1130-0108/2014/106/3/171-194
Revista Española de Enfermedades Digestivas
Copyright © 2014 Arán Ediciones, S. L.
Rev Esp Enferm Dig (Madrid
Vol. 106, N.º 3, pp. 171-194, 2014
REVIEW
Liver regeneration – The best kept secret. A model of tissue injury
response
Javier A.-Cienfuegos, Fernando Rotellar, Jorge Baixauli, Fernando Martínez-Regueira,
Fernando Pardo and José Luis Hernández-Lizoáin
Department of General Surgery. Clínica Universidad de Navarra. Pamplona, Navarra. Spain
ABSTRACT
Liver regeneration (LR) is one of the most amazing tissue injury
response. Given its therapeutic significance has been deeply studied
in the last decades.
LR is an extraordinary complex process, strictly regulated, which
accomplishes the characteristics of the most evolutionary biologic
systems (robustness) and explains the difficulties of reshaping it with
therapeutic goals.
TH reproduces the physiological tissue damage response
pattern, with a first phase of priming of the hepatocytes –cell-cycle
transition G0-G1–, and a second phase of proliferation –cell-cycle
S/M phases– which ends with the liver mass recovering.
This process has been related with the tissue injury response
regulators as: complement system, platelets, inflammatory cytokines
(TNF-a, IL-1b, IL-6), growth factors (HGF, EGF, VGF) and antiinflammatory factors (IL-10, TGF-b).
Given its complexity and strict regulation, illustrates the unique
alternative to liver failure is liver transplantation.
The recent induced pluripotential cells (iPS) description and the
mesenchymal stem cell (CD133+) plastic capability have aroused
new prospects in the cellular therapy field. Those works have
assured the cooperation between mesenchymal and epithelial cells.
Herein, we review the physiologic mechanisms of liver
regeneration.
Key words: Liver regeneration. Sterile inflammatory response.
Cell-cycle. p53. Hyperproliferative stress response. Induced
pluripotentianl cells (iPS).
A.-Cienfuegos J, Rotellar F, Baixauli J, Martínez-Regueira F,
Pardo F, Hernández-Lizoáin JL. Liver regeneration – The best
kept secret. A model of tissue injury response. Rev Esp Enferm
Dig 2014;106:171-194.
Received: 19-07-2013
Accepted: 12-11-2013
Correspondence: Javier A.-Cienfuegos. Department of General Surgery.
Clínica Universidad de Navarra. Avda. Pío XII, nº 36. 31008 Pamplona,
Navarra. Spain
e-mail: [email protected]
ABBREVIATIONS
AP-1: Activating protein-1.
Abs: Biliary acids.
ATP: Adenosine 5-tryphosphate.
AR: Amphiregulin.
ARNm: Messenger ribonucleic acid.
Cdc25b: Protein phosphatases that dephosphorylates
Cdks.
Cdk: Cyclin-dependent kinase.
CD117: Hematopoyetic progenitor cells.
CD133: Endothelial progenitor.
Ckls: Cdk-cyclin complex inhibitor.
Cl4C: Carbon tetrachloride.
C-met: HGF receptor.
CT-1: Cardiotrophin-1.
C3a: Proteolitic fragment “a” from C3 complement
protein.
C3b: Proteolitic fragment “b” from C3 complement
protein.
C5a: Proteolitic fragment “a” from C5 complement
protein.
Check-point R: Cell-cycle “restriction” check-point.
DAMP: Damage-associated molecular pattern.
DNA: Deoxyribonucleic acid.
EGF: Epidermal growth factor.
EGFR: Epidermal growth factor receptor.
EM: Extracellular matrix.
FGF: Fibroblast growth factors.
FXR: Farnesoid X receptor.
gp 130: Glycoprotein 130.
GSK3b: Glycogen synthase kinase 3b.
G0: Quiescent or resting cell state.
G1: GAP 1 phase. Period within cell-cycle following
mitosis.
G2: GAP 2 phase. Period within cell-cycle between the
end of DNA synthesis and the beginning of M phase.
HB-EGF: Heparin-bound epidermal growth factor.
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J.A.-Cienfuegos ET AL.
HGF: Hepatocyte growth factor.
HIF-1a: Hypoxia induced transcription factor-1a.
HMGB1: High mobility group Box 1.
Hsp: Heat shock proteins.
IkbKb: Cytoplasmic NF-Kb inhibitor.
IL: Interleukin.
IL-1b: Interleukin 1 b.
IL-6: Interleukin 6.
IL-18: Interleukin 18.
IL-6R/gp130: IL-6 glycoprotein 130 receptor.
iPS: Induced pluripotent stem cells.
JAK: Tyrosine kinase Janus or Janus kinase.
KO: Knout-out.
LPS: Lipopolysaccharide protein.
LR: Liver regeneration.
M phase: Cell-cycle mitosis phase.
MAPK: Mitogen-activated protein kinase.
Myc: Myc oncoprotein.
NF-Kb: Nuclear factor Kappa b.
NK: Natural killer.
NKT: Natural killer T cell.
NLRP: NOD-like receptors.
NOD: Nucleotide digomerization domain – containing
protein.
PAF: Platelet activator factor.
PAMP: Pathogen associated molecular patterns.
PDGF: Platelet derived growth factor.
PHx: Partial hepatectomy.
p53: p53 protein.
