Liver regeneration observed across the different classes of vertebrates from an evolutionary perspective

Abstract

The liver is a key organ that performs diverse functions such as metabolic processing of nutrients or disposal of dangerous substances (xenobiotics). Accordingly, it seems to be protected by several mechanisms throughout the life of organisms, one of which is compensatory hyperplasia, also known as liver regeneration. This review is a recapitulation of the scientific reports describing the different ways in which the various classes of vertebrates deal with liver injuries, where since mammals have an improved molecular toolkit, exhibit optimized regeneration of the liver compared to lower vertebrates. The main molecules involved in the compensatory process, such as proinflammatory and inhibitory cytokines, are analyzed across vertebrates with an evolutionary perspective. In addition, the possible significance of this mechanism is discussed in the context of the long life span of vertebrates, especially in the case of mammals.

Keywords: Compensatory hyperplasia; Cytokines; Evolution; Liver regeneration; Vertebrates.

Figure 1

Communication among different hepatic cell types mediating signals to achieve compensatory hyperplasia after partial hepatectomy. During the priming phase, Kupffer cells (KCs) produce TNF-α and IL-6, which through paracrine communication stimulate hepatocytes to respond to growth factors such as the hepatocyte growth factor (HGF) and proliferate. Hepatocytes respond by autocrine mechanisms to TGF-α and HGF in the proliferative phase. Finally, TGF-β synthesized by hepatic stellate cells (HSCs) and KCs stimulate the hepatocytes to counteract the effects of TGF-α and return to the G0 phase. Liver sinusoidal endothelial cells (LSECs) also communicate through paracrine pathways with hepatocytes and HSCs. Different types of lymphocytes are shown in the sinusoid (T and B cells from the adaptive immune system; and Natural killer cells -NK-, from the innate immune system). The portal triad comprises the bile duct (BD) composed by biliary epithelial cells (BECs), the hepatic artery (HA), and the portal vein (PV). Based on functional/metabolic differences and specific markers, hepatocytes are grouped in zones 1 to 3.

Figure 2

Main events of the regeneration phases after partial hepatectomy (PH). At the priming stage, soon after PH the urokinase-type plasminogen activator (uPA) increases its activity and then activates the hepatocyte growth factor (HGF) in the extracellular matrix (ECM) and it is released into peripheral blood. The complement system is activated through proteolysis of C3 and it prompts Kupffer cells to release TNF-α and IL-6 which after binding to their receptors activate several signaling pathways (JAK/STAT, MAPK, and PI3/AKT) and hepatocytes become responsive to several growth factors (HGF, TGF-α, and EGF) making the transition to the G1 phase of the cell cycle (proliferative phase) that permit mitogenesis. When hepatocytes proliferate, they produce growth factors that are mitogenic for other hepatic cell types. Once the liver tissue reaches its original mass, in the termination phase, inhibitory cytokines of the TGF-β superfamily (TGF-β and activins) produced by hepatic stellate cells (HSCs) and Kupffer cells, bind their receptors in hepatocytes to phosphorylate and activate SMADs, which in this state bind to SMAD4, forming a complex that is translocated to the nucleus where it activates the transcription of another set of target genes, which facilitates the return of the hepatic cells to the G0 phase and finally, ECM and liver vasculature are reestablished.

Figure 3

Summary of the evolution of vertebrates and their different mechanisms for the repair of tissues. Epimorphic regeneration is characteristic of amphibians and reptiles but it is absent in birds and mammals. Liver regeneration takes place in all vertebrate classes; however, the improved molecular toolkit present in mammals supports optimized regeneration of the liver compared to lower vertebrates. Several studies show that C3, a component of the complement system (innate immunity) as well as the cytokines TNF, IL-6, and TGF-β along with growth factors such as fibroblast growth factor (FGF) have been present since the appearance of the first metazoans (ca. 550 million years ago). In addition, it has been shown a different balance of lipids in bile acids from mammal species, with a notably high content of phosphatidylcholine and cholesterol. PL: phospholipids; CHOL: cholesterol.