Interdisciplinary Approaches to Studying Human Liver Biology and Promoting Organ Regeneration: Understanding the Curse of Prometheus

A topical collection in Cells (ISSN 2073-4409). This collection belongs to the section "Tissues and Organs".

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Editors


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Collection Editor
Chair of Tissue Engineering, Institute for Regeneration and Repair, Centre for Regenerative Medicine, The University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
Interests: pluripotent stem cells; liver; hepatocyte; tissue engineering
Special Issues, Collections and Topics in MDPI journals

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Collection Editor
Institute of Biodiversity, Animal Health and Comparative Medicine, University of Glasgow, Glasgow G12 8TA, UK
Interests: lipid storage; metabolism; liver; adipose tissue

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Collection Editor
PhD Student, Institute for Regeneration and Repair, Centre for Regenerative Medicine, The University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
Interests: 3D cell culture; pluripotent stem cells; fatty liver disease; liver metabolism; sex hormones

Topical Collection Information

Dear Colleagues,

As you all know, the liver is a remarkable organ, which performs multiple vital functions, while retaining the ability to rapidly regenerate following damage. The regenerative capacity of the liver has been recognised for centuries, most notably in the tale of Prometheus the Titan in Greek mythology. Key to the liver’s function and resilience is its intricate structure, consisting of parenchymal and non-parenchymal cell types which form the basic architecture of the acinus. The acinar structure can be divided into three zones. The first zone surrounds the periportal region and contains the most oxygenated blood. The blood becomes less oxygenated as it moves through zones 2 and 3, which, alongside other factors, drives functional changes in liver tissue, with the parenchymal component, the hepatocyte, being particularly affected. In the healthy liver, tissue function and renewal is maintained.

In contrast, during disease, the structure of the liver is perturbed by the build-up of scar tissue leading to dysregulated function and regenerative capacity. These alterations, if not kept in check, can lead to chronic liver disease. This currently affects millions of people per annum across the globe and is increasing year on year. Although serious liver disease is curable via organ transplant, these procedures are limited by the availability of donor organs and the requirement for lifelong immunosuppression. Therefore, alternative therapeutic approaches require development to treat an ever-expanding patient population and to better understand the drivers of human liver disease.

Liver formation and homeostasis is governed by numerous factors. During human development, following fertilisation and gastrulation, the liver is formed from the diverticulum lined by endodermal cells. Those cells form hepatoblasts and become columnar in shape as they transition to a pseudostratified epithelium. The signals that control this process are provided by the neighbouring mesenchyme. Following this, hepatoblasts delaminate and invade the septum transversum, forming hepatic cords that expand to form the liver bud. The liver then goes through a series of development stages that refine its structure and functional capacity in utero and postnatally. Mammalian liver development was initially characterised in rodent and avian species, which provided the blueprint for human in vitro and ex vivo studies using tissue and cell types with varying potency. This includes the use of stem cells, cell lines and somatic cell types to build human liver tissue in simple monolayer and more complex formats. These systems are now providing valuable models to study human liver biology ranging from virus infection, to cancer and gene therapy, to drug induced liver injury. This, in conjunction with current knowledge in disease, immunology and sexual dimorphism, for example, provide the field with a sophisticated toolbox to address complex human disease.

Such a renewable cell-based resource, which could be precisely genetically modified and manufactured at scale to treat disease, is of significant interest to the clinic. This would offer the prospect of routine and personalised treatments to treat human liver disease. While significant progress has been made from many perspectives, there remains a need to improve cell-based system manufacture for both basic and complex organ modelling, and the development of pioneering treatments for liver disease. Essential to those endeavours are interdisciplinary scientific investigation and collaboration. The combination of biology with engineering, chemistry, physics, informatics and mathematics are key to the development of reliable products which can be produced at scale, the generation of new intellectual property and successful commercialisation of prototypes. With this in mind we have prepared this Topical Collection of Cells and request your expert opinion and contribution. Please let us know if you would like any clarification or more information regarding the editorial and review processes.

