim
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt.
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17
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Ge XL, Zhang X, Li CH, Pan K, He L, Ren WZ. Bile Acid Overload Induced by Bile Duct and Portal Vein Ligation Improves Survival after Staged Hepatectomy in Rats. Curr Med Sci 2023; 43:1013-1022. [PMID: 37837571 DOI: 10.1007/s11596-023-2779-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 06/26/2023] [Indexed: 10/16/2023]
Abstract
OBJECTIVE Compared to portal vein ligation (PVL), simultaneous bile duct and portal vein ligation (BPL) can significantly enhance hypertrophy of the intact liver. This study aimed to investigate whether BPL could improve survival after extended hepatectomy independently of an increased remnant liver. METHODS We adopted rat models of 90% BPL or 90% PVL. To investigate the role of bile acids (BAs) the BA pools in the PVL and BPL groups were altered by the diet. Staged resection preserving 10% of the estimated liver weight was performed 3 days after BPL; PVL; or sham operation. Histology, canalicular network (CN) continuity; and hepatocyte polarity were evaluated. RESULTS At 3 days after BPL; PVL; or sham operation when the volumetric difference of the intended liver remained insignificant, the survival rates after extended hepatectomy were 86.7%, 47%, and 23.3%, respectively (P<0.01). BPL induced faster restoration of canalicular integrity along with an intensive but transient BA overload. Staged hepatectomy after BPL shortened the duration of the bile CN disturbance and limited BA retention. Decreasing the BA pools in the rats that underwent BPL could compromise these effects, whereas increasing the BA pools of rats that underwent PVL could induce similar effects. The changes in CN restoration were associated with activation of LKB1. CONCLUSION In addition to increasing the future remnant liver, BPL shortened the duration of the spatial disturbance of the CN and could significantly improve the tolerance of the hypertrophied liver to staged resection. BPL may be a safe and efficient future option for patients with an insufficient remnant liver.
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Affiliation(s)
- Xin-Lan Ge
- Faculty of Hepato-Pancreato-Biliary Surgery, First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
- Institute of Hepatobiliary Surgery of Chinese PLA, Beijing, 100853, China
- Key Laboratory of Digital Hepatobiliary Surgery, PLA, Beijing, 100853, China
| | - Xuan Zhang
- Faculty of Hepato-Pancreato-Biliary Surgery, First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
- Institute of Hepatobiliary Surgery of Chinese PLA, Beijing, 100853, China
- Key Laboratory of Digital Hepatobiliary Surgery, PLA, Beijing, 100853, China
| | - Chong-Hui Li
- Faculty of Hepato-Pancreato-Biliary Surgery, First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
- Institute of Hepatobiliary Surgery of Chinese PLA, Beijing, 100853, China
- Key Laboratory of Digital Hepatobiliary Surgery, PLA, Beijing, 100853, China
| | - Ke Pan
- Faculty of Hepato-Pancreato-Biliary Surgery, First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
- Institute of Hepatobiliary Surgery of Chinese PLA, Beijing, 100853, China
- Key Laboratory of Digital Hepatobiliary Surgery, PLA, Beijing, 100853, China
| | - Lei He
- Faculty of Hepato-Pancreato-Biliary Surgery, First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China.
- Institute of Hepatobiliary Surgery of Chinese PLA, Beijing, 100853, China.
- Key Laboratory of Digital Hepatobiliary Surgery, PLA, Beijing, 100853, China.
| | - Wei-Zheng Ren
- Faculty of Hepato-Pancreato-Biliary Surgery, First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China.
- Institute of Hepatobiliary Surgery of Chinese PLA, Beijing, 100853, China.
- Key Laboratory of Digital Hepatobiliary Surgery, PLA, Beijing, 100853, China.
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18
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Hora S, Wuestefeld T. Liver Injury and Regeneration: Current Understanding, New Approaches, and Future Perspectives. Cells 2023; 12:2129. [PMID: 37681858 PMCID: PMC10486351 DOI: 10.3390/cells12172129] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 08/18/2023] [Accepted: 08/21/2023] [Indexed: 09/09/2023] Open
Abstract
The liver is a complex organ with the ability to regenerate itself in response to injury. However, several factors can contribute to liver damage beyond repair. Liver injury can be caused by viral infections, alcoholic liver disease, non-alcoholic steatohepatitis, and drug-induced liver injury. Understanding the cellular and molecular mechanisms involved in liver injury and regeneration is critical to developing effective therapies for liver diseases. Liver regeneration is a complex process that involves the interplay of various signaling pathways, cell types, and extracellular matrix components. The activation of quiescent hepatocytes that proliferate and restore the liver mass by upregulating genes involved in cell-cycle progression, DNA repair, and mitochondrial function; the proliferation and differentiation of progenitor cells, also known as oval cells, into hepatocytes that contribute to liver regeneration; and the recruitment of immune cells to release cytokines and angiogenic factors that promote or inhibit cell proliferation are some examples of the regenerative processes. Recent advances in the fields of gene editing, tissue engineering, stem cell differentiation, small interfering RNA-based therapies, and single-cell transcriptomics have paved a roadmap for future research into liver regeneration as well as for the identification of previously unknown cell types and gene expression patterns. In summary, liver injury and regeneration is a complex and dynamic process. A better understanding of the cellular and molecular mechanisms driving this phenomenon could lead to the development of new therapies for liver diseases and improve patient outcomes.
