Liver Injury and Regeneration: From Basic to Translational Research

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell and Gene Therapy".

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 24708

Special Issue Editor

Department of Medicine, Duke University, Durham, NC, USA
Interests: liver fibrosis; NAFLD; drug-induced liver injury; mitochondrial biology; cell death; cell metabolism

Special Issue Information

Dear Colleagues,

The liver is the largest internal organ of our body, and plays a central role in all metabolic processes. However, it is constantly exposed to a plethora of insults, including hepatitis virus, alcohol, high-fat diet and drugs/chemicals, which can act either individually or in combination to cause liver injury. Interestingly, the liver has a unique and remarkable ability to regenerate, a phenomenon that was recognized more than two millennia ago in the myth of Prometheus from the ancient Greeks. In acute and transient injury caused by insults like partial hepatectomy or accidental acetaminophen overdose, the liver mass and function can be restored within a week by proliferation and remodeling of the remaining cells. However, in many chronic conditions, such as prolonged alcohol abuse, non-alcoholic fatty liver disease (NAFLD), viral hepatitis infection, as well as autoimmune and genetic disorders, the injury can persist and the regenerative capacity of the liver eventually becomes impaired, resulting in progressive deterioration of liver functions and eventually hepatic scarring and cirrhosis. Therefore, the outcome of liver injury is also dictated by the effectiveness of liver regeneration and repair. In this Special Issue, we invite you to improve the current knowledge of any aspect of cellular and molecular mechanisms of liver injury and regeneration with original research articles, and to summarize the current state of this intriguing field with compelling reviews. Manuscripts providing translational value will be particularly welcome.

Dr. Kuo Du
Guest Editor

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Keywords

  • liver injury
  • liver regeneration
  • liver repair
  • hepatotoxicity
  • liver diseases

Published Papers (10 papers)

