Liver, Development and Regeneration Potential

SAGE Encyclopedia of Stem Cell Research 2nd Edition 2015

The liver is the largest internal organ and it is responsible for many exocrine, endocrine and
metabolic functions in the body. Liver is majorly comprised of hepatocytes and biliary epithelial
cells which are derived from endoderm. Liver development occurs as a result of cellular
interactions between endoderm and mesoderm, many of these pathways have been identified.
Regeneration of the liver is a complex and intricate process involving growth factors, matrix
remodeling and numerous feedback systems among various liver cells. Recent advancements in
field of liver regenerative medicine include the successful growth of human liver-like tissue
outside human body on resorb able scaffolds, which can be used as a substitute to liver
transplants in patients of chronic liver diseases and cirrhosis.
Liver is comprised of cells of both endodermal and mesodermal embryonic origin. Hepatocytes
are the principal cell type which form almost 70% of the liver mass in an adult. Along with
biliary epithelial cells, these are derived from the endoderm. While the stromal cells, stellate
cells, Kipper cells and blood vessels are of mesodermal origin.
Formation of Endoderm
In amniotes, the definitive endoderm forms from the anterior end of the primitive streak during
gastrulation. The primitive streak is a narrow groove which appears on the 15th to 16th of
development on the embryonic disc. The endodermal germ layer initially forms the epithelial
lining of the primitive gut but later it differentiates to form the lining of respiratory tract, urinary
bladder, urethra and glands of thyroid, parathyroid, pancreas and liver.
Formation of the Foregut
At the 22nd day of development, the flat embryonic disc begins to fold at the head and tail as well
as on the sides. As a result, a large portion of the initial endoderm is incorporated into the body
of embryo, forming the primitive gut. The gut is furthered patterned along the anterior to
posterior axis to form foregut, midgut and hind gut.
Receptor studies show that the formation of the head and tail parts of this gut is by no co
incidence and cells from the initial endoderm are predetermined to form the head or the tail.
Cells that form the anterior part (foregut) have a higher level of nodal signaling and emerge first
from the primitive streak. Moreover, mesodermal interaction and expression of certain
transcription factors differentiates the foregut (Hhex), mid (Pdx1) and hind gut (Cdx). Among
other factors secreted by the adjacent mesoderm, two factors (Wnt and FGF4) play the most
important role in determining the regional identity of the gut. Experimental studies reveal that
blocking these mesodermal interaction pathways in the hind gut resulted in the formation of liver
buds in the intestine.
Hepatic Induction
Growth factors from heart and surrounding mesenchyme (septum transversum mesenchyme)
induce hepatic fate in cells of ventral foregut endoderm. In the absence of these signals, liver
cells fail to form.
Development of Liver Bud

In the middle of third week of development, the first morphological sign of the embryonic liver
is seen; the formation of the hepatic diverticulum, an out-pocket of thickened ventral foregut
epithelium adjacent to the developing heart. The hepatic endoderm cells, also called
hepatoblasts, invade the septum transversum. The anterior portion of the hepatic diverticulum
gives rise to the liver and intrahepatic biliary tree, while the posterior portion narrows during
rapid proliferation forming the gall bladder and extra hepatic bile ducts.
Origin of Adult Liver Cells
The hepatoblasts are bi-potential and develop into hepatocytes, the principal liver cells and
biliary epithelial cells which are the cells lining biliary tract. The hepatoblasts adjacent to the
portal vein down regulate hepatic factors and up regulate biliary transcription factors resulting
into the formation of biliary pre cursors and later the Intrahepatic Biliary Duct (IHBD).
Hepatoblasts in the liver parenchyma that are not in contact with portal veins gradually
differentiate into mature hepatocytes. Hepatocytes acquire their characteristic epithelial
morphology arranged in hepatic chords with bile canaliculi on the apical surfaces.
The mesoderm of the septum transversum contributes fibroblasts, stellate cells, hematopoietic
cells Kupffer cells and other connective tissue cells of the liver.
Growth of the Liver Bud
By the 10th week, the weight of liver is approximately 10% of the total body weight. This is due
to rapid growth of the liver bud and the formation of large nests of proliferating red and white
blood cells contributing to the hematopoietic function of the liver. A wide array of factors from
the septum transversum and hepatic mesenchyme and genes encoding regulators of proliferation,
cell survival or metabolic stress are required for liver bud growth.
Liver Regeneration Potential
Though the liver is proliferatively quiescent but it maintains a balance between cell loss and gain
and initiates a rapid regenerative process in the case of haptic loss. The adult liver has a
remarkable regenerative capacity and can completely re-grow when up to 70% of its mass is
removed.
Liver regeneration is a multistep process that includes both the initiation and termination of
regeneration. The principal regenerative capacity is because of the hepatocyte which make up
70% of the adult liver mass. They are the first to enter the DNA synthesis cycle in case of hepatic
injury, within 5 minutes to 5-7 days. The process of regeneration starts from the peri portal area
and extends to the peri central areas in waves of replication. The hepatocytes nearest to the
central are the last to replicate. However this ability is impaired in numerous diseases such as
advanced cirrhosis and hepatitis for which organ transplantation is currently the only treatment
option. As an alternative, researchers have attempted to generate hepatocytes from a variety of
adult, fetal and embryonic stem cell. Proliferation of biliary epithelial cells occurs after
hepatocytes. Endothelial cells contribute to the regenerative process 2-3 days after hepatectomy
and continues for 4-5 days. The stellate cells are thought to assist in the process of regeneration
by producing angiogenic factors and remodeling of extracellular matrix by production of matrix
metalloproteinases. However, recent studies implicate that stellate cells may, through
mesenchymal to epithelial transition, may give rise to hepatocytes. Bone marrow (BM) as a