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Affiliation(s)
- Shainan Hora
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome, Singapore 138672, Singapore;
| | - Torsten Wuestefeld
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome, Singapore 138672, Singapore;
- National Cancer Centre Singapore, Singapore 168583, Singapore
- School of Biological Science, Nanyang Technological University, Singapore 637551, Singapore
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19
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Jeong H, Lee C, Lee MJ, Jung Y. Therapeutic strategies to improve liver regeneration after hepatectomy. Exp Biol Med (Maywood) 2023; 248:1313-1318. [PMID: 37786387 PMCID: PMC10625346 DOI: 10.1177/15353702231191195] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/04/2023] Open
Abstract
Chronic liver disease is one of the most common diseases worldwide, and its prevalence is particularly high among adults aged 40-60 years; it takes a toll on productivity and causes significant economic burden. However, there are still no effective treatments that can fundamentally treat chronic liver disease. Although liver transplantation is considered the only effective treatment for chronic liver disease, it has limitations in that the pool of available donors is vastly insufficient for the number of potential recipients. Even if a patient undergoes liver transplantation, side effects such as immune rejection or bile duct complications could occur. In addition, impaired liver regeneration due to various causes, such as aging and metabolic disorders, may cause liver failure after liver resection, even leading to death. Therefore, further research on the liver regeneration process and therapeutic strategies to improve liver regeneration are needed. In this review, we describe the process of liver regeneration after hepatectomy, focusing on various cytokines and signaling pathways. In addition, we review treatment strategies that have been studied to date to improve liver regeneration, such as promotion of hepatocyte proliferation and metabolism and transplantation of mesenchymal stem cells. This review helps to understand the physiological processes involved in liver regeneration and provides basic knowledge for developing treatments for successful liver regeneration.
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Affiliation(s)
- Hayeong Jeong
- Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Korea
| | - Chanbin Lee
- Institute of Systems Biology, College of Natural Science, Pusan National University, Pusan 46241, Korea
| | - Min Jae Lee
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Kangwon National University, Chuncheon 24341, Korea
| | - Youngmi Jung
- Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Korea
- Department of Biological Sciences, College of Natural Science, Pusan National University, Pusan 46241, Korea
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20
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Carmona-Rodríguez L, Gajadhar AS, Blázquez-García I, Guerrero L, Fernández-Rojo MA, Uriarte I, Mamani-Huanca M, López-Gonzálvez Á, Ciordia S, Ramos A, Herrero JI, Fernández-Barrena MG, Arechederra M, Berasain C, Quiroga J, Sangro B, Argemi J, Pardo F, Rotellar F, López D, Barbas C, Ávila MA, Corrales FJ. Mapping early serum proteome signatures of liver regeneration in living donor liver transplant cases. Biofactors 2023; 49:912-927. [PMID: 37171157 DOI: 10.1002/biof.1954] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 04/02/2023] [Indexed: 05/13/2023]
Abstract
The liver is the only solid organ capable of regenerating itself to regain 100% of its mass and function after liver injury and/or partial hepatectomy (PH). This exceptional property represents a therapeutic opportunity for severe liver disease patients. However, liver regeneration (LR) might fail due to poorly understood causes. Here, we have investigated the regulation of liver proteome and phosphoproteome at a short time after PH (9 h), to depict a detailed mechanistic background of the early LR phase. Furthermore, we analyzed the dynamic changes of the serum proteome and metabolome of healthy living donor liver transplant (LDLT) donors at different time points after surgery. The molecular profiles from both analyses were then correlated. Insulin and FXR-FGF15/19 signaling were stimulated in mouse liver after PH, leading to the activation of the main intermediary kinases (AKT and ERK). Besides, inhibition of the hippo pathway led to an increased expression of its target genes and of one of its intermediary proteins (14-3-3 protein), contributing to cell proliferation. In association with these processes, metabolic reprogramming coupled to enhanced mitochondrial activity cope for the energy and biosynthetic requirements of LR. In human serum of LDLT donors, we identified 56 proteins and 13 metabolites statistically differential which recapitulate some of the main cellular processes orchestrating LR in its early phase. These results provide mechanisms and protein mediators of LR that might prove useful for the follow-up of the regenerative process in the liver after PH as well as preventing the occurrence of complications associated with liver resection.
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Affiliation(s)
| | | | - Irene Blázquez-García
- Functional Proteomics Laboratory, Centro Nacional de Biotecnología (CSIC), Madrid, Spain
| | - Laura Guerrero
- Functional Proteomics Laboratory, Centro Nacional de Biotecnología (CSIC), Madrid, Spain
| | - Manuel A Fernández-Rojo
- Hepatic Regenerative Medicine Laboratory, Madrid Institute for Advanced Studies in Food, Madrid, Spain
- School of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Iker Uriarte
- Proteobotics SL, Madrid, Spain
- CIMA, Universidad de Navarra, Pamplona, Spain
- Clínica Universidad de Navarra, Pamplona, Spain
| | | | | | - Sergio Ciordia
- Functional Proteomics Laboratory, Centro Nacional de Biotecnología (CSIC), Madrid, Spain
| | - Antonio Ramos
- Instituto de Investigaciones Sanitarias de Navarra-IdiSNA, Pamplona, Spain
| | - José Ignacio Herrero
- CIMA, Universidad de Navarra, Pamplona, Spain
- Clínica Universidad de Navarra, Pamplona, Spain
- Centre for Metabolomics and Bioanalysis (CEMBIO), Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Madrid, Spain
| | - Maite G Fernández-Barrena
- Proteobotics SL, Madrid, Spain
- CIMA, Universidad de Navarra, Pamplona, Spain
- Clínica Universidad de Navarra, Pamplona, Spain
| | - María Arechederra
- Proteobotics SL, Madrid, Spain
- CIMA, Universidad de Navarra, Pamplona, Spain
- Clínica Universidad de Navarra, Pamplona, Spain
| | - Carmen Berasain
- Proteobotics SL, Madrid, Spain
- CIMA, Universidad de Navarra, Pamplona, Spain
- Clínica Universidad de Navarra, Pamplona, Spain
| | - Jorge Quiroga
- CIMA, Universidad de Navarra, Pamplona, Spain
- Clínica Universidad de Navarra, Pamplona, Spain
- Centre for Metabolomics and Bioanalysis (CEMBIO), Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Madrid, Spain
| | - Bruno Sangro
- CIMA, Universidad de Navarra, Pamplona, Spain
- Clínica Universidad de Navarra, Pamplona, Spain
- Centre for Metabolomics and Bioanalysis (CEMBIO), Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Madrid, Spain
| | - Josepmaría Argemi
- CIMA, Universidad de Navarra, Pamplona, Spain
- Clínica Universidad de Navarra, Pamplona, Spain
