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

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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