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Research

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17 pages, 5876 KiB  
Article
AdhMMP8 Vector Administration in Muscle: An Alternate Strategy to Regress Hepatic Fibrosis
by Jesús García-Bañuelos, Edén Oceguera-Contreras, Ana Sandoval-Rodríguez, Blanca Estela Bastidas-Ramírez, Silvia Lucano-Landeros, Daniela Gordillo-Bastidas, Belinda C. Gómez-Meda, Arturo Santos, Eira Cerda-Reyes and Juan Armendariz-Borunda
Cells 2023, 12(17), 2127; https://doi.org/10.3390/cells12172127 - 22 Aug 2023
Viewed by 1041
Abstract
The development of several vaccines against the SARS-CoV2 virus and their application in millions of people have shown efficacy and safety in the transfer of genes to muscle turning this tissue into a protein-producing factory. Established advanced liver fibrosis, is characterized by replacement [...] Read more.
The development of several vaccines against the SARS-CoV2 virus and their application in millions of people have shown efficacy and safety in the transfer of genes to muscle turning this tissue into a protein-producing factory. Established advanced liver fibrosis, is characterized by replacement of hepatic parenchyma by tissue scar, mostly collagen type I, with increased profibrogenic and proinflammatory molecules gene expression. Matrix metalloproteinase 8 (MMP-8) is an interstitial collagen-degrading proenzyme acting preferentially on collagen type I when activated. This study was carried out to elucidate the effect of an intramuscularly delivered adenoviral vector containing proMMP-8 gene cDNA (AdhMMP8) in male Wistar rats with experimental advanced liver fibrosis induced by thioacetamide. Therapeutic effects were monitored after 1, 2, or 3 weeks of a single dose (3 × 1011 vp/kg) of AdhMMP8. Circulating and liver concentration of MMP-8 protein remained constant; hepatic fibrosis decreased up to 48%; proinflammatory and profibrogenic genes expression diminished: TNF-α 2.28-fold, IL-1 1.95-fold, Col 1A1 4-fold, TGF-β1 3-fold and CTGF 2-fold; and antifibrogenic genes expression raised, MMP-9 2.8-fold and MMP-1 10-fold. Our data proposes that the administration of AdhMMP8 in muscle is safe and effective in achieving liver fibrosis regression at a comparable extent as when the adenoviral vector is delivered systemically to reach the liver, using a minimally invasive procedure. Full article
(This article belongs to the Special Issue Liver Injury and Regeneration: From Basic to Translational Research)
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20 pages, 4559 KiB  
Article
Targeted Deletion of Thymosin Beta 4 in Hepatic Stellate Cells Ameliorates Liver Fibrosis in a Transgenic Mouse Model
by Jieun Kim, Chanbin Lee, Jinsol Han, Hayeong Jeong, Sihyung Wang, Yung Hyun Choi and Youngmi Jung
Cells 2023, 12(12), 1658; https://doi.org/10.3390/cells12121658 - 18 Jun 2023
Viewed by 1374
Abstract
Liver fibrosis is the most common feature of liver disease, and activated hepatic stellate cells (HSCs) are the main contributors to liver fibrosis. Thus, finding key targets that modulate HSC activation is important to prevent liver fibrosis. Previously, we showed that thymosin β4 [...] Read more.
Liver fibrosis is the most common feature of liver disease, and activated hepatic stellate cells (HSCs) are the main contributors to liver fibrosis. Thus, finding key targets that modulate HSC activation is important to prevent liver fibrosis. Previously, we showed that thymosin β4 (Tβ4) influenced HSC activation by interacting with the Hedgehog pathway in vitro. Herein, we generated Tβ4 conditional knockout (Tβ4-flox) mice to investigate in vivo functions of Tβ4 in liver fibrosis. To selectively delete Tβ4 in activated HSCs, double-transgenic (DTG) mice were generated by mating Tβ4-flox mice with α-smooth muscle actin (α-Sma)-Cre-ERT2 mice, and these mice were administered carbon tetrachloride (CCl4) or underwent bile duct ligation to induce liver fibrosis. Tβ4 was selectively suppressed in the activated HSCs of DTG mouse liver, and this reduction attenuated liver injury, including fibrosis, in both fibrotic models by repressing Hedgehog (Hh) signaling. In addition, the re-expression of Tβ4 by an adeno-associated virus reversed the effect of HSC-specific Tβ4 deletion and led to liver fibrosis with Hh activation in CCl4-exposed mice treated with tamoxifen. In conclusion, our results demonstrate that Tβ4 is a crucial regulator of HSC activation, suggesting it as a novel therapeutic target for curing liver fibrosis. Full article
(This article belongs to the Special Issue Liver Injury and Regeneration: From Basic to Translational Research)
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16 pages, 2471 KiB  
Article
TREM2 Regulates the Removal of Apoptotic Cells and Inflammatory Processes during the Progression of NAFLD