- Centre for Metabolomics and Bioanalysis (CEMBIO), Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Madrid, Spain
| | - Fernando Pardo
- CIMA, Universidad de Navarra, Pamplona, Spain
- Clínica Universidad de Navarra, Pamplona, Spain
- Centre for Metabolomics and Bioanalysis (CEMBIO), Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Madrid, Spain
| | - Fernando Rotellar
- CIMA, Universidad de Navarra, Pamplona, Spain
- Clínica Universidad de Navarra, Pamplona, Spain
- Centre for Metabolomics and Bioanalysis (CEMBIO), Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Madrid, Spain
| | - Daniel López
- Thermo Fisher Scientific, San Jose, California, USA
| | - Coral Barbas
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Matías A Ávila
- Proteobotics SL, Madrid, Spain
- CIMA, Universidad de Navarra, Pamplona, Spain
- Clínica Universidad de Navarra, Pamplona, Spain
| | - Fernando J Corrales
- Functional Proteomics Laboratory, Centro Nacional de Biotecnología (CSIC), Madrid, Spain
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21
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Satilmis B, Akbulut S, Sahin TT, Dalda Y, Tuncer A, Kucukakcali Z, Ogut Z, Yilmaz S. Assessment of Liver Regeneration in Patients Who Have Undergone Living Donor Hepatectomy for Living Donor Liver Transplantation. Vaccines (Basel) 2023; 11:vaccines11020244. [PMID: 36851123 PMCID: PMC9962137 DOI: 10.3390/vaccines11020244] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Revised: 01/17/2023] [Accepted: 01/19/2023] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND Inflammation and the associated immune pathways are among the most important factors in liver regeneration after living donor hepatectomy. Various biomarkers, especially liver function tests, are used to show liver regeneration. The aim of this study was to evaluate the course of liver regeneration following donor hepatectomy (LDH) by routine and regeneration-related biomarkers. METHOD Data from 63 living liver donors (LLDs) who underwent LDH in Inonu University Liver Transplant Institute were prospectively analyzed. Serum samples were obtained on the preoperative day and postoperative days (POD) 1, 3, 5, 10, and 21. Regenerative markers including alfa-fetoprotein (AFP), des carboxy prothrombin (DCP), ornithine decarboxylase (ODC), retinol-binding protein 4 (RBP4), and angiotensin-converting enzyme isotype II (ACEII) and liver function tests including alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP) and total bilirubin levels were all analyzed. RESULTS The median age of the LLDs was 29.7 years and 28 LLDs were female. Eight LLDs developed postoperative complications requiring relaparotomy. The routine laboratory parameters including AST (<0.001), ALT (<0.001), ALP (<0.001), and total bilirubin (<0.001) showed a significant increase over time until postoperative day (POD) 3. For the regeneration-related parameters, except for the RBP4, all parameters including ACEII (p = 0.006), AFP (p = 0.002), DCP (p = 0.007), and ODC (p = 0.002) showed a significant increase in POD3. The regeneration parameters showed a different pattern of change. In right-lobe liver grafts, ACEII (p = 0.002), AFP (p = 0.035), and ODC (p = 0.001) showed a significant increase over time. DCP (p = 0.129) and RBP4 (p = 0.335) showed no significant changes in right-lobe liver grafts. CONCLUSIONS Regenerative markers are increased in a sustained fashion following LDH. This is more prominent following right-lobe grafts which are indicative of progenitor-associated liver regeneration.
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Affiliation(s)
- Basri Satilmis
- Department of Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya 244280, Turkey
- Department of Biochemistry, Inonu University Faculty of Pharmacy, Malatya 244280, Turkey
| | - Sami Akbulut
- Department of Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya 244280, Turkey
- Department of Biostatistics, and Medical Informatics, Inonu University Faculty of Medicine, Malatya 44280, Turkey
- Correspondence:
| | - Tevfik Tolga Sahin
- Department of Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya 244280, Turkey
| | - Yasin Dalda
- Department of Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya 244280, Turkey
| | - Adem Tuncer
- Department of Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya 244280, Turkey
| | - Zeynep Kucukakcali
- Department of Biostatistics, and Medical Informatics, Inonu University Faculty of Medicine, Malatya 44280, Turkey
| | - Zeki Ogut
- Department of Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya 244280, Turkey
| | - Sezai Yilmaz
- Department of Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya 244280, Turkey
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Ai H, Meng F, Ai Y. PathwayKO: An integrated platform for deciphering the systems-level signaling pathways. Front Immunol 2023; 14:1103392. [PMID: 37033947 PMCID: PMC10080220 DOI: 10.3389/fimmu.2023.1103392] [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: 11/20/2022] [Accepted: 03/01/2023] [Indexed: 04/11/2023] Open
Abstract
Systems characterization of immune landscapes in health, disease and clinical intervention cases is a priority in modern medicine. High-throughput transcriptomes accumulated from gene-knockout (KO) experiments are crucial for deciphering target KO signaling pathways that are impaired by KO genes at the systems-level. There is a demand for integrative platforms. This article describes the PathwayKO platform, which has integrated state-of-the-art methods of pathway enrichment analysis, statistics analysis, and visualizing analysis to conduct cutting-edge integrative pathway analysis in a pipeline fashion and decipher target KO signaling pathways at the systems-level. We focus on describing the methodology, principles and application features of PathwayKO. First, we demonstrate that the PathwayKO platform can be utilized to comprehensively analyze real-world mouse KO transcriptomes (GSE22873 and GSE24327), which reveal systemic mechanisms underlying the innate immune responses triggered by non-infectious extensive hepatectomy (2 hours after 85% liver resection surgery) and infectious CASP-model sepsis (12 hours after CASP-model surgery). Strikingly, our results indicate that both cases hit the same core set of 21 KO MyD88-associated signaling pathways, including the Toll-like receptor signaling pathway, the NFκB signaling pathway, the MAPK signaling pathway, and the PD-L1 expression and PD-1 checkpoint pathway in cancer, alongside the pathways of bacterial, viral and parasitic infections. These findings suggest common fundamental mechanisms between these immune responses and offer informative cues that warrant future experimental validation. Such mechanisms in mice may serve as models for humans and ultimately guide formulating the research paradigms and composite strategies to reduce the high mortality rates of patients in intensive care units who have undergone successful traumatic surgical treatments. Second, we demonstrate that the PathwayKO platform model-based assessments can effectively evaluate the performance difference of pathway analysis methods when benchmarked with a collection of proper transcriptomes. Together, such advances in methods for deciphering biological insights at the systems-level may benefit the fields of bioinformatics, systems immunology and beyond.
