Liver regeneration biology: Implications for liver tumour therapies

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.

Keywords: Liver; Liver regeneration potential; Regeneration biology; Therapies; Tumour.

Figure 1

Cytokine priming of hepatocytes. PH induced increase in portal pressure exerts sheer stress on LSEC inducing IL6 secretion. Gut derived LPS, complement components C3 & C5, ICAM1, and LTXα from T lymphocytes all induce IL6 and TNF expression from Kupffer cells. IL6 & TNFα prime hepatocytes after binding to IL6R and TNFαR. LTXα also acts directly on hepatocytes via the TNFαR. LSEC: Liver sinusoidal endothelial cell; IL6: Interleukin 6; IL6R: Interleukin 6 receptor; LPS: Lipopolysaccharide; TLR: Toll-like receptor; TNFα: TNF alpha; TNFαR: TNF alpha receptor; CtR: Complement receptor; ICAM1: Intercellular adhesion molecule 1; ICAM1R: Intercellular adhesion molecule 1 receptor; LTXα: Lymphotoxin alpha; LTXαR: Lymphotoxin alpha receptor.

Figure 2

Summary of ligand binding to epidermal growth factor receptor in liver regeneration. Endocrine EGFR signalling by EGF from Brunner’s glands and salivary glands. Paracrine EGFR signalling by HB EGF from LSEC and Kupffer cells, autocrine EGFR signalling by amphiregulin and TGFα from hepatocytes. LSEC: Liver sinusoidal endothelial cell; EGF: Epidermal growth factor; EGFR: Epidermal growth factor receptor; HB EGF: Heparin bound EGF-like growth factor; TGFα: Transforming growth factor α.

Figure 3

Intracellular signal transduction map. A: Intracellular signal transduction in liver regeneration; B: Ligand overlap and receptor binding redundancy; C: Intracellular cross talk between signalling pathways. HGF: Hepatocyte growth factor; FGF: Fibroblast growth factor; VEGF: Vascular endothelial cell growth factor; EGFR: Epidermal growth factor receptor; IL6: Interleukin 6; TNF: Tumour necrosis factor; LPS: Lipopolysaccharide; RTK: Receptor tyrosine kinase family (including HGF receptor, FGF receptor, VEGF receptor, EGF receptor); GPCR: G protein coupled receptor; IL6R: Interleukin 6 receptor; TNFR: Tumour necrosis factor receptor; TLR: Toll like receptor; RAS/RAF/MEK/ERK: signalling components downstream of receptor tyrosine kinase; PI3K: Phosphatidylinositol 3’-kinase; AKT: Akt kinase (also known as protein kinase B); mTOR: Mammalian target of rapamycin; JAK: Janus Kinase; STAT3: Signal Transducer And Activator Of Transcription 3; YAP: Yes-associated protein; NFκb: Nuclear factor kappa B.