by Imke Liebold, Simon Meyer, Markus Heine, Anastasia Kuhl, Jennifer Witt, Leah Eissing, Alexander W. Fischer, Anja Christina Koop, Johannes Kluwe, Julian Schulze zur Wiesch, Malte Wehmeyer, Uwe Knippschild, Ludger Scheja, Joerg Heeren, Lidia Bosurgi and Anna Worthmann
Cells 2023, 12(3), 341; https://doi.org/10.3390/cells12030341 - 17 Jan 2023
Cited by 3 | Viewed by 3675
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common liver pathology worldwide. In mice and humans, NAFLD progression is characterized by the appearance of TREM2-expressing macrophages in the liver. However, their mechanistic contributions to disease progression have not been completely elucidated. Here, we [...] Read more.
Nonalcoholic fatty liver disease (NAFLD) is the most common liver pathology worldwide. In mice and humans, NAFLD progression is characterized by the appearance of TREM2-expressing macrophages in the liver. However, their mechanistic contributions to disease progression have not been completely elucidated. Here, we show that TREM2+ macrophages prevent the generation of a pro-inflammatory response elicited by LPS-laden lipoproteins in vitro. Further, Trem2 expression regulates bone-marrow-derived macrophages (BMDMs) and Kupffer cell capacity to phagocyte apoptotic cells in vitro, which is dependent on CD14 activation. In line with this, loss of Trem2 resulted in an increased pro-inflammatory response, which ultimately aggravated liver fibrosis in murine models of NAFLD. Similarly, in a human NAFLD cohort, plasma levels of TREM2 were increased and hepatic TREM2 expression was correlated with higher levels of liver triglycerides and the acquisition of a fibrotic gene signature. Altogether, our results suggest that TREM2+ macrophages have a protective function during the progression of NAFLD, as they are involved in the processing of pro-inflammatory lipoproteins and phagocytosis of apoptotic cells and, thereby, are critical contributors for the re-establishment of liver homeostasis. Full article
(This article belongs to the Special Issue Liver Injury and Regeneration: From Basic to Translational Research)
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19 pages, 4685 KiB  
Article
Hepatic ROS Mediated Macrophage Activation Is Responsible for Irinotecan Induced Liver Injury
by Bohao Liu, Cong Ding, Wenbin Tang, Chen Zhang, Yiying Gu, Zhiqiang Wang, Tingzi Yu and Zhuan Li
Cells 2022, 11(23), 3791; https://doi.org/10.3390/cells11233791 - 26 Nov 2022
Cited by 7 | Viewed by 1939
Abstract
Irinotecan is the first line chemotherapy drug used for treatment of metastatic colorectal cancer worldwide. There is increasing evidence suggesting that liver damage, including steatosis and steatohepatitis, can be caused during the treatment involving irinotecan. However, molecular mechanisms by which irinotecan-induced liver injury [...] Read more.
Irinotecan is the first line chemotherapy drug used for treatment of metastatic colorectal cancer worldwide. There is increasing evidence suggesting that liver damage, including steatosis and steatohepatitis, can be caused during the treatment involving irinotecan. However, molecular mechanisms by which irinotecan-induced liver injury remain elusive. In this study, we found that irinotecan treatment caused significant elevation of ALT, inflammation, and fat accumulation in the liver, which are associated with hepatic macrophage activation. Depletion of macrophages by clodronate liposome improved irinotecan induced liver injury and inflammatory response in mice. In vitro data indicated that irinotecan induced intracellular ROS production in primary hepatocyte and upregulating of toll-like receptor (TLRs) family expression in macrophages. Supernatant from irinotecan treated hepatocyte triggered macrophage activation and upregulation of TLRs in macrophage, and N-acetylcysteine (NAC) abolished these effects. By using co-culture system, we further revealed that irinotecan activated macrophage induced impairment of lipid metabolism and promoted apoptosis in hepatocyte and NAC prevented macrophage-induced cell death and partially revered impaired lipid metabolism in hepatocytes. By using the irinotecan liver injury model, we demonstrated that combining NAC with irinotecan prevented irinotecan-induced macrophage activation, TLR upregulation, liver injury, and partially prevented the accumulation of triglycerides in liver. Our results thus indicated that macrophages play a critical role in irinotecan-induced liver injury, and targeting ROS provides new options for development of hepatoprotective drugs in clinical practice. Full article
(This article belongs to the Special Issue Liver Injury and Regeneration: From Basic to Translational Research)
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18 pages, 3156 KiB  
Article
Premature Macrophage Activation by Stored Red Blood Cell Transfusion Halts Liver Regeneration Post-Partial Hepatectomy in Rats