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Affiliation(s)
- Hannan Ai
- State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
- Department of Electrical and Computer Engineering, The Grainger College of Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, United States
- National Center for Quality Supervision and Inspection of Automatic Equipment, National Center for Testing and Evaluation of Robots (Guangzhou), CRAT, SINOMACH-IT, Guangzhou, China
- *Correspondence: Hannan Ai, ; Yuncan Ai, .cn
| | - Fanmei Meng
- State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Yuncan Ai
- State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
- The Second Affiliated Hospital, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, Center for Inflammation, Immunity & Immune-mediated Disease, Sino-French Hoffmann Institute, Guangzhou Medical University, Guangzhou, Guangdong, China
- *Correspondence: Hannan Ai, ; Yuncan Ai, .cn
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Han J, Lee C, Hur J, Jung Y. Current Therapeutic Options and Potential of Mesenchymal Stem Cell Therapy for Alcoholic Liver Disease. Cells 2022; 12:cells12010022. [PMID: 36611816 PMCID: PMC9818513 DOI: 10.3390/cells12010022] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/16/2022] [Accepted: 12/17/2022] [Indexed: 12/24/2022] Open
Abstract
Alcoholic liver disease (ALD) is a globally prevalent chronic liver disease caused by chronic or binge consumption of alcohol. The therapeutic efficiency of current therapies for ALD is limited, and there is no FDA-approved therapy for ALD at present. Various strategies targeting pathogenic events in the progression of ALD are being investigated in preclinical and clinical trials. Recently, mesenchymal stem cells (MSCs) have emerged as a promising candidate for ALD treatment and have been tested in several clinical trials. MSC-released factors have captured attention, as they have the same therapeutic function as MSCs. Herein, we focus on current therapeutic options, recently proposed strategies, and their limitations in ALD treatment. Also, we review the therapeutic effects of MSCs and those of MSC-related secretory factors on ALD. Although accumulating evidence suggests the therapeutic potential of MSCs and related factors in ALD, the mechanisms underlying their actions in ALD have not been well studied. Further investigations of the detailed mechanisms underlying the therapeutic role of MSCs in ALD are required to expand MSC therapies to clinical applications. This review provides information on current or possible treatments for ALD and contributes to our understanding of the development of effective and safe treatments for ALD.
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Affiliation(s)
- Jinsol Han
- Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea
| | - Chanbin Lee
- Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea
- Institute of Systems Biology, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea
| | - Jin Hur
- Department of Convergence Medicine, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea
- PNU GRAND Convergence Medical Science Education Research Center, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea
- Correspondence: (J.H.); (Y.J.); Tel.: +82-51-510-8074 (J.H.); +82-51-510-2262 (Y.J.)
| | - Youngmi Jung
- Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea
- Department of Biological Sciences, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea
- Correspondence: (J.H.); (Y.J.); Tel.: +82-51-510-8074 (J.H.); +82-51-510-2262 (Y.J.)
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YAP affects the efficacy of liver progenitor cells transplantation in CCl4-induced acute liver injury. Biochem Biophys Res Commun 2022; 634:129-137. [DOI: 10.1016/j.bbrc.2022.10.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 09/27/2022] [Accepted: 10/01/2022] [Indexed: 11/16/2022]
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Liver Regeneration by Hematopoietic Stem Cells: Have We Reached the End of the Road? Cells 2022; 11:cells11152312. [PMID: 35954155 PMCID: PMC9367594 DOI: 10.3390/cells11152312] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/22/2022] [Accepted: 07/22/2022] [Indexed: 02/01/2023] Open
Abstract
The liver is the organ with the highest regenerative capacity in the human body. However, various insults, including viral infections, alcohol or drug abuse, and metabolic overload, may cause chronic inflammation and fibrosis, leading to irreversible liver dysfunction. Despite advances in surgery and pharmacological treatments, liver diseases remain a leading cause of death worldwide. To address the shortage of donor liver organs for orthotopic liver transplantation, cell therapy in liver disease has emerged as a promising regenerative treatment. Sources include primary hepatocytes or functional hepatocytes generated from the reprogramming of induced pluripotent stem cells (iPSC). Different types of stem cells have also been employed for transplantation to trigger regeneration, including hematopoietic stem cells (HSCs), mesenchymal stromal cells (MSCs), endothelial progenitor cells (EPCs) as well as adult and fetal liver progenitor cells. HSCs, usually defined by the expression of CD34 and CD133, and MSCs, defined by the expression of CD105, CD73, and CD90, are attractive sources due to their autologous nature, ease of isolation and cryopreservation. The present review focuses on the use of bone marrow HSCs for liver regeneration, presenting evidence for an ongoing crosstalk between the hematopoietic and the hepatic system. This relationship commences during embryogenesis when the fetal liver emerges as the crossroads between the two systems converging the presence of different origins of cells (mesoderm and endoderm) in the same organ. Ample evidence indicates that the fetal liver supports the maturation and expansion of HSCs during development but also later on in life. Moreover, the fact that the adult liver remains one of the few sites for extramedullary hematopoiesis—albeit pathological—suggests that this relationship between the two systems is ongoing. Can, however, the hematopoietic system offer similar support to the liver? The majority of clinical studies using hematopoietic cell transplantation in patients with liver disease report favourable observations. The underlying mechanism—whether paracrine, fusion or transdifferentiation or a combination of the three—remains to be confirmed.