ROS: Oxygen free radicals.
RRP: Patron recognition receptors.
RTK: Receptor tyrosine kinases.
RTT: Toll-like receptors.
S phase: Cell-cycle DNA replication: synthesis
phase.
SOCS: Suppression protein of cytokine signaling.
SOCS-3: Cytokine signaling suppression.
STAT3: Signal transducer and activator of transcription.
TFG: Transforming growth factor
A
B
Rev Esp Enferm Dig (Madrid)
TNF-a: Tumor necrosis factor-a.
TNF-R: Tumor necrosis factor receptor.
TPM1: Tryptofan hydrolasa.
VEGF: Endothelial-vascular growth factor.
“Nature adapts the organ to the function
and not the function to the organ”
Aristotle, on The parts of the animals
BACKGROUND
Liver regeneration (LR), is one of the most enigmatic
and fascinating phenomenon of the animal scale. The rapid volume and function recovery following a major liver
resection (> 70 %) or liver injury and its strict regulation
at the initiation and termination periods is an exclusive
characteristic of the liver (1-9).
In addition, LR is the scientific background of several clinical procedures as the extended liver resections
(> 70 % of the liver parenchyma or five segments), split
liver transplantation, liver donor procedure, two-stage
hepatectomies, isolated portal vein embolization or associated with “in situ” liver transection, the artificial liver
support in acute hepatic failure and the clinical application of cellular therapy as well (10-21) (Fig. 1).
Albeit the liver regenerative ability was described in
the punishment inflicted to Prometheus by Zeus, the first
scientific description was reported in 1879 (22-24). This
ability represents one of the most extraordinary physiological response in maintaining the internal homeostasis.
Besides the myriad of metabolic functions, the liver is the
major immune organ and the first natural filter for microorganisms (bacteria, virus) and xenobiotics originated in
the intestines (25-28). In the last 50 years has been an
extraordinary interest in knowing the underlying mechanisms of the LR, and the mentioned clinical applications
(4,7,29-31).
In the present article we review the physiologic basis
underlying LR and its relations with clinical conditions.
C
Fig. 1. A. Intraoperative view of the remnant liver (segments 1, 2, 3, 4) following right hepatectomy in a living donor procedure. B. Radiologic imaging
of the regenerating remnant left lobe (segments 1, 2, 3, and 4) 1.5 months post-hepatectomy after right hepatectomy in a living donor procedure
(courtesy of Dr. A. Benito. Radiology Department. Clínica Universidad de Navarra).
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Liver regeneration – The best kept secret. A model of tissue injury response
LIVER REGENERATION CHARACTERISTICS
In basal conditions the hepatocytes remain in quiescent
state (phase G0 of the cell cycle), but retain the ability to
reinitiate the cell cycle with occasion of tissue damage,
tissue loss or exogen stimulus (growth factors, mitogens)
(32-35). LR has been studied in diverse experimental
models; from cellular cultures to “in vivo” induced liver
injury by toxics (Cl4C, galactosamine, thioacetamide),
bacterial particles (LPS), virus and surgical models as
partial hepatectomy (PHx) or segmental liver transplantation. Knock-out (KO) and knock-in animals with a genetic
over-expression or a specific gen deletion have been used
too (2,5,36-38). Others authors have investigated the gen
expression profile with microarray techniques (39-43).
Some of the mentioned models are summarized in table I.
From the above mentioned models highlight those in
which the liver volume, function and survival were evaluated. Yet the KO models have been crucial for the signal
pathway identification, their assessments have been difficult because LR pleiomorphic feature (40).
The 70 % PHx procedure in rodents and in big animals
as well, is the most used, because represents the major regeneration stimulus and elicits the synchronic and homogeneous response of the remnant liver (36-38). This model
has allowed to compare the regeneration between control
animals (wild type) with the genetic modified on signalizing molecules, receptors and cell cycle regulators (2,5,44).
The liver mass recovery following a PHx or after an
acute injury is achieved by a compensatory hyperplasia
in contrast with a true epimorphic regeneration of the lost
tissue; that takes place in the inferior vertebrate-Zebra
fish, Salamander or amphibians which are able to renew
the removed limbs or other anatomical structures-major
appendages, inferior jaw, portions of intestine, cardiac
ventricle along the life time (45-49). These animals regenerate the lost tissue from the “blastema” formed by the
transdifferentiaton of adult cells into mesenchymal cells
(45,47,48).
The liver regeneration characteristics can be summarized in the following:
1. It is a phenomenon present in all vertebrates from
Zebra fish to the human; in whom common mechanisms are involved: Thrombin activation, innate
immune system participation, ploidy and aneuploidy development, tissue remodeling and the strict
regulation of liver volume at the end of the process
known as “hepatostat” regulation (34,46,50,51).
2. LR represents a strict regulated response, according
with the pattern depicted in figure 2. The hepatocyte
duplication, the mesenchymal cells duplication sequences, the morphogenesis and volume reached
at the end of the process are genetically regulated.
It is phenomenon different form embryogenesis or
wound healing although share common signaling
and transcription pathways (4,49,52).
Table I. Genetic altered animal models to study liver regeneration
Targeted gen
Brief description of findings
Ref.
