Development of human liver

1. DEVELOPMENT OF HUMAN
LIVER
Presented by:
MAHAM ABBASI (1)
SADAQAT BIBI (12)
MAHNOOR HAYAT (14)
HAMNA RASHID DAR (29)
HUMA PERVEEN (30)
UROOJ BIBI (28)
BS BIOLOGY(1st batch)
Presented to : Dr. Hafizah Fizzah Riaz

2. LIVER:
• INTRODUCTION:
• The workhouse of
digestive system and
largest internal organ.
• Liver is derived from
foregut endoderm.
• It weighs about 3 to 3.5
pounds.
• Only organ of human
body that can regenerate.
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3. FUNCTIONS OF LIVER IN
FETUS:
• Fetal liver’s function is mainly cardiovascular.
 As a vascular connection, between
developing placental vessels to the heart.
 As a haemopoietic tissue.
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4. LIVER DEVELOPMENT IN FETUS:
• The gallbladder, bile ducts, and liver
begin to develop during the 4th week of
embryogenesis.
• It occurs in two stages:
 Liver bud formation and expansion
 Epithelial differentiation
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5. LIVER BUD FORMATION AND
EXPANSION:
• Liver develops from the hepatic diverticulum(at
the distal end of foregut).
• Now, hepatic diverticulum grows/expands and
penetrates into the septum transversum.
• The hepatic diverticulum divides within it to form
the liver and thus gives rise to the ventral
mesentery of the foregut.
• This in turn is the precursor of the lesser
omentum, the visceral peritoneum of the liver and
the falciform ligament.
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7. EPITHELIAL DIFFERENTIATION:
• Hepatoblasts, the major cells present in hepatic
diverticulum, show bi potential behavior.
• Hepatoblasts proliferate to form hepatocytes
and biliary epithelial cells in fetus liver.
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8. COMPONENTS OF THE LIVER
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9. Gall bladder
The gallbladder is a small pouch that sits just under the
liver. The gallbladder stores bile produced by the liver. After meals,
the gallbladder is empty and flat, like a deflated balloon.
Hepatic duct:
A duct that carries bile from the liver into the common
bile duct which conveys it to the duodenum.
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10. Hindgut region
During development of the gut: the pancreas remains retroperitoneal
throughout its development. the liver is derived from the midgut.
the hindgut is supplied by the celiac artery.
Foregut diverticulum
The hepatic diverticulum (or liver bud) is a primordial cellular
extension of the embryonic foregut endoderm that gives rise to the
parenchyma of the liver and the [[bile duct].
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11. Lobes of liver
The human liver is divided grossly into four parts
or lobes. The four lobes are the right lobe, the
left lobe, the caudate lobe, and the quadrate lobe.
Seen from the front – the diaphragmatic surface
the liver is divided into two lobes the right lobe,
and the left lobe.

12. Common bile duct
The common bile duct is a small, tube-like structure
formed where the common hepatic duct and the
cystic duct join. Its physiological role is to carry bile from
the gallbladder and empty it into the upper part of the small
intestine (the duodenum)
Mid gut region
The liver is derived from the midgut. the hindgut is
supplied by the celiac artery. the smooth muscle in the wall
of the esophagus is derived from splanchnic mesoderm.
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13. Septum transversum
Liver with the septum transversum. Human embryo 3
mm. long. The septum transversum is a thick mass of cranial
mesenchyme, formed in the embryo, that gives rise to parts of
the thoracic diaphragm and the ventral mesentery of the foregut
in the developed human being and other mammals.
Hepatic sinusoid
A liver sinusoid is a type of capillary known as
a sinusoidal capillary, discontinuous capillary or sinusoid, that
is similar to a fenestrated capillary, having discontinuous
endothelium that serves as a location for mixing of the oxygen-
rich blood from the hepatic artery and the nutrient-rich blood
from the portal.
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15. Specification
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Liver development requires two linked processes: differentiation of the various hepatic cell
types
from their embryonic progenitors and the arrangement of those cells into structures that
permit the distinctive circulatory, metabolic, and excretory functions of the liver and these are
further controlled or mediated by many essential regulators which include several signaling
molecules and transcription factors.
The first stage of liver development is specification, during which endoderm cells after
receiving inductive signals from the adjacent cardiogenic mesoderm and the septum
transversum mesenchyme (STM) via BMP, bone morphogenetic protein &FGF, fibroblast growth
factor begin to differentiate into hepatoblasts, These factors are important in development. For
example, in the absence of FGF signaling from the cardiac mesoderm, the ventral endoderm
develops into pancreas, but too high a concentration of FGF results in differentiation toward
lung.
• This is followed by liver bud formation and expansion: the hepatoblasts proliferate and
penetrate the endoderm basement membrane (of the most caudal portion of foregut) to form
the liver bud or also called hepatic diverticulum . In humans, this occurs at approximately day
25 . Initially, the liver bud is separated from the mesenchyme of the septum transversum by
basement membrane. Shortly, however, the basement membrane surrounding the liver bud is
lost, and cells delaminate from the bud and invade the septum transversum as cords of
hepatoblasts—bipotential cells that differentiate into hepatocytes and cholangiocytes.