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26
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Tao J, Chen Y, Zhuang Y, Wei R, Getachew A, Pan T, Yang F, Li Y. Inhibition of Hedgehog Delays Liver Regeneration through Disrupting the Cell Cycle. Curr Issues Mol Biol 2022; 44:470-482. [PMID: 35723318 PMCID: PMC8928988 DOI: 10.3390/cimb44020032] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 01/05/2022] [Accepted: 01/12/2022] [Indexed: 11/16/2022] Open
Abstract
Liver regeneration is a complicated biological process orchestrated by various liver resident cells. Hepatic cell proliferation and reconstruction of the hepatic architecture involve multiple signaling pathways. It has been reported that the Hh signal is involved in liver regeneration. However, the signal transduction pathways and cell types involved are ill studied. This study aimed to investigate hedgehog signal response cell types and the specific molecular mechanism involved in the process of liver regeneration. Partial hepatectomy (PH) of 70% was performed on ICR (Institute of Cancer Research) mice to study the process of liver regeneration. We found that the hedgehog signal was activated significantly after PH, including hedgehog ligands, receptors and intracellular signaling molecules. Ligand signals were mainly expressed in bile duct cells and non-parenchymal hepatic cells, while receptors were expressed in hepatocytes and some non-parenchymal cells. Inhibition of the hedgehog signal treated with vismodegib reduced the liver regeneration rate after partial hepatectomy, including inhibition of hepatic cell proliferation by decreasing Cyclin D expression and disturbing the cell cycle through the accumulation of Cyclin B. The current study reveals the important role of the hedgehog signal and its participation in the regulation of hepatic cell proliferation and the cell cycle during liver regeneration. It provides new insight into the recovery of the liver after liver resection.
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Affiliation(s)
- Jiawang Tao
- Institute of Public Health, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Guangzhou 510530, China; (J.T.); (Y.C.); (Y.Z.); (R.W.); (A.G.); (T.P.)
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yan Chen
- Institute of Public Health, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Guangzhou 510530, China; (J.T.); (Y.C.); (Y.Z.); (R.W.); (A.G.); (T.P.)
| | - Yuanqi Zhuang
- Institute of Public Health, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Guangzhou 510530, China; (J.T.); (Y.C.); (Y.Z.); (R.W.); (A.G.); (T.P.)
| | - Ruzhi Wei
- Institute of Public Health, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Guangzhou 510530, China; (J.T.); (Y.C.); (Y.Z.); (R.W.); (A.G.); (T.P.)
| | - Anteneh Getachew
- Institute of Public Health, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Guangzhou 510530, China; (J.T.); (Y.C.); (Y.Z.); (R.W.); (A.G.); (T.P.)
| | - Tingcai Pan
- Institute of Public Health, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Guangzhou 510530, China; (J.T.); (Y.C.); (Y.Z.); (R.W.); (A.G.); (T.P.)
| | - Fan Yang
- Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China;
| | - Yinxiong Li
- Institute of Public Health, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Guangzhou 510530, China; (J.T.); (Y.C.); (Y.Z.); (R.W.); (A.G.); (T.P.)
- University of Chinese Academy of Sciences, Beijing 100049, China
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou 510530, China
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou 510005, China
- State Key Laboratory of Respiratory Disease, Guangzhou 510530, China
- Correspondence: ; Tel.: +86-(020)-3201-5207
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27
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Hadjittofi C, Feretis M, Martin J, Harper S, Huguet E. Liver regeneration biology: Implications for liver tumour therapies. World J Clin Oncol 2021; 12:1101-1156. [PMID: 35070734 PMCID: PMC8716989 DOI: 10.5306/wjco.v12.i12.1101] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 06/22/2021] [Accepted: 11/28/2021] [Indexed: 02/06/2023] Open
Abstract
The liver has remarkable regenerative potential, with the capacity to regenerate after 75% hepatectomy in humans and up to 90% hepatectomy in some rodent models, enabling it to meet the challenge of diverse injury types, including physical trauma, infection, inflammatory processes, direct toxicity, and immunological insults. Current understanding of liver regeneration is based largely on animal research, historically in large animals, and more recently in rodents and zebrafish, which provide powerful genetic manipulation experimental tools. Whilst immensely valuable, these models have limitations in extrapolation to the human situation. In vitro models have evolved from 2-dimensional culture to complex 3 dimensional organoids, but also have shortcomings in replicating the complex hepatic micro-anatomical and physiological milieu. The process of liver regeneration is only partially understood and characterized by layers of complexity. Liver regeneration is triggered and controlled by a multitude of mitogens acting in autocrine, paracrine, and endocrine ways, with much redundancy and cross-talk between biochemical pathways. The regenerative response is variable, involving both hypertrophy and true proliferative hyperplasia, which is itself variable, including both cellular phenotypic fidelity and cellular trans-differentiation, according to the type of injury. Complex interactions occur between parenchymal and non-parenchymal cells, and regeneration is affected by the status of the liver parenchyma, with differences between healthy and diseased liver. Finally, the process of termination of liver regeneration is even less well understood than its triggers. The complexity of liver regeneration biology combined with limited understanding has restricted specific clinical interventions to enhance liver regeneration. Moreover, manipulating the fundamental biochemical pathways involved would require cautious assessment, for fear of unintended consequences. Nevertheless, current knowledge provides guiding principles for strategies to optimise liver regeneration potential.