Interleucina-6 (IL-6)
Hepatic necrosis. Severe impaired LR. Role of IL-6 in GO
225
STAT3
DNA synthesis decreasing. Alterations in cell-cycle regulation
192, 195
TNF-a
Stimulates G0 to G1 transition of cell-cycle
44, 72, 118
Gp 130
LR impairment following LPS administration
72, 196
IKK2
Deletion of IKK2 inhibitor, promotes innate response and hepatocyte proliferation
196
Complement C3a/C5a
Complement fractions are essential in early phases
170, 199
Farnesoid X receptor (FXR)
Mice deficient in FXR suffer a LR delay and increasing mortality
180
C-met
HGF and MET receptor are vital in cell-cycle entry following PHx
197, 271
FosM1b
Overexpression stimulates hepatocytes mitosis entry
247
EGF
Mortality increasing after PHx. K0 mice suffer a delay in hepatocyte division
274
Inhibitor ILK
KO mice develop increasing proliferation and hepatomegaly
299, 300
TGF-a
Overexpression induces hepatomegaly. DNA synthesis augmentation
280, 281
TGF-b
Transgenic mice suffer a delay in cellular proliferation
289, 290
TGF-b R2
K0 mice show an early DNA synthesis
291
p53
KO mice develop high ploidy. p53 regulates the three phases of LR
117
Priming phase
Proliferation phase
Termination phase and regulation
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J.A.-Cienfuegos ET AL.
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Hepatocitos
C. Kupffer
Colangiocitos
Día 1
6h
G1
Día 2
Día 3
12h
G2
C. Sinusoidales
Día 4
18h
Día 5
24h
G1
Día 6
30h
G2
Día 7
36h
Día 8
Día 9
Día 10
Fase S
Mitosis
Citocinesis
Fig. 2. Schematic representation of the sequential replicative pattern of epithelial –hepatocyte, cholangiocite– and mesenchymal cells following a
hepatectomy. Modified from Nevzorova YA and Morgan DO (Ref. 6 y 93).
3. It is a very rapid and explosive process which initiates in seconds and ends in few days –depending
on the age and species– with the recovering of the
hepatic volume and involves the signaling mechanisms –autocrine, paracrine, endocrine– of cell
proliferation, morphogenesis, liver zonation and
metabolism regulation genes (1,2,4,5,37,44,53).
In recent years, diverse signaling and transcription pathways have been described, many of them
related with the physiologic liver response to cell
injury. Herein we shall describe how LR process
reproduces the tissue damage response pattern
(54-56).
LR begins with the recognition of the pathogenassociated molecular patterns (PAMPs) and the
damage-associated molecular patterns (DAMPs);
triggering the natural immune response-C3a and
C5a complement fraction activation, TNF-a,
TNF-a secretion, IL-6, IL-1b, IL-18 synthesiswhich induce the hepatocytes to proliferate. The
transition from the resting G0 state to the G1 phase
of the cell cycle (priming phase), comes about during the first 4 hours after liver resection (57-67).
4. The cell cycle phases are reproduced throughout
the LR response, having arouse a great interest
in knowing the gene expression of the regulatory
mechanisms involved and its translation to other
fields such as cancer (33,35,42). The cellular proliferation accounts in a chronological and sequen-
tial order; the hepatocytes divide first following by
the kupffer, endothelial cells, vascular and biliary
canaliculi neoformation just before the hepatic
structure is replicated.
Early following a 70 % HPx; 95 % of the hepatocytes transient form the G0 phase to the G1 cell
cycle phase (1,4,68); at the end of which exists the
critical control point denominated “R” (restriction
point), which decides if the cells divide irreversible. Until then, the process is reversible, allowing
the hepatocytes to return to the previous state (G0)
if the conditions were not favorable. Beyond this
point the progression of the cell cycle is completed
until the hepatocyte division is accomplished (69,
70) (Fig. 2).
An increasing in the preformed cytosolic preformed factors (TFs) –signal transducer and activator of transcription (STAT3), nuclear-Kappa
b factor (NFKb) and activating protein 1 (AP1)– have been described in the first 30 min posthepatectomy as consequence of the signaling
transductions induced by cytokines bindings with
their receptors. TFs trigger the protein synthesis
and gene expression required for initiating the cell
cycle (known as priming phase). DNA synthesis
increasing (phase S) has been reported during the
24 and 36 hours post-hepatectomy in the rat and
in mouse respectively. The hepatocytes enter into
mitosis at 48 hours post-PHx, following by kupffer
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Liver regeneration – The best kept secret. A model of tissue injury response
cells. The stellate and biliary epithelial cells enter
into S phase 48 hours post-hepatectomy and proliferate in slow pattern. Endothelial cells proliferate in the third day showing a peak at the fifth postPHx day (3,4,42,68,71-73).
Additionally, a hepatocyte population return to the
resting state (G0) at 72 hours post-hepatectomy
meanwhile other reinitiate the cell division until
reaching the original liver size (4,6,72). It has been
postulated, that the second proliferative wave is
due to growth factors secreted by the own hepatocytes and to the additive effect of co-mitogens
such as norepinephrine, insulin, somatostatin and
glucagon (1,2,4).
Miyaoka et al. (52) has recently described that
hepatocytes duplicate their size and increase the
hepatocyte number by 1,5 fold, following PHx.