Prof. Dr. David Hay
Dr. Matthew Sinton
Alvile Kasarinaite
Collection Editors

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Keywords

  • organ function
  • liver repair
  • tissue engineering
  • interdisciplinary research
  • in vitro modelling
  • in vivo transplant
  • technology scale-up
  • technology commercialisation

Published Papers (5 papers)

2024

Jump to: 2023, 2022

11 pages, 1339 KiB  
Communication
Screening a Compound Library to Identify Additives That Boost Cytochrome P450 Enzyme Function in Vascularised Liver Spheres
by Baltasar Lucendo-Villarin, Yu Wang, Sunil K. Mallanna, Erin A. Kimbrel and David C. Hay
Cells 2024, 13(18), 1594; https://doi.org/10.3390/cells13181594 - 22 Sep 2024
Viewed by 1179
Abstract
To accurately study human organ function and disease ‘in the dish’, it is necessary to develop reliable cell-based models that closely track human physiology. Our interest lay with the liver, which is the largest solid organ in the body. The liver is a [...] Read more.
To accurately study human organ function and disease ‘in the dish’, it is necessary to develop reliable cell-based models that closely track human physiology. Our interest lay with the liver, which is the largest solid organ in the body. The liver is a multifunctional and highly regenerative organ; however, severe liver damage can have dire consequences for human health. A common cause of liver damage is adverse reactions to prescription drugs. Therefore, the development of predictive liver models that capture human drug metabolism patterns is required to optimise the drug development process. In our study, we aimed to identify compounds that could improve the metabolic function of stem cell-derived liver tissue. Therefore, we screened a compound library to identify additives that improved the maturity of in vitro-engineered human tissue, with the rationale that by taking such an approach, we would be able to fine-tune neonatal and adult cytochrome P450 metabolic function in stem cell-derived liver tissue. Full article
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2023

Jump to: 2024, 2022

26 pages, 4483 KiB  
Review
The Influence of Sex Hormones in Liver Function and Disease
by Alvile Kasarinaite, Matthew Sinton, Philippa T. K. Saunders and David C. Hay
Cells 2023, 12(12), 1604; https://doi.org/10.3390/cells12121604 - 11 Jun 2023
Cited by 30 | Viewed by 8919
Abstract
The liver performs a multitude of bodily functions, whilst retaining the ability to regenerate damaged tissue. In this review, we discuss sex steroid biology, regulation of mammalian liver physiology and the development of new model systems to improve our understanding of liver biology [...] Read more.
The liver performs a multitude of bodily functions, whilst retaining the ability to regenerate damaged tissue. In this review, we discuss sex steroid biology, regulation of mammalian liver physiology and the development of new model systems to improve our understanding of liver biology in health and disease. A major risk factor for the development of liver disease is hepatic fibrosis. Key drivers of this process are metabolic dysfunction and pathologic activation of the immune system. Although non-alcoholic fatty liver disease (NAFLD) is largely regarded as benign, it does progress to non-alcoholic steatohepatitis in a subset of patients, increasing their risk of developing cirrhosis and hepatocellular carcinoma. NAFLD susceptibility varies across the population, with obesity and insulin resistance playing a strong role in the disease development. Additionally, sex and age have been identified as important risk factors. In addition to the regulation of liver biochemistry, sex hormones also regulate the immune system, with sexual dimorphism described for both innate and adaptive immune responses. Therefore, sex differences in liver metabolism, immunity and their interplay are important factors to consider when designing, studying and developing therapeutic strategies to treat human liver disease. The purpose of this review is to provide the reader with a general overview of sex steroid biology and their regulation of mammalian liver physiology. Full article
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16 pages, 25725 KiB  
Article
Microencapsulated Hepatocytes Differentiated from Human Induced Pluripotent Stem Cells: Optimizing 3D Culture for Tissue Engineering Applications
by Marwa Hussein, Mattia Pasqua, Ulysse Pereira, Nassima Benzoubir, Jean-Charles Duclos-Vallée, Anne Dubart-Kupperschmitt, Cecile Legallais and Antonietta Messina
Cells 2023, 12(6), 865; https://doi.org/10.3390/cells12060865 - 10 Mar 2023
Cited by 3 | Viewed by 2529
Abstract
Liver cell therapy and in vitro models require functional human hepatocytes, the sources of which are considerably limited. Human induced pluripotent stem cells (hiPSCs) represent a promising and unlimited source of differentiated human hepatocytes. However, when obtained in two-dimensional (2D) cultures these hepatocytes [...] Read more.
Liver cell therapy and in vitro models require functional human hepatocytes, the sources of which are considerably limited. Human induced pluripotent stem cells (hiPSCs) represent a promising and unlimited source of differentiated human hepatocytes. However, when obtained in two-dimensional (2D) cultures these hepatocytes are not fully mature and functional. As three-dimensional culture conditions offer advantageous strategies for differentiation, we describe here a combination of three-dimensional (3D) approaches enabling the successful differentiation of functional hepatocytes from hiPSCs by the encapsulation of hiPSC-derived hepatoblasts in alginate beads of preformed aggregates. The resulting encapsulated and differentiated hepatocytes (E-iHep-Orgs) displayed a high level of albumin synthesis associated with the disappearance of α-fetoprotein (AFP) synthesis, thus demonstrating that the E-iHep-Orgs had reached a high level of maturation, similar to that of adult hepatocytes. Gene expression analysis by RT-PCR and immunofluorescence confirmed this maturation. Further functional assessments demonstrated their enzymatic activities, including lactate and ammonia detoxification, as well as biotransformation activities of Phase I and Phase II enzymes. This study provides proof of concept regarding the benefits of combining three-dimensional techniques (guided aggregation and microencapsulation) with liver differentiation protocols as a robust approach to generate mature and functional hepatocytes that offer a permanent and unlimited source of hepatocytes. Based on these encouraging results, our combined conditions to produce mature hepatocytes from hiPSCs could be extended to liver tissue engineering and bioartificial liver (BAL) applications at the human scale for which large biomasses are mandatory. Full article
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16 pages, 1237 KiB  
Review
Surgical Models of Liver Regeneration in Pigs: A Practical Review of the Literature for Researchers
by Lorenzo Cinelli, Edoardo Maria Muttillo, Emanuele Felli, Andrea Baiocchini, Fabio Giannone, Jacques Marescaux, Didier Mutter, Michel De Mathelin, Sylvain Gioux, Eric Felli and Michele Diana
Cells 2023, 12(4), 603; https://doi.org/10.3390/cells12040603 - 13 Feb 2023
Cited by 2 | Viewed by 2656
Abstract
The remarkable capacity of regeneration of the liver is well known, although the involved mechanisms are far from being understood. Furthermore, limits concerning the residual functional mass of the liver remain critical in both fields of hepatic resection and transplantation. The aim of [...] Read more.
The remarkable capacity of regeneration of the liver is well known, although the involved mechanisms are far from being understood. Furthermore, limits concerning the residual functional mass of the liver remain critical in both fields of hepatic resection and transplantation. The aim of the present study was to review the surgical experiments regarding liver regeneration in pigs to promote experimental methodological standardization. The Pubmed, Medline, Scopus, and Cochrane Library databases were searched. Studies evaluating liver regeneration through surgical experiments performed on pigs were included. A total of 139 titles were screened, and 41 articles were included in the study, with 689 pigs in total. A total of 29 studies (71% of all) had a survival design, with an average study duration of 13 days. Overall, 36 studies (88%) considered partial hepatectomy, of which four were an associating liver partition and portal vein ligation for staged hepatectomy (ALPPS). Remnant liver volume ranged from 10% to 60%. Only 2 studies considered a hepatotoxic pre-treatment, while 25 studies evaluated additional liver procedures, such as stem cell application, ischemia/reperfusion injury, portal vein modulation, liver scaffold application, bio-artificial, and pharmacological liver treatment. Only nine authors analysed how cytokines and growth factors changed in response to liver resection. The most used imaging system to evaluate liver volume was CT-scan volumetry, even if performed only by nine authors. The pig represents one of the best animal models for the study of liver regeneration. However, it remains a mostly unexplored field due to the lack of experiments reproducing the chronic pathological aspects of the liver and the heterogeneity of existing studies. Full article
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2022