source of heterogeneous populations of stem cells hematopoietic stem cells (HSC), mesenchymal
stem cells (MSCs), has been shown to contribute in liver regeneration.
Immediately after partial hepatectomy, the expression of over 100 genes is seen which are
responsible for the entry of hepatocytes in the replicative cell cycle. Recent researches have
shown that this replicative processes is more like hyperplasia, the process that results in
increased cell number and has less to do with increased expression of transcription factors. The
first biochemical changes seen are an increased activity of urokinase plasminogen activator
(uPA) along with hemodynamic changes including tripled portal contribution of blood. It is
proposed that these hemodynamic changes trigger the signaling pathways in liver regeneration.
The relationship is between increased activity of urokinase plasminogen activator and increased
hemodynamic changes is not clearly understood. However, research has shown increased
urokinase plasminogen activator levels in cells as a reaction to mechanical stress due to turbulent
blood flow.
The events that occur within the first 5 hours after hepatectomy or liver injury are known as
priming. The term is used to denote all the events that occur to prepare the cells to enter the
replicative cycle. All such events are induced by cytokines only. The priming of the hepatocyte
occurs by factors released by Kupffer cells when they come in close contact with the hepatic
cells. However, the events involved in the priming of non-parenchymal cells are not very clear.
The priming is followed by a complex orchestra of interactions between the cells of the liver that
induce each other to regenerate. The hepatocytes being the first to replicate release Hepatocyte
Growth Factor (HGF) that induces other stromal cells to regenerate, this is followed by release of
HGF by endothelial and stellate cells.
The regeneration is terminated by a specific cytokine TGF1, which inhibits cell replication and
is produced by mesenchymal cells. At the end of regeneration, the size of the lobes is much
increased and the hepatic plates are doubled in size as compared to the normal plates.
.
Fatima Sajid
Army Medical College

See Also:
Adult stem cells, Liver, Stem and Progenitor Cell in Adults, Liver, Existing or Potential
Regenerative Medicine Strategies, Liver Tissue Function

Further Readings:
Krishna, K., Krishna, K., Berrocal, R., Tummala, A., Rao, K. and Rao, K. (2011). A review on
the therapeutic potential of embryonic and induced pluripotent stem cells in hepatic
repair. Journal of natural science, biology, and medicine, 2(2), p.141.
Liu, H., Kim, Y., Sharkis, S., Marchionni, L. and Jang, Y. (2011). In vivo liver regeneration
potential of human induced pluripotent stem cells from diverse origins. Science translational
medicine, 3(82), pp.8239--8239.

Miyajima, A., Tanaka, M. and Itoh, T. (2014). Stem/Progenitor Cells in Liver Development,
Homeostasis, Regeneration, and Reprogramming. Cell Stem Cell, 14(5), pp.561--574.
Michalopoulos, G. and DeFrances, M. (1997). Liver regeneration. Science, 276(5309), pp.60-66.