These authors have reported an increase in the hepatocyte size by 1,6 and 0,7 divisions per cell suggesting that LR underlies two different processes:
Hypertrophy and proliferation. The same authors
observed in 30 % liver resection model the liver
remnant increasing size was due to a significant
1,5-fold increase in the hepatocyte size without
undergoing cellular division (52).
From the morphological point of view, several
cluster of hepatocytes (10-14 mononuclear and
binuclear ploidy cells –tetraploid (4n), octaploid
(8n), 16n…) were observed shortly after PHx.
A replication of the stellate and sinusoidal cells,
increasing the size of liver lobules, was observed
two-four post-hepatectomy days (35,74,75).
Ding et al. (76) has described the secretion of
angiocrine factors and vascular neo-formation.
The relative hypoxia of the residual liver-due to
overactive hepatic arterial buffer response, stimulates the hypoxia-induced factor 1 alpha (HIF-1a)
–within the first 12-48 post-hepatectomy hours–
which activates the vascular-endothelial growth
factor (VEGF), the fibroblast-growth factor (FGF)
and the inducible nitric oxide (NO) synthase (7781). Proliferation of hepatocytes proceeds from
the periportal to pericentral areas of the liver lobule: Once the original size has been restored an
apoptotic remodeling and zonalizing process takes
place (42,44,72,82,83).
5. In contrast to other solid organs, as skin, or the intestines, the restoration of liver mass is achieved
by the mature hepatocytes and mesenchymal cells
proliferation neither by pluripotent stem cell differentiation or oval cells; although its participation
has been described whenever hepatocyte division
is impaired or abolished as occurs in chronic liver
diseases (1,2,3,5,42,44,72,84-87).
With occasion of the oval cell-hepatocyte precursor description and the plasticity of the hemato-
Rev Esp Enferm Dig 2014; 106 (3): 171-194
175
poietic cells, endothelial progenitor cells (CD133,
CD117) and the induced pluripotential cell
(iPS) described by the 2012 Nobel Prize Shinya
Yamanaka (88-90); an explosion of articles regarding cellular therapy in liver diseases have been
published (91,92). Given the enormous number of
papers, we refer to excellent reviews (93-97).
Despite the aroused expected outcomes, the results have shown limited efficacy so far. Even trials performed with isolated adult hepatocytes in
inborn errors of metabolism the results are very
limited. In the majority of cases only a temporarily
improvement was achieved (20,98). Preliminary
clinical trials using bone marrow growing factors (G-CSF) in acute-on-chronic liver failure, and
bone marrow progenitor cells (CD133) in chronic
disease have recently published (96-99). Clinical
results as happened with other solid organs (heart,
pancreas, intestine) suggest that tissue regeneration is indeed a complex process which depends of
the cooperation between different cellular lineages
(87,100-102).
6. The liver regenerative capacity is almost unlimited. Seven consecutive 50 % partial hepatectomies,
without developing liver failure or preventing the
regenerative response has been described in the rat
(2-4). In a model of homozygote tyrosinemia (FAH
–/–), the metabolic disorder was reverted after syngeneic hepatocyte transplantation. When the grafted
hepatocytes were again isolated and transplanted
they were able to reverse the enzymatic deficit in a
FAH –/– second generation, and successively until
10 generations! It has been estimated that mouse hepatocytes could undergo up to 69 divisions, equivalent to generate 50 livers (103,104).
7. Another intriguing enigma of LR is the tight relationship between the hepatic volume and body
surface; known as Liver Index (liver weight/body
weight x 100 ~ 2.5 %); called as “hepatostat” regulation. In clinical and in experimental liver transplantation field, it is well known the adaptation of
the donor liver size to the recipient body surface;
small grafts in big recipients and vice versa. This
phenomenon has even been reported in the baboon
xenograft to the human (4,105-107).
Albeit most of the cellular changes throughout LR
have been related with the cell nuclear changes;
during cell division the organelles have to duplicate too. The regulation between cell growth and
chromosome duplication is poorly understood
(69,108-110). The majority of growth factors (epidermal growth factor –EGF–, hepatocyte growth
factor –HGF–, insulin growth factor –IGF-1–) besides to their mitogenic effect, they increase the
growth rate and promote cell survival by inhibiting
apoptosis (5,69,108).
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J.A.-Cienfuegos ET AL.
Fig. 3. Microscopic imaging of a liver section showing diploid and
tetraploid hepatocytes in an 8 weeks old mouse after 30 hours of fasting
(H&E, courtesy of M. Bustos. CIMA. University of Navarra).
In inferior vertebrates and mammals is common
to observe ploidy hepatocytes, tetraploid (4n) or
octaploid (8n), mononucleated or binucleated
(2x2n, 2x4n, 2x8n) as consequence of incomplete
cytokinesis (Figs. 3 and 4). Ploidy degree differs
across many species. In rats, 80 % of hepatocytes
are polyploid and aneuploid, 60 % in mouse and
Rev Esp Enferm Dig (Madrid)
30 % in human being (75,111). Ploydia´s first
consequence is the hepatocyte increasing size
(2,112,113). It has been pointed out that cellular
size relies upon the DNA nuclear amount. Likely
an increase in the chromosome number correlates
with an increase in cell size (114-116).
