The influence of tissue spatial geometry and functional organisation on liver regeneration

Abstract

The adult liver exerts crucial functions, including nutrient metabolism and storage, bile production and drug detoxification. These complex functions expose the liver to constant damage induced by toxins, metabolic intermediates and oxidative stress. However, the adult liver exhibits an exceptional regenerative potential, which allows fast and efficient restoration of tissue architecture and function both after tissue resection and toxic damage. To accomplish its vital role, the liver shows a peculiar tissue architecture into functional units, which follow the gradient of oxygen and nutrients within the parenchyma. Much less is known about the influence of tissue spatial geometry and functional organisation on adult liver regeneration. Here I examine the experimental evidence in mouse models showing that the spatial organisation of the epithelial and mesenchymal compartments plays a key role in liver regeneration and favours the establishment of regenerative adult liver progenitors following liver injury. I also discuss the advantages and limitations of human and mouse 3D hepatic organoid systems, which recapitulate key aspects of liver function and architecture, as models of liver regeneration and disease. Finally, I analyse the role of the YAP/TAZ transcriptional co-activators as a central hub sensing the extracellular matrix (ECM), metabolic and epigenetic remodelling that regulate liver regeneration and promote liver disease, such as fibrosis, chronic liver disease and liver cancer. Together, the findings summarised here demonstrate that local physical and functional cellular interactions determined by the liver peculiar spatial geometry, play a crucial role in liver regeneration, and that their alterations have important implications for human liver disease.

Three-Dimensional Sulfated Bacterial Cellulose/Gelatin Composite Scaffolds for Culturing Hepatocytes

“…Meanwhile, as the center of metabolism in the body, liver is susceptible to damage and failure, leading to cirrhosis, fatty liver, liver fibrosis, and liver cancer. Culturing hepatocytes, the major parenchymal liver cell, especially in a 3-dimensional (3D) form, mimics both the metabolic and regenerative functions of the liver and therefore provides indispensable roles in studying liver diseases [ 2 ]. Hepatocytes cultured 2-dimensionally (2D) differs substantial from the microenvironment in which cells are grown in vivo and some key cellular phenotypes are lost.…”

Chimeric Livers: Interspecies Blastocyst Complementation and Xenotransplantation for End-Stage Liver Disease

“…In fact, when assessing the cellular composition of post-implantation pig embryos following blastocyst complementation with human PSCs, approximately 1 out of every 100,000 cells were that of human origin and the more human cells contained within the chimeric embryo, the less developed the embryo was overall. 36 In a separate study involving monkey-pig chimeras, over 4000 pig embryos underwent blastocyst complementation with monkey-derived ESCs, and 10 piglets made it to term, with only two of those piglets being chimeras. Tragically, all 10 piglets then died within one week of birth due to unknown medical issues.…”