Jump to: 2024, 2023

18 pages, 1901 KiB  
Review
The Influence of Interdisciplinary Work towards Advancing Knowledge on Human Liver Physiology
by Blanca Delgado-Coello, Nalu Navarro-Alvarez and Jaime Mas-Oliva
Cells 2022, 11(22), 3696; https://doi.org/10.3390/cells11223696 - 21 Nov 2022
Cited by 2 | Viewed by 2413
Abstract
The knowledge accumulated throughout the years about liver regeneration has allowed a better understanding of normal liver physiology, by reconstructing the sequence of steps that this organ follows when it must rebuild itself after being injured. The scientific community has used several interdisciplinary [...] Read more.
The knowledge accumulated throughout the years about liver regeneration has allowed a better understanding of normal liver physiology, by reconstructing the sequence of steps that this organ follows when it must rebuild itself after being injured. The scientific community has used several interdisciplinary approaches searching to improve liver regeneration and, therefore, human health. Here, we provide a brief history of the milestones that have advanced liver surgery, and review some of the new insights offered by the interdisciplinary work using animals, in vitro models, tissue engineering, or mathematical models to help advance the knowledge on liver regeneration. We also present several of the main approaches currently available aiming at providing liver support and overcoming organ shortage and we conclude with some of the challenges found in clinical practice and the ethical issues that have concomitantly emerged with the use of those approaches. Full article
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