Following a hepatectomy in rodents a 20 % to 5 %
decreasing in binucleated hepatocytes and an increasing in tetraploid-4n-and octaploid-8n-, and
even up to 16n hepatocytes have been described
at 72 hrs post-HPx; showing that HPx represents
and intense stimulus for DNA replication before
cytokinesis (2,112,116,117). In those animals in
which chromosome separation was inhibited, the
recovery of liver mass following HPx took place
by the hepatocyte polyploidy response, 18n, 32n,
and higher degree (118,119).
This phenomenon coined as endorreduplication
gives rise to chromosome replicating sequences
without cellular division, generating cells with several genome copies, enhancing gene expression (120).
Duncan et al. (35,74,111) has recently described the
ability of hepatocytes to develop polyploidia and its
reversion to aneuploidy state as an adapting response
to xenobiotics or dietetic stimulus. It is remarkable
that the liver function remained stable throughout
the process, revealing the functional equivalence between 2n, 4n, and 8n hepatocytes (2,112).
Fig. 4. Microscopic imaging showing diploid and hepatocytes in a 8 weeks old mouse after 30 hours of fasting (β-catenin staining, courtesy of M. Bustos.
CIMA. University of Navarra).
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Vol. 106, N.º 3, 2014
common features: Pleomorphism, redundancy and
biofeedback mechanisms.
This makes that LR´s global understanding is extremely difficult and as consequence therapeutic
interventions on LR is still lacking (2,4,10,44).
PHASES OF LIVER REGENERATION: PRIMING,
PROGRESSION AND TERMINATION
It is a merit of Nelson Fausto (1,2), who has integrated
the cellular and molecular mechanisms of LR in a threephase model. LR can be divided into three phases: An
initial phase of induction or priming phase which corresponds to hepatocytes transition from quiescent state, or
G0 to G1 phase of the cell cycle, which takes place in the
first 4 h post-HPx. A second phase or progression phase
corresponds with the transition from G1 to the completion
of mitosis; and a third phase or “apoptotic” phase of tissue remodeling and finally return to the initial G0 phase.
The above model has been assessed in different species
and has the virtue of corresponding with the cell-cycle
phases, from which some basic aspects are reviewed
(32,69,136-138).
Cell-cycle is divided into four phases: G1, S, G2 and M
according with figure 5. DNA synthesis takes place in S
phase (from synthesis). The chromosome segregation occurs in the M phase or mitosis, which is divided into four
B
CDC2
G0
NTRO
P. CO
CDK4/6
M
M
G2
Profase, metafase,
anafase, telofase
SE
FA
NA
/A
E
AS
AF
ET
M
OL
R
NT
CO
D
L G2/
Kurinna et al. (117) has recently published the p53
control role in quiescent hepatocyte as well as during regeneration (7 days). The authors described
that KO mouse for p53 (p53 –/–), show a higher
ploidy degree than control mouse (wild type, p53
+/+), and that they initiate earlier the cellular division, develop an increasing nuclei and cytoplasm
size, and a higher degree of ploidy contrasting
with p53 +/+ (wild type) after 70 % hepatectomy.
p53 lacking impairs ploidy reversion, confirming
that regeneration in p53 –/– rodents likely is based
in cell size augmentation as well. The mentioned
authors found more errors in chromosomal integrity in p53 –/– mouse (multipolar spindle, lagging
chromosomes) than in control animals (p53 +/+);
yet the recovery of liver mass at 7 days post-hepatectomy was equivalent (52,117,121,122).
8. Several authors have pointed out that a more intense liver damage (extreme liver resections >
70 %, living donors transplantation with small
grafts < 30 %, submassive hepatic necrosis), induces a stronger proliferative liver response
(52,113-116). In liver donor transplantation setting
using smaller grafts (≤ 30 % of standard liver volume) an accelerating in graft regeneration has been
described (123,124). This pattern is similar to the
classical physiological stress response or to tissue
damage response as well (32,125-132).
9. Despite its amazing metabolic complexity, the
liver keeps the homeostatic functions-albumin,
coagulation factors synthesis, xenobiotic clearance, etc., throughout the regeneration process. A
selective enhancing of proliferative genes and a
temporarily silencing of carbohydrates metabolic
genes were reported in the first 40 post-hepatectomy hours (42,72). Studies with light microscopy
have revealed periportal changes of the classical
lobule structure, 24 hours after 70 % hepatectomy
(34,42,72).
Three peaks of hepatocyte DNA synthesis was reported by Wu et al. (82), initially in zone 1 and later
in the mid-zonal “zone 2” of Rappaport´s classical
lobule description. Approximately 15 % of hepatocytes do not enter into cell division meanwhile
11 % of them divide by three fold. The underlying
mechanism of this phenomenon remains elusive.
10. Besides brain, the liver is the organ with major capacity of reacting to broad internal perturbations
and keeping its structure and function as well. This
quality is also present in several biological systems
just as: Physiologic homeostasis, tissue development, cell-cycle, ecological resilience, circadian
rhythm, and even cancer development (133-135).
This phenomenon was coined as “robustness” and
has concerned great interest in evolutionary biology in the last decade. LR shares all the robustness
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Liver regeneration – The best kept secret. A model of tissue injury response
P.
G1
S
P.