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Affiliation(s)
- Christopher Hadjittofi
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Michael Feretis
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Jack Martin
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Simon Harper
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Emmanuel Huguet
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
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28
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Wang Z, Jiang T, Aji T, Aimulajiang K, Liu Y, Lv G, Wen H. Netrin-1 promotes liver regeneration possibly by facilitating vagal nerve repair after partial hepatectomy in mice. Cell Signal 2021; 91:110227. [PMID: 34954393 DOI: 10.1016/j.cellsig.2021.110227] [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: 09/01/2021] [Revised: 12/18/2021] [Accepted: 12/20/2021] [Indexed: 12/14/2022]
Abstract
Hepatic regeneration after hepatectomy is a great concern in clinical practice. Recently, the neuronal guidance protein netrin-1 has been reported to enhance regeneration after nerve injury. The goal of this study was to preliminarily investigate whether netrin-1 stimulates vagus nerve regeneration to promote liver regeneration after partial hepatectomy in mice. The expression of netrin-1 in murine remnant livers after partial hepatectomy (PHx) was evaluated in initial studies. C57BL/6 mice that received exogenous netrin-1 after PHx were used to examine liver regeneration. PHx was performed in wild-type mice after adeno-associated virus injection (Ntn1 gene silencing) to detect the impact of endogenous netrin-1. After PHx and hepatic branch vagotomy (HV), the mice were injected with or without netrin-1 to evaluate the effects on hepatic regeneration and vagal nerve recovery. Significant reductions in netrin-1 at the transcript and protein levels in murine liver tissue after hepatectomy were observed. Subsequent studies of netrin-1 administration revealed the promotion of hepatocyte proliferation and specific growth factors contributing to liver repair and a decrease in hepatic-specific injury enzymes. Furthermore, the opposite results were observed in the netrin-1 knockdown group. HV delayed liver regeneration after PHx. However, this retardation was reversed by exogenous netrin-1 supplementation. In addition, the results of nerve growth and vagal nerve repair in the remnant liver suggested that netrin-1 promoted vagal nerve regeneration after hepatectomy. Netrin-1 accelerates liver regeneration after partial hepatectomy in mice, and the potential mechanism is related to the promotion of vagus nerve repair and regeneration.
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Affiliation(s)
- Zongding Wang
- State Key Laboratory of Pathogenesis, Prevention, and Treatment of High Incidence Diseases in Central Asia, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, PR China; Hepatobiliary and Hydatid Disease Department, First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, PR China
| | - Tiemin Jiang
- State Key Laboratory of Pathogenesis, Prevention, and Treatment of High Incidence Diseases in Central Asia, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, PR China; Hepatobiliary and Hydatid Disease Department, First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, PR China
| | - Tuerganaili Aji
- State Key Laboratory of Pathogenesis, Prevention, and Treatment of High Incidence Diseases in Central Asia, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, PR China; Hepatobiliary and Hydatid Disease Department, First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, PR China
| | - Kalibixiati Aimulajiang
- State Key Laboratory of Pathogenesis, Prevention, and Treatment of High Incidence Diseases in Central Asia, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, PR China
| | - Yanshi Liu
- Department of Micro-repair and Reconstruction, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, PR China
| | - Guodong Lv
- State Key Laboratory of Pathogenesis, Prevention, and Treatment of High Incidence Diseases in Central Asia, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, PR China
| | - Hao Wen
- State Key Laboratory of Pathogenesis, Prevention, and Treatment of High Incidence Diseases in Central Asia, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, PR China; Hepatobiliary and Hydatid Disease Department, First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, PR China.
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Liver Regeneration and Cell Transplantation for End-Stage Liver Disease. Biomolecules 2021; 11:biom11121907. [PMID: 34944550 PMCID: PMC8699389 DOI: 10.3390/biom11121907] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/12/2021] [Accepted: 12/14/2021] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation is the only curative option for end-stage liver disease; however, the limitations of liver transplantation require further research into other alternatives. Considering that liver regeneration is prevalent in liver injury settings, regenerative medicine is suggested as a promising therapeutic strategy for end-stage liver disease. Upon the source of regenerating hepatocytes, liver regeneration could be divided into two categories: hepatocyte-driven liver regeneration (typical regeneration) and liver progenitor cell-driven liver regeneration (alternative regeneration). Due to the massive loss of hepatocytes, the alternative regeneration plays a vital role in end-stage liver disease. Advances in knowledge of liver regeneration and tissue engineering have accelerated the progress of regenerative medicine strategies for end-stage liver disease. In this article, we generally reviewed the recent findings and current knowledge of liver regeneration, mainly regarding aspects of the histological basis of regeneration, histogenesis and mechanisms of hepatocytes' regeneration. In addition, this review provides an update on the regenerative medicine strategies for end-stage liver disease. We conclude that regenerative medicine is a promising therapeutic strategy for end-stage liver disease. However, further studies are still required.
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Abstract
In this editorial, the roles of orosomucoid (ORM) in the diagnoses and follow-up assessments of both nonneoplastic diseases and liver tumors are discussed with respect to the publication by Zhu et al presented in the previous issue of World Journal of Gastroenterology (2020; 26(8): 840-817). ORM, or alpha-1 acid glycoprotein (AGP), is an acute-phase protein that constitutes 1% to 3% of plasma proteins in humans and is mainly synthesized in the liver. ORM exists in serum as two variants: ORM1 and ORM2. Although the variants share 89.6% sequence identity and have similar biological properties, ORM1 constitutes the main component of serum ORM. An interesting feature of ORM is that its biological effects differ according to variations in glycosylation patterns. This variable feature makes ORM an attractive target for diagnosing and monitoring many diseases, including those of the liver. Recent findings suggest that a sharp decrease in ORM level is an important marker for HBV-associated acute liver failure (ALF), and ORM1 plays an important role in liver regeneration. In viral hepatitis, increases in both ORM and its fucosylated forms and the correlation of these increases with fibrosis progression suggest that this glycoprotein can be used with other markers as a noninvasive method in the follow-up assessment of diseases. In addition, similar findings regarding the level of the asialylated form of ORM, called asialo-AGP (AsAGP), have been reported in a follow-up assessment of fibrosis in chronic liver disease. An increase in ORM in serum has also been shown to improve hepatocellular carcinoma (HCC) diagnosis performance when combined with other markers. In addition, determination of the ORM level has been useful in the diagnosis of HCC with AFP concentrations less than 500 ng/mL. For monitoring patients with AFP-negative HCC, a unique trifucosylated tetra-antennary glycan of ORM may also be used as a new potential marker. The fact that there are very few studies investigating the expression of this glycoprotein and its variants in liver tissues constitutes a potential limitation, especially in terms of revealing all the effects of ORM on carcinogenesis and tumor behavior. Current findings indicate that ORM2 expression is decreased in tumors, and this is related to the aggressive course of the disease. Parallel to this finding, in HCC cell lines, ORM2 decreases HCC cell migration and invasion, supporting reports of its tumor suppressor role. In conclusion, the levels of ORM and its different glycosylated variants are promising additional biomarkers for identifying ALF, for monitoring fibrosis in viral hepatitis, and for diagnosing early HCC. Although there is evidence that the loss of ORM2 expression in HCC is associated with poor prognosis, further studies are needed to support these findings. Additionally, investigations of ORM expression in borderline dysplastic nodules and hepatocellular adenomas, which pose diagnostic problems in the differential diagnosis of HCC, especially in biopsy samples, may shed light on whether ORM can be used in histopathological differential diagnosis.
