MBSJ MCC Young Scientist Award 2012 Liver regeneration: a unique and flexible reaction depending on the type of injury

Abstract

The liver can be thought of as a mysterious organ, because it has an elegant regenerative capability. This phenomenon has been well known since ancient times and is already applied to medical treatments for severe hepatic disorders by transplanting portions of liver received from living donors. However, it was not until quite recently that the mechanism underlying the principle of liver regeneration was investigated more deeply. Recent advances in the technologies for characterizing cell properties and examining the molecular nature of cells are enabling us to understand what occurs in the regenerating liver. After acute liver damage, hepatocytes actively proliferate in response to external stimulation by humoral factors. However, in the chronically injured liver, hepatocytes cannot proliferate well, but biliary cells appearing after chronic liver damage form primitive ductules around portal veins of the liver. These biliary cells may have a multiple origin, including hepatocytes, and contain progenitor cells giving rise to both hepatocytes and biliary cells, or represent cells that can be directly converted into hepatocytes. Although liver regeneration is more complicated than we had thought, unremitting efforts by researchers will certainly connect the numerous findings obtained in basic research with the development of new therapeutic strategies for liver diseases.

The PPAR–microbiota–metabolic organ trilogy to fine‐tune physiology

“…Being an essential organ performing a wide range of functions, the liver is capable of regulating different metabolic processes such as glucose, lipid, protein, bile, and xenobiotic metabolism as well as synthesizing different factors to ensure the normal functioning of the whole body such as essential hormones (IGFs), serum proteins (albumin and globulins), and urinary proteins (major urinary proteins) (194)(195)(196)(197)(198). The liver is the only visceral organ that is capable of regenerating itself when damaged, and this regenerative ability is highly plastic depending on the type of injury (199). Being a highly complex immunogenic lymphoid organ, the liver is also responsible for producing systemic factors that regulate bacteria such as antimicrobial proteins and hepcidin (200).…”

Regulation of hepatocyte identity and quiescence

“…This hypothesis was recently supported by a lineage-tracing study of SOX-9-positive biliary cells in intrahepatic bile ducts, showing that labeled cells in the normal adult mouse liver expanded rather quickly (weeks to months) across the lobule in a porto-central direction, suggesting that almost all lobular cells would be derived from a biliary compartment [113]. However, a number of different labeling and tracing approaches looking at both hepatocytes and biliary epithelial cells that could eventually give rise to hepatocytes (reviewed in [114] ) do not sustain this streaming liver model, suggesting that the above-mentioned SOX-9 labeling studies should be interpreted more carefully [115]. Therefore, the current belief is that under normal conditions (i.e., in the absence of noxious stimuli), the cellular population of the liver is maintained by the replication of existing cells and progenitor cells have little implication in this maintenance liver remodeling.…”

Wnt/β-Catenin Signaling Drives Thioacetamide-Mediated Heteroprotection Against Acetaminophen-Induced Lethal Liver Injury

“… 7 A few recent studies examined such mechanisms underlying the tightly regulated compensatory liver regeneration. 8 - 10 However, the precise mechanisms that can act as a flexible switch to effectively mount and timely terminate compensatory liver regeneration after toxic liver injury have not been understood so far. This necessitates the investigation of such mechanisms to understand the toxicodynamics of the autoprotection and heteroprotection models of toxicity.…”