C
ON
TR
OL
A
CDC2
R
E
A
CDK2
CDK2
Fig. 5. Overview of the eukaryotic and mammals cell-cycle: Phase G1,
phase S (DNA synthesis, chromosome duplication), phase G2 and phase
M (mitosis, divided in: prophase, metaphase, anaphase y telophase). It
has been included the phase G0 or quiescent state. The three control
points are represented: point “R”, G2/M and point M (metaphase/
anaphase transition). The cyclins –D, E, A, B– are depicted with the
cyclin –dependent kinases (Cdk: Cdk 4/6, Cdk2, Cdc2).
178
J.A.-Cienfuegos ET AL.
Bacteria
Necrosis celular
H 2O
C3a C5a
C. Kupffer
PAMP’s LPS
NF-KB
TLR4
TNF
IL-6
TNF
TNFR
Damp’s
HMGB1
Alarminas
Espacio
extracelular C3a C5a
IL-6
IL-6R
JAK
GP130
STAT3 P
STAT3 P NF-KB
STAT3
STAT3
TLR4
Genes respuesta
precoz inmediata
Hepatocito
Proliferación
Antiapoptosis
Reactantes
fase aguda
Fig. 6. Representation of priming phase of hepatocytes, activating the
natural immune system (PAMPs or DAMPs) (PAMPs: Pathogen associated
to molecular patterns. DAMPs: Damage associated to molecular patterns.
LPS: Lipopolysaccharide protein. C3a, C5a: Proteolytic fragment “a” from
C3 and C5 complement protein. HMGB1: High mobility group Box 1.
TLR4: Toll-like receptors 4. IL-6: Interleukin 6. TNF: Tumor necrosis factor.
IL-6R: IL-6 receptor. JAK: Tyrosine kinase Janus. gp130: Glycoprotein 130
IL-6 receptor. NF-Kβ: Nuclear factor Kappa-β. STAT-3: Signal transducer
and activator of transcription. TNF-R: Tumor necrosis factor receptor).
stages: Prophase, metaphase, anaphase and telophase (the
cellular division ends with the cytokinesis giving rise to
two daughter cells, which can reinitiate the cell cycle or
return to the previous G0 state). G1 and G2 phases also
known as gap phases take place before DNA synthesis (S
phase) and mitosis (M phase) respectively, adding extra
time for cellular growing and surveillance of the transition to the following phases according with the extracellular and intracellular signals (69,137-139).
The cell-cycle has three control checkpoints: restriction or “R” check-point which defines the entry into
the cycle in late G1 phase; and the two mitotic control
check-points: The G2/M check-point which regulates mitosis entry and the metaphase-anaphase transition control
check-point where the final mitosis events are initiated
giving rise to the sister chromatides and mitosis cessation
(69,70,136,140,142). The control “R” check-point regulates the rate of cell division and determines the cell cycle
irreversibility, at whatever time cell progress beyond “R”
point (69).
The majority of mitogens and growth factors- such as,
platelet derived growth factor (PDEGF), EGF, HGF, and
transforming b growth factors regulate the rate of cell division in the “R” check-point, when the cell is more sensitive to external factors (138-140).
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Initial priming phase
Sterile inflammatory response
According with the mentioned model, LR represents a
physiological response to liver damage (63,143). The tissue injury can be expressed as “cellular stress” or as one
of the knowing forms of cellular death: Necrosis, apoptosis or necro-apoptosis (58,144-147). Necrosis induces the
recognition of DAMPs by the pattern recognition receptors
(PRRs) which triggers the innate immune system. PRR´s
receptors have been described in the cell membrane, endososomal membranes and in the mesenchymal and hepatocytes cytoplasm as well (44,54,55,61,62,148,149).
The regenerative response could restore the threatening
situation or fail, depending of tissue injury severity. In
the latter condition, liver is unable to restore the homeostasis, being associated with a high mortality and requiring in most of the cases a liver transplant as definitive
solution (example: Fulminant hepatic failure, small-forsize syndrome, acute-on-chronic liver failure, or posthepatectomy liver failure) (150-152). In the above mentioned situations a progressive cholestasis, coagulopathy,
encephalopathy, sepsis and multiple organ failure takes
place. Some authors have related it with an innate immune “paralysis”; others have suggested that an excessive
mitogenic stimulus could provoke a “hyperproliferation
stress response” which leads to cellular apoptosis and failing liver (153-155).
In 1994 Polly Matzinger described the DANGER
theory by which the natural immune system, besides recognizing pathogen germs and their wall components also
recognizes the endogen ligands released by cellular damage and necrosis, giving rise to the denominated “sterile
inflammation response” (54,55,59,156-158).
Necrotic cells leak the intracellular content –DAMPs–
out to the extracellular compartment where bind to the
patron receptors PRRs. Among those receptors belong
the complement system and Toll-Like receptors (TLRS)
which are expressed in the membranes and in the cytosol
of macrophages, sinusoidal endothelial, dendritic cells,
natural killer (NK) and hepatocytes (159-163) (Fig. 6).
DAMPS are also recognized by a subsets of stress and
damage receptors, known as NLRP which belong to the
NOD-like receptors (NOD). Once they are triggered, give
raise the “inflammosoma” complex, releasing pro-inflammatory and mitogenic cytokines such as: interleukin-1b
(IL-1b) and interleukin 18 (IL-18). The NLRP receptor
role has raised great interest in recent years regarding the
mechanism of inflammation and survival (164-166).