by Nathalie Abudi, Omri Duev, Tal Asraf, Simcha Blank, Idit Matot and Rinat Abramovitch
Cells 2022, 11(21), 3522; https://doi.org/10.3390/cells11213522 - 07 Nov 2022
Cited by 1 | Viewed by 1861
Abstract
Liver resection is a common treatment for various conditions and often requires blood transfusions to compensate for operative blood loss. As partial hepatectomy (PHx) is frequently performed in patients with a pre-damaged liver, avoiding further injury is of paramount clinical importance. Our aim [...] Read more.
Liver resection is a common treatment for various conditions and often requires blood transfusions to compensate for operative blood loss. As partial hepatectomy (PHx) is frequently performed in patients with a pre-damaged liver, avoiding further injury is of paramount clinical importance. Our aim was to study the impact of red blood cell (RBC) resuscitation on liver regeneration. We assessed the impact of RBC storage time on liver regeneration following 50% PHx in rats and explored possible contributing molecular mechanisms using immunohistochemistry, RNA-Seq, and macrophage depletion. The liver was successfully regenerated after PHx when rats were transfused with fresh RBCs (F-RBCs). However, in rats resuscitated with stored RBCs (S-RBCs), the regeneration process was disrupted, as detected by delayed hepatocyte proliferation and lack of hypertrophy. The delayed regeneration was associated with elevated numbers of hemorrhage-activated liver macrophages (Mhem) secreting HO-1. Depletion of macrophages prior to PHx and transfusion improved the regeneration process. Gene expression profiling revealed alterations in numerous genes belonging to critical pathways, including cell cycle and DNA replication, and genes associated with immune cell activation, such as chemokine signaling and platelet activation and adhesion. Our results implicate activated macrophages in delayed liver regeneration following S-RBC transfusion via HO-1 and PAI-1 overexpression. Full article
(This article belongs to the Special Issue Liver Injury and Regeneration: From Basic to Translational Research)
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21 pages, 5094 KiB  
Article
Multi-Channel Metabolomics Analysis Identifies Novel Metabolite Biomarkers for the Early Detection of Fatty Liver Disease in Dairy Cows
by Xuan Zhang, Tingjun Liu, Xianpeng Hou, Chengzhang Hu, Letian Zhang, Shengxuan Wang, Qin Zhang and Kerong Shi
Cells 2022, 11(18), 2883; https://doi.org/10.3390/cells11182883 - 15 Sep 2022
Cited by 2 | Viewed by 2568
Abstract
Fatty liver disease, a type of metabolic disorder, frequently occurs in dairy cows during the parturition period, causing a high culling rate and, therefore, considerable economic losses in the dairy industry owing to the lack of effective diagnostic methods. Here, metabolite biomarkers were [...] Read more.
Fatty liver disease, a type of metabolic disorder, frequently occurs in dairy cows during the parturition period, causing a high culling rate and, therefore, considerable economic losses in the dairy industry owing to the lack of effective diagnostic methods. Here, metabolite biomarkers were identified and validated for the diagnosis of metabolic disorders. A total of 58 participant cows, including severe fatty liver disease and normal control groups, in the discovery set (liver biopsy tested, n = 18), test set (suspected, n = 20) and verification set (liver biopsy tested, n = 20), were strictly recruited and a sample collected for their feces, urine, and serum. Non-targeted GC-MS-based metabolomics methods were used to characterize the metabolite profiles and to screen in the discovery set. Eventually, ten novel biomarkers involved in bile acid, amino acid, and fatty acid were identified and validated in the test set. Each of them had a higher diagnostic ability than the traditional serum biochemical indicators, with an average area under the receiver operating characteristic curve of 0.830 ± 0.0439 (n = 10) versus 0.377 ± 0.182 (n = 9). Especially, combined biomarker panels via different metabolic pipelines had much better diagnostic sensitivity and specificity than every single biomarker, suggesting their powerful utilization potentiality for the early detection of fatty liver disease. Intriguingly, the serum biomarkers were confirmed perfectly in the verification set. Moreover, common biological pathways were found to be underlying the pathogenesis of fatty liver syndrome in cattle via different metabolic pipelines. These newly-discovered and non-invasive metabolic biomarkers are meaningful in reducing the high culling rate of cows and, therefore, benefit the sustainable development of the dairy industry. Full article
(This article belongs to the Special Issue Liver Injury and Regeneration: From Basic to Translational Research)
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Review

