Liver regeneration and fibrosis after inflammation
Tanaka and Miyajima Inflammation and Regeneration
Liver regeneration and fibrosis after inflammation
Minoru Tanaka 1
Atsushi Miyajima 0
0 Institute of Molecular and Cellular Biosciences, The University of Tokyo , Tokyo , Japan
1 Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine , Tokyo , Japan
The liver is a unique organ with an extraordinary capacity to regenerate upon various injuries. In acute and transient liver injury by insults such as chemical hepatotoxins, the liver in rodents returns to the original architecture by proliferation and remodeling of the remaining cells within a week. In contrast, chronic liver inflammation due to various etiologies, e.g., virus infection and metabolic and immune disorders, results in liver fibrosis, often leading to cirrhosis and carcinogenesis. In both acute and chronic inflammation, a variety of immune and non-immune cells in the liver is involved in the processes resulting in either regeneration or fibrosis. In addition, chronic hepatitis often accompanies proliferation of atypical biliary cells, also known as liver progenitor cells or oval cells. Although the origin of liver progenitor cells and its contribution to hepatic repair is still under intense debate, recent studies have revealed a regulatory role for immune cells in progenitor proliferation and differentiation. In this review, we summarize recent studies on liver regeneration and fibrosis in the viewpoint of inflammation.
Fibrosis; Hepatic stellate cell; Liver sinusoidal endothelial cell; Liver progenitor cell
-
Background
The liver is a central organ for homeostasis and carries
out a wide variety of functions, including metabolism,
glycogen storage, drug detoxification, production of
various serum proteins, and bile secretion. Most of
those liver functions are carried out by hepatocytes,
the liver parenchymal cells, which account for
approximately 60 % of total liver cells and 80 % of the
total liver volume. Hepatocytes are highly polarized
epithelial cells and form cords (Fig. 1). Their
basolateral surfaces face the sinusoid, a unique form of
capillary in the liver, which consists of fenestrated liver
sinusoidal endothelial cells (LSECs) and hepatic
stellate cells (HSCs). Tight junctions formed between
hepatocytes create a canaliculus surrounded by the
apical membrane of neighboring hepatocytes. Bile
secreted from hepatocytes is exported sequentially
through the bile canaliculi, intrahepatic bile ducts,
extrahepatic bile ducts, and finally into the duodenum.
The bile duct is formed by another type of epithelial
cell, biliary epithelial cell (BEC), also known as
cholangiocyte. Hepatocyte and BEC are derived from a
common progenitor, “hepatoblast,” during
development [1]. In the similar context of liver progenitors,
the adult liver also harbors a specialized type of cells
which proliferates clonally in vitro and gives rise to
hepatocyte and BEC depending on culture conditions
[2, 3]. It has been believed that such a tissue stem
celllike progenitor contributes to hepatic repair in a case
of emergency, e.g., severe or chronic liver injury.
However, whether and where stem cells exist in the adult
liver is still under debate.
Historically, the regenerative capacity of the liver is
well known, and the mechanisms underlying liver
regeneration have been investigated for many years. In 1931,
Higgins and Anderson developed an experimental model
of liver regeneration, i.e., surgical removal of rat median
and left lobes that correspond to two thirds of the total
liver mass [4]. Since then, the two-thirds partial
hepatectomy (PHx) has been used as a standard model for liver
regeneration. In this model, the remnant liver lobes
enlarge to compensate for the lost mass, which is known
as compensatory hyperplasia. After decades of studies
on the liver regeneration from two-thirds PHx, it was
believed that one or two replications of the remaining
hepatocytes should be empirically sufficient to recover
© 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Structure of hepatic lobule
Fig. 1 Schematic overview of the hepatic lobule. Blood flows into the liver from the portal vein and the hepatic artery toward the central vein
through the sinusoid surrounded by fenestrated liver sinusoidal endothelial cells (LSECs). Bile produced by hepatocytes is collected into the bile
ducts via the bile canaliculi surrounded by the a (...truncated)