Since the DANGER theory description by Matzinger,
new tissue injury related DAPMs have been described
just as: high mobility Group Box 1 (HMGB1), heat shock
proteins (Hsps, Hsp60, Hsp70), uric acid, genomic DNA,
ATP, adenosine heparin sulfate, oligosaccharides, degradation fragments of hyaluronic acid, mitochondrial N
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formilated peptides, which have been denominated with
the general term as “alarmines” (59,63,167-169).
It is indicative that recognizing proteins involved in
the innate immune system are phylogenetic previous to
the separation between vegetals and animals (thousand of
million years ago) and to the acquisition of the adaptive
immune system. On account of the seminal description
of TLRs in Drosophila Melanogaster and in humans, as
well as the DANGER theory, the paradigm of the innate
immune system response and tissue regeneration has been
reported (170-176).
The interaction between TLRs and their ligands triggers several signaling cascades which generate IL-6,
TNF-b, IL-1b synthesis, and the activation of cytosolic
transcription factors (NF-Kb, STAT-3, AP-1) conveying
the pro-proliferative stimulus to the nucleus (62). TLRs
regulate the regeneration process in colon intestinal mucosa, lung, skin and post-hepatectomy regenerative response by eliciting pro-survival signals and apoptosis
inhibition too (63,170,177-179).
LR has also related with the endogenous ligands present in portal blood: Bile acids (BAs), xenobiotic, LPS and
components of extracellular matrix-fibronectin, heparan
sulfate, fibrinogen, hialuronic acid oligosaccharides- released by tissue injury (surgical manipulation) (180-185).
The nonparenchymal cells –specially macrophages–
synthesize pro-inflammatory cytokines just as: IL-1b,
TNF-a, IL-6, gamma-interferon (IFN-Y), protaglandins
and activating platelet derived factor with antiapoptotic
and proliferative functions (63,167,186-188).
TNF-a and IL-6 cytokines initiate the “priming”
phase of hepatocytes (transition G0-G1 of cell cycle).
These cytokines signalize through the TNF receptors
(TNF-R1, TNF-R2 and IL-6 (IL-R/gp130). They are tyrosine kinase receptors similar to growth factor receptors, which lead to enzymatic cascades as the mitogenactivated protein (MAP) kinase cascades. Janus Kinase
–JAK– is part of this group, which upon activation phosphorylates preformed transcription factor STAT-3 (JAK/
STAT signaling). STAT-3 protein binds to the DNA activating the immediately-early response genes expression (IEGs): c-fos, c-jun, c-myc (known as oncogenes)
which promote the cell-cycle entry (Fig. 6). More than
180 of these genes have been described, which synthesize the required protein to leave the quiescent G0 state
(1,4,5,42,44,72,118,188-191).
The priming phase initiates in the first 30 minutes longing for the first 4 hours post-hepatectomy. In addition to
STAT-3 factor, others involved transcription factors are
Kappa-b nuclear factor (NF-Kb) and the activating protein 1 (AP-1) required for the “novo” synthesis of G0-G1
and G1/S regulation proteins. The STAT-3, NF-Kb and
AP-1 participation were assessed in conditional KO animals, with genetic manipulation techniques (192-195).
Animals with mutations in TNF-a receptor (TNF-R1),
showed an inhibition of NF-Kb transcription and a se-
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179
vere deficit in liver regeneration, confirming that NF-Kb
transduction is crucial in the Kupffer cells response to cytokines. KO mouse for IL-6 receptors (gp 130) showed
minor defects in cellular proliferation. In KO animals for
IL-6 (IL-6 –/–) and its receptor (gp130), LPS administration following a partial hepatectomy significantly decreased the survival; confirming that IL-6 has a protector
role in regeneration. Hepato-specific deletion of STAT-3
and AP-1, decrease the cyclin expression; which is mandatory for the G0-G1 transition in the cell cycle. On the
other hand, when NF-Kb factor was up-raised by blocking
its cytoplasmatic inhibitor IkbKb, a more intense inflammatory and proliferative response was assessed (72,196).
In addition to the mentioned inflammatory mediatorsTNF-a, IL-6, C3a, C3b, LPS, growth factors as HGF,
PDGF and EGF, also stimulate G0-G1 transition. The
HGF signalizes through the C-met receptor, and activates
the immediately early response genes. Mouse with a conditional mutation in Met receptor, showed a defect in LR
(6,197,198).
As it will be described in the proliferation phase, HGF
regulates gene expression of other cell cycle phases and
exerts “pro-survival” effects by inhibiting apoptosis (4).
Complement system and liver regeneration
In mouse models of liver injury Cl4C, partial hepatectomy and in patients submitted to a hepatectomy, a rising
in the activated fractions of C3a and C5a were described
in the first 24 hours post-procedure (131,132,149).
Deficient mouse (KO) for C3 fraction (C3 –/–) and C5
fraction (C5 –/–), showed an impaired regeneration after 70 % hepatectomy. In these animals a decrease in the
TNF-a, and IL-6 mRNA levels were assessed, in addition
to a reduction in NF-Kb and STAT-3 transcription factors (172-174). C5a receptor (C5aR) antagonist administration, provoked similar effects increasing the mortality;
verifying the role of the complement in the initiation of
the priming phase (199).
Both C3 –/– and C5 –/– KO animals developed more
severe liver lesions than control animals following Cl4C
infusion or following a PHx. The regeneration impairment and hepatocellular injury were restored when C3a
and C5a were administered. The same phenomenon was
observed in double knockout animals (C3/C5 –/–) as well
as regeneration recovering after C3 and C5 fractions administration.