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21 pages, 1880 KiB  
Review
Liver Injury and Regeneration: Current Understanding, New Approaches, and Future Perspectives
by Shainan Hora and Torsten Wuestefeld
Cells 2023, 12(17), 2129; https://doi.org/10.3390/cells12172129 - 22 Aug 2023
Cited by 2 | Viewed by 3249
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. [...] Read more.
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. Full article
(This article belongs to the Special Issue Liver Injury and Regeneration: From Basic to Translational Research)
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14 pages, 1896 KiB  
Review
Glycolysis in Chronic Liver Diseases: Mechanistic Insights and Therapeutic Opportunities
by Hengdong Qu, Junli Liu, Di Zhang, Ruoyan Xie, Lijuan Wang and Jian Hong
Cells 2023, 12(15), 1930; https://doi.org/10.3390/cells12151930 - 26 Jul 2023
Cited by 2 | Viewed by 2367
Abstract
Chronic liver diseases (CLDs) cover a spectrum of liver diseases, ranging from nonalcoholic fatty liver disease to liver cancer, representing a growing epidemic worldwide with high unmet medical needs. Glycolysis is a conservative and rigorous process that converts glucose into pyruvate and sustains [...] Read more.
Chronic liver diseases (CLDs) cover a spectrum of liver diseases, ranging from nonalcoholic fatty liver disease to liver cancer, representing a growing epidemic worldwide with high unmet medical needs. Glycolysis is a conservative and rigorous process that converts glucose into pyruvate and sustains cells with the energy and intermediate products required for diverse biological activities. However, abnormalities in glycolytic flux during CLD development accelerate the disease progression. Aerobic glycolysis is a hallmark of liver cancer and is responsible for a broad range of oncogenic functions including proliferation, invasion, metastasis, angiogenesis, immune escape, and drug resistance. Recently, the non-neoplastic role of aerobic glycolysis in immune activation and inflammatory disorders, especially CLD, has attracted increasing attention. Several key mediators of aerobic glycolysis, including HIF-1α and pyruvate kinase M2 (PKM2), are upregulated during steatohepatitis and liver fibrosis. The pharmacological inhibition or ablation of PKM2 effectively attenuates hepatic inflammation and CLD progression. In this review, we particularly focused on the glycolytic and non-glycolytic roles of PKM2 in the progression of CLD, highlighting the translational potential of a glycolysis-centric therapeutic approach in combating CLD. Full article
(This article belongs to the Special Issue Liver Injury and Regeneration: From Basic to Translational Research)
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24 pages, 1062 KiB  
Review
Advances in Recellularization of Decellularized Liver Grafts with Different Liver (Stem) Cells: Towards Clinical Applications
by Burak Toprakhisar, Catherine M. Verfaillie and Manoj Kumar
Cells 2023, 12(2), 301; https://doi.org/10.3390/cells12020301 - 13 Jan 2023
Cited by 12 | Viewed by 2814
Abstract
Liver transplantation is currently the only curative therapy for patients with acute or chronic liver failure. However, a dramatic gap between the number of available liver grafts and the number of patients on the transplantation waiting list emphasizes the need for valid liver [...] Read more.
Liver transplantation is currently the only curative therapy for patients with acute or chronic liver failure. However, a dramatic gap between the number of available liver grafts and the number of patients on the transplantation waiting list emphasizes the need for valid liver substitutes. Whole-organ engineering is an emerging field of tissue engineering and regenerative medicine. It aims to generate transplantable and functional organs to support patients on transplantation waiting lists until a graft becomes available. It comprises two base technologies developed in the last decade; (1) organ decellularization to generate a three-dimensional (3D) extracellular matrix scaffold of an organ, and (2) scaffold recellularization to repopulate both the parenchymal and vascular compartments of a decellularized organ. In this review article, recent advancements in both technologies, in relation to liver whole-organ engineering, are presented. We address the potential sources of hepatocytes and non-parenchymal liver cells for repopulation studies, and the role of stem-cell-derived liver progeny is discussed. In addition, different cell seeding strategies, possible graft modifications, and methods used to evaluate the functionality of recellularized liver grafts are outlined. Based on the knowledge gathered from recent transplantation studies, future directions are summarized. Full article
(This article belongs to the Special Issue Liver Injury and Regeneration: From Basic to Translational Research)
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20 pages, 1533 KiB  
Review
Current Therapeutic Options and Potential of Mesenchymal Stem Cell Therapy for Alcoholic Liver Disease
by Jinsol Han, Chanbin Lee, Jin Hur and Youngmi Jung
Cells 2023, 12(1), 22; https://doi.org/10.3390/cells12010022 - 21 Dec 2022
Cited by 6 | Viewed by 2404
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Liver Injury and Regeneration: From Basic to Translational Research)
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