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Affiliation(s)
- Gulsum Ozlem Elpek
- Department of Pathology, Akdeniz University Medical School, Antalya 07070, Turkey
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Christ B, Collatz M, Dahmen U, Herrmann KH, Höpfl S, König M, Lambers L, Marz M, Meyer D, Radde N, Reichenbach JR, Ricken T, Tautenhahn HM. Hepatectomy-Induced Alterations in Hepatic Perfusion and Function - Toward Multi-Scale Computational Modeling for a Better Prediction of Post-hepatectomy Liver Function. Front Physiol 2021; 12:733868. [PMID: 34867441 PMCID: PMC8637208 DOI: 10.3389/fphys.2021.733868] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 10/26/2021] [Indexed: 01/17/2023] Open
Abstract
Liver resection causes marked perfusion alterations in the liver remnant both on the organ scale (vascular anatomy) and on the microscale (sinusoidal blood flow on tissue level). These changes in perfusion affect hepatic functions via direct alterations in blood supply and drainage, followed by indirect changes of biomechanical tissue properties and cellular function. Changes in blood flow impose compression, tension and shear forces on the liver tissue. These forces are perceived by mechanosensors on parenchymal and non-parenchymal cells of the liver and regulate cell-cell and cell-matrix interactions as well as cellular signaling and metabolism. These interactions are key players in tissue growth and remodeling, a prerequisite to restore tissue function after PHx. Their dysregulation is associated with metabolic impairment of the liver eventually leading to liver failure, a serious post-hepatectomy complication with high morbidity and mortality. Though certain links are known, the overall functional change after liver surgery is not understood due to complex feedback loops, non-linearities, spatial heterogeneities and different time-scales of events. Computational modeling is a unique approach to gain a better understanding of complex biomedical systems. This approach allows (i) integration of heterogeneous data and knowledge on multiple scales into a consistent view of how perfusion is related to hepatic function; (ii) testing and generating hypotheses based on predictive models, which must be validated experimentally and clinically. In the long term, computational modeling will (iii) support surgical planning by predicting surgery-induced perfusion perturbations and their functional (metabolic) consequences; and thereby (iv) allow minimizing surgical risks for the individual patient. Here, we review the alterations of hepatic perfusion, biomechanical properties and function associated with hepatectomy. Specifically, we provide an overview over the clinical problem, preoperative diagnostics, functional imaging approaches, experimental approaches in animal models, mechanoperception in the liver and impact on cellular metabolism, omics approaches with a focus on transcriptomics, data integration and uncertainty analysis, and computational modeling on multiple scales. Finally, we provide a perspective on how multi-scale computational models, which couple perfusion changes to hepatic function, could become part of clinical workflows to predict and optimize patient outcome after complex liver surgery.
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Affiliation(s)
- Bruno Christ
- Cell Transplantation/Molecular Hepatology Lab, Department of Visceral, Transplant, Thoracic and Vascular Surgery, University of Leipzig Medical Center, Leipzig, Germany
| | - Maximilian Collatz
- RNA Bioinformatics and High-Throughput Analysis, Faculty of Mathematics and Computer Science, Friedrich Schiller University Jena, Jena, Germany
- Optisch-Molekulare Diagnostik und Systemtechnologié, Leibniz Institute of Photonic Technology (IPHT), Jena, Germany
- InfectoGnostics Research Campus Jena, Jena, Germany
| | - Uta Dahmen
- Experimental Transplantation Surgery, Department of General, Visceral and Vascular Surgery, Jena University Hospital, Jena, Germany
| | - Karl-Heinz Herrmann
- Medical Physics Group, Institute of Diagnostic and Interventional Radiology, Jena University Hospital, Jena, Germany
| | - Sebastian Höpfl
- Faculty of Engineering Design, Production Engineering and Automotive Engineering, Institute for Systems Theory and Automatic Control, University of Stuttgart, Stuttgart, Germany
| | - Matthias König
- Systems Medicine of the Liver Lab, Institute for Theoretical Biology, Humboldt-University Berlin, Berlin, Germany
| | - Lena Lambers
- Faculty of Aerospace Engineering and Geodesy, Institute of Mechanics, Structural Analysis and Dynamics, University of Stuttgart, Stuttgart, Germany
| | - Manja Marz
- RNA Bioinformatics and High-Throughput Analysis, Faculty of Mathematics and Computer Science, Friedrich Schiller University Jena, Jena, Germany
| | - Daria Meyer
- RNA Bioinformatics and High-Throughput Analysis, Faculty of Mathematics and Computer Science, Friedrich Schiller University Jena, Jena, Germany
| | - Nicole Radde
- Faculty of Engineering Design, Production Engineering and Automotive Engineering, Institute for Systems Theory and Automatic Control, University of Stuttgart, Stuttgart, Germany
| | - Jürgen R. Reichenbach
- Medical Physics Group, Institute of Diagnostic and Interventional Radiology, Jena University Hospital, Jena, Germany
| | - Tim Ricken
- Faculty of Aerospace Engineering and Geodesy, Institute of Mechanics, Structural Analysis and Dynamics, University of Stuttgart, Stuttgart, Germany
| | - Hans-Michael Tautenhahn
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, Jena, Germany