Lambris´s group (170) has reported that C3a fraction
triggers the IL-4 synthesis by NKT cells in the first 24
hours post-PHx and elicits the complement protein synthesis by macrophages during the priming phase. Besides
the elimination of pathogens and tumor cells, complement
system represents the more speed humoral component for
recognizing tissue injury through DAMPs exposure and
triggering the reparative response (170,199).
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Platelets and liver regeneration
In addition to the well known haemostatic functions,
platelets express Toll-like-receptors, 2, 4 and 9, and participate in the innate immune response. These receptors
recognize the previous mentioned PAMPs and DAMPs,
by which some authors refer them as the “circulating
guardians” of tissue injury similar to the hemocyte vestige
in the invertebrates (200,201).
Platelets contain fibrinogen, Von Willebrand factor,
adhesion proteins, angiogenic factors, hepatoprotective
factors (VEGF, PDGF, HGF, IGF, EGF-1 and TGF-b)
and 95 % of the circulating serotonin! Although they are
non-nucleated cells, they have ARN and retain the synthesis capacity of more than 300 different proteins, among
highlights the TGF-b (202,203).
In 1996 Tomikawa et al. (204) described that the
thrombocytosis induced by a splenectomy significantly
enhanced liver regeneration in rodents. Same findings
were confirmed by other authors as well the opposite effects secondary to thrombocytopenia. The same group
described an improving survival in a model of sublethal hepatectomy (> 90 % resected parenchyma) model
by inducing thrombocytosis. Other groups have related
platelets with a protective effect on the post-hepatectomy
liver dysfunction and operative mortality with a threshold
platelet count < 100,000/uL. The mentioned authors related these outcomes with the above cited growth factors
and the insulin-growth factor-1 (IGF-1) (205,206).
Lesurtel published in 2006 the enhancing effect of
serotonin in hepatic regeneration “in vivo” although its
mitogen effects were already known in fibroblasts and hepatocytes “in vitro” (207). The confirmation of these findings were reported by the same group using KO animals
for serotonin synthesis (TPM1 –/–) as well as improving
survival following the administration of synthetic serotonin agonist (5HT2B) in a small-for-size murine model.
The authors reported an increase of the endothelial fenestrations of grafts in the treated animals (208).
The same authors described the sinusoidal “pseudocapillarization” reversion in old animals as an increase in the
survival rate following the agonist administration after
PHx; suggesting that opening of the sinusoidal-endothelial fenestration would facilitate the direct contact of platelets, cytokines and growth factors with the hepatocytes
(208). Others studies have related the serotonin proliferative effect with VEGF synthesis. Although Matondo et
al. (209) did not observe any effect in a murine model of
deficient membrane carrier, KO (TOH1 –/–) after 70 %
PHx.
Cytokines, growth factors and hormones
In 1967, Moolten and Bucher reported that the plasma
from previously hepatectomized rats induced mitogenic
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effects on hepatocytes “in vitro” as well as “in vivo”.
Since then, several cytokines, growth factors, hormones
and metabolites have been associated with the hepatocytes and mesenchymal cell cycle (4,210-213).
Family IL-6 cytokines
The IL-6 is an interleukin type I, associated with the
innate immune response. Due to its cytoprotective, proliferative and anti-apoptototic effects is the most related
with LR. In addition to IL-6 another interleukins sharing
the Tyr-Kinase-coupled gp80 and gp130 receptors and
signal transducing pathway have been described and referred as IL-6 family cytokines: IL-6, interleukin-11, leukemia-inhibitory factor (LIF), oncostatin (OSM), ciliary
neurotrophic factor (CNTF), cardiotrophin-1 (CT-1) and
IL-27 (186-188,214-217).
IL-6 is rapidly secreted by macrophages during the
initial injury tissue response. IL-6 exerts local effects on
hepatocytes as well systemic-fever, somnolence, ACTH
and vasopressin secretion –inherent to the stress inflammatory response. IL-6 induces the acute-phase protein
synthesis by the liver (reactive C-protein, A-amiloid) and
exerts similar inflammatory effects to TNF-a and IL-1
(218-221).
IL-6 binds to gp130 membrane receptors, provoking
the dimerization of two gp130 subunits (222). Each cytokine receptors associate with cytoplasmic Tyr-Kinases of
the Janus Kinase family, termed Janus type (JAK1, JAK2,
JAK3 and Tyk2-Tyrosine Kinase 2). Thereupon gp130
dimerization and its binding to the receptor (IL-Ra) promote JAK kinase activation which activates the STAT3 (Signal Transducers and Activators of Transcription)
transcription. The STAT proteins (7 in the human being)
localized in the cytoplasm, migrate inside the nucleus,
bind to the DNA promoter and activate the transcription
genes related with cell proliferation, survival/apoptosis
(223,224) (Fig. 6).
The activated STAT-3 induces the transcription of
immediate-early genes c-jun, c-myc, c-fos and the early
growth (EGR-1). Moreover the IL-6/KAK-STAT-3 signaling pathway provides the antiapoptotic protein Bcl-2,
Bcl-x synthesis. The KAK-STAT pathway is one of the
more straightforward strategy of signaling transduction
from the cell