18. Hepatoblast to hepatocytes:
Hepatoblasts now undergo proliferation and differentiate into two types of cells:
 Hepatocytes and cholangiocytes.
• Hepatoblast differentiation: the generation of hepatocytes and cholangiocytes
• Hepatoblasts start differentiating at 56-58 days of gestation in humans.
• Cholangiocyte differentiation then terminates at ∼30 weeks of gestation in
humans.
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19. Liver diverticulum and bud formation in mouse.
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20.  The hepatic diverticulum (or liver bud) arises as an out pouching of the lumen of the
distal foregut during the fourth week of development .
 The liver bud gives rise to the gallbladder and bile duct, as well as to the parenchyma of the liver.
The liver bud grows toward the anterior body wall, at first completely buried in the mesenchyme of
the septum transversum.
 Rapid growth causes the liver bud to bulge into the abdominal cavity, freeing it on all but the
cephalic surface. There it remains in contact with the septum transversum as the latter forms part of
the diaphragm.
 After development is complete, this area of contact between the liver and the diaphragm is known as
the “bare area of the liver” because it is not covered with capsule or peritoneum.
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21. • Hepatocyte maturation and heterogeneity
• Hepatocytes consist of a heterogeneous population;
heterogeneity is thought to arise via a phenomenon called as
‘metabolic zonation’, whereby liver functions are
compartmentalized in the hepatic lobule. the spatial
organization of the various metabolic pathways and functions
forms the basis for the efficient adaptation of
liver metabolism to the different nutritional requirements of
the whole organism in different metabolic states.
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Timeline of mouse liver development

23. Hematopoiesis
• Formation and development of
various type of blood cell in liver.
• Begins in liver during sixth week
and give reddish appearance to
liver.
• By 9th week, liver accounts for
10% of total fetus weight.
• Bile formation begins during the
12th week.
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25. CELLULAR ARCHITECTURE OF
LIVER
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26. Cellular architecture of the liver:
• The liver consist of the largest reticulo-endothelial cell
network ,comprised of parenchymal cells and many different
types of non-parenchymal cells.
• Cellular architecture of the liver show hepatocytes arranged in
hepatic plates separated by sinusoid spaces radiating around a
central vein.
• Bile canaliculi on the surface of hepatocytes drain bile into the
bile duct, which run parallel to portal veins and hepatic arteries
to form the “portal triad”.
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28. Hepatocyctes and other liver cells
development:
• Hepatocytes:
Hepatocyctes are parenchymal, polygonal epithelial cells of the
liver with abundant eosinophilic, granular cytoplasm and large,
centrally located round nuclei. Account for 70%of liver.
• Cholangiocytes:
Forming 3–5% of the liver, heterogeneous ,highly dynamic
population of epithelial cells lining the bile duct, involves in the
modification of hepatocyte-derived bile.
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30. Development of hepatocyctes and cholangiocyctes
Fetal hepatocyctes
• Derived from hepatoblast endoderm that emerges from primitive
streak of embryo in gastrulation stage
• Identifiable in third week of human gestation, with potential to
differentiate into either hepatocyctes
or cholangiocyctes
Cholangiocyctes
• Differentiate from hepatoblasts
near ductal plate, while remaining
hepatoblasts differentiate into
hepatocyctes.
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31. Stellate cells
fat storing cells, or lipocytes, reside in the perisinusoidal region known as the
space of Disse, narrow region between endothelial cells and hepatocytes.
 Kupffer cells
phagocytes derived from monocytes
located within the vascular spaces of
hepatic sinusoids lining the endothelial
surfaces .
 Oval cells
pluripotent stem cells due to their
ability to differentiate into several
different cell types, functions in repopulation of hepatocytes and other
hepatic.
 Pit cells
short-lived granular lymphocytes that reside within hepatic sinusoids and
contribute to immunity.
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32. Development of these cells:
 These cells are of mesodermal
origin.
 Stellate cells derived from
septum
transversum derived endothelium.
 Kuppers cells
develop from bone marrow and
their presence in fetal liver
proceed bone marrow development
and may originate from yolk sac.
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33. Regulation of Liver Development by
Cell Signaling Pathways
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34. Cell Signaling- The process of cellular communication
within the body driven by cells releasing and receiving hormones
and other signaling molecules.
Stages of cell signaling:
• Reception.
• Transduction.
• Response.
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35.  Morphogenetic movements (generated by a combination of
changes in cell behaviours) expose cells to different signaling
centers during liver development.
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36. •In Hepatogenesis, different growth factors, transcription factors and
morphogenic proteins play role during cell signaling pathways.
•In recent years, the mechanisms by which these signaling pathways
influence the various stages of liver development have been elucidated.
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37. •Role of transforming growth factor β
(TGF-β):
It acts in the process of differentiation of hepatoblasts to either
hepatocytes or cholangiocytes and biliary morphogenesis in
the developing liver parenchyma.
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39. •Role of Bone Morphogenic Protein (BMP) and Fibroblast
Growth Factor (GFG):
Bone Morphogenetic Proteins (BMPs) belong to the Transforming
Growth Factor-β (TGF-β) family.BMP and FGF signaling are
essential for hepatic specification.Both FGF and Bmp signaling play
crucial roles in gastrulation and embryonic patterning.
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41. •Transcription factors Hnf4:
The transcription factor HNF4(hepatocyte nuclear factor-4) and
C/EBPα (CCAAT/enhancer binding protein-α) promote the terminal
differentiation of hepatocytes as the organ ceases to be a site of
haematopoiesis and begins to control metabolite and protein levels in
the blood, during the perinatal period.
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42. Genetic control of liver development
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43. • Development of liver is highly controlled
process. Along with signaling pathways many
transcriptional factors, epigenetic regulators
and genes take part in its development that are
listed below.
FOXA transcription factor
GATA GENE family
WNTF TRANSCRIPTION FACTOR
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44. FOXA transcription factor
• It consists of subclasses FOXA1 and FOxA2 FOXA3.
• Fox A transcription factors help to activate livers genes in
development by binding to regulatory sequences in precursor
endoderm.
• The specification of liver required competence within the
foregut endoderm.
• That competence is provided by FOX A1 and FOX A2
transcription factor.
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45. • In the liver, Foxm1b is required for hepatocyte
proliferation.
• the first Foxa gene to be activated is Foxa2,
whose protein gene expression are first
detectable at embryonic day 6.5 (E6.5)
• Foxa1 is also broadly expressed in the early
embryo, in a very similar pattern to Foxa2,
although Foxa1 mRNA is not detectable until
E7.0
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46. • The early activation of the Foxa genes in the
hepatogenic region of the foregut endoderm,
combined with the abundance of liver-
specific Foxa target genes, has been interpreted as
evidence that Foxa genes play a key role in regulating
hepatogenesis.
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47. Gata gene family
• GATA gene family is essential for the development of tissues
derived from all three germ layers.
• Originally divided as hematopoietic (GATA1/2/3) and cardiac
(GATA4/5/6) GATA factors, .
• Acting as a priming factor, GATA4 promotes hepatocyte
specification and liver-specific gene expression .
• GATA4, together with another factor, FOXA3, can reprogram
fibroblasts toward the hepatocyte lineage
• The mutation of Gata4 in liver cells switches discontinuous
liver sinusoids into continuous capillaries Thus, GATA4 is not
only important for regulation of hepatocyte differentiation but
also for hepatic microvascular endothelium specification.
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49. Wnt transcription factor
• Wnt–β-catenin signalling is a highly-conserved and
tightly-controlled molecular pathway that regulates
cell fate during embryogenesis and hepatobiliary
development, as well as liver homeostasis and repair
in adulthood.
• Abnormal Wnt–β-catenin signalling promotes the
development and/or progression of different liver
diseases, including cancer.
• Mutations in key regulatory genes of the Wnt–β-
catenin pathway are characteristic of hepatobiliary
tumours and promote their growth, dedifferentiation
and dissemination
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51. Summary of liver development
(A)The blastocyst harbors the inner cell mass that derives ES cells.
(B)During late postimplantation, the epiblast gives rise to three germ layers-
ectoderm, mesoderm, and endoderm.
(C) The foregut is formed under the regulation of transcription factors such as
FOXA2 and GATA4.
(D) Part of the foregut generates the liver bud, the primordial diverticulum that
gives rise to the liver parenchyma. FGFs from the cardiac mesoderm and
BMPs from the STM cooperatively specify the liver fate in the foregut
endoderm.
(E) As hepatoblasts proliferate and migrate into the STM, the liver diverticulum
becomes thicker to form the liver bud.
HGF that is expressed in the STM, hepatoblasts, and endothelial cells
surrounding the liver bud plays a critical role in the outgrowth of the liver
bud.
(F) OSM, in a paracrine manner, induces the differentiation of immature
hepatocytes to functional hepatocytes of the neonatal liver. HGF is also
implicated in hepatocyte differentiation.
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