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Álvarez-Mercado AI, Caballeria-Casals A, Rojano-Alfonso C, Chávez-Reyes J, Micó-Carnero M, Sanchez-Gonzalez A, Casillas-Ramírez A, Gracia-Sancho J, Peralta C. Insights into Growth Factors in Liver Carcinogenesis and Regeneration: An Ongoing Debate on Minimizing Cancer Recurrence after Liver Resection. Biomedicines 2021; 9:biomedicines9091158. [PMID: 34572344 PMCID: PMC8470173 DOI: 10.3390/biomedicines9091158] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 08/29/2021] [Accepted: 09/01/2021] [Indexed: 01/18/2023] Open
Abstract
Hepatocellular carcinoma has become a leading cause of cancer-associated mortality throughout the world, and is of great concern. Currently used chemotherapeutic drugs in the treatment of hepatocellular carcinoma lead to severe side effects, thus underscoring the need for further research to develop novel and safer therapies. Liver resection in cancer patients is routinely performed. After partial resection, liver regeneration is a perfectly calibrated response apparently sensed by the body’s required liver function. This process hinges on the effect of several growth factors, among other molecules. However, dysregulation of growth factor signals also leads to growth signaling autonomy and tumor progression, so control of growth factor expression may prevent tumor progression. This review describes the role of some of the main growth factors whose dysregulation promotes liver tumor progression, and are also key in regenerating the remaining liver following resection. We herein summarize and discuss studies focused on partial hepatectomy and liver carcinogenesis, referring to hepatocyte growth factor, insulin-like growth factor, and epidermal growth factor, as well as their suitability as targets in the treatment of hepatocellular carcinoma. Finally, and given that drugs remain one of the mainstay treatment options in liver carcinogenesis, we have reviewed the current pharmacological approaches approved for clinical use or research targeting these factors.
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Affiliation(s)
- Ana I. Álvarez-Mercado
- Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, 18071 Granada, Spain
- Institute of Nutrition and Food Technology, Biomedical Research Center, University of Granada, 18016 Armilla, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, Complejo Hospitalario Universitario de Granada, 18014 Granada, Spain
- Correspondence: (A.I.Á.-M.); (C.P.)
| | - Albert Caballeria-Casals
- Hepatic Ischemia-Reperfusion Injury Department, Institut de Recerca Biomèdica August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (A.C.-C.); (C.R.-A.); (M.M.-C.)
| | - Carlos Rojano-Alfonso
- Hepatic Ischemia-Reperfusion Injury Department, Institut de Recerca Biomèdica August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (A.C.-C.); (C.R.-A.); (M.M.-C.)
| | - Jesús Chávez-Reyes
- Facultad de Medicina e Ingeniería en Sistemas Computacionales Matamoros, Universidad Autónoma de Tamaulipas, Matamoros 87300, Mexico; (J.C.-R.); (A.C.-R.)
| | - Marc Micó-Carnero
- Hepatic Ischemia-Reperfusion Injury Department, Institut de Recerca Biomèdica August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (A.C.-C.); (C.R.-A.); (M.M.-C.)
| | - Alfredo Sanchez-Gonzalez
- Teaching and Research Department, Hospital Regional de Alta Especialidad de Ciudad Victoria “Bicentenario 2010”, Ciudad Victoria 87087, Mexico;
| | - Araní Casillas-Ramírez
- Facultad de Medicina e Ingeniería en Sistemas Computacionales Matamoros, Universidad Autónoma de Tamaulipas, Matamoros 87300, Mexico; (J.C.-R.); (A.C.-R.)
- Teaching and Research Department, Hospital Regional de Alta Especialidad de Ciudad Victoria “Bicentenario 2010”, Ciudad Victoria 87087, Mexico;
| | - Jordi Gracia-Sancho
- Liver Vascular Biology Research Group, Barcelona Hepatic Hemodynamic Laboratory, IDIBAPS Biomedical Research Institute, CIBEREHD, 03036 Barcelona, Spain;
- Barcelona Hepatic Hemodynamic Laboratory, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 08036 Barcelona, Spain
| | - Carmen Peralta
- Hepatic Ischemia-Reperfusion Injury Department, Institut de Recerca Biomèdica August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (A.C.-C.); (C.R.-A.); (M.M.-C.)
- Correspondence: (A.I.Á.-M.); (C.P.)
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Meyenberg M, Ferreira da Silva J, Loizou JI. Tissue Specific DNA Repair Outcomes Shape the Landscape of Genome Editing. Front Genet 2021; 12:728520. [PMID: 34539755 PMCID: PMC8446275 DOI: 10.3389/fgene.2021.728520] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 08/05/2021] [Indexed: 12/26/2022] Open
Abstract
The use of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 has moved from bench to bedside in less than 10years, realising the vision of correcting disease through genome editing. The accuracy and safety of this approach relies on the precise control of DNA damage and repair processes to achieve the desired editing outcomes. Strategies for modulating pathway choice for repairing CRISPR-mediated DNA double-strand breaks (DSBs) have advanced the genome editing field. However, the promise of correcting genetic diseases with CRISPR-Cas9 based therapies is restrained by a lack of insight into controlling desired editing outcomes in cells of different tissue origin. Here, we review recent developments and urge for a greater understanding of tissue specific DNA repair processes of CRISPR-induced DNA breaks. We propose that integrated mapping of tissue specific DNA repair processes will fundamentally empower the implementation of precise and safe genome editing therapies for a larger variety of diseases.
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Affiliation(s)
- Mathilde Meyenberg
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Joana Ferreira da Silva
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Joanna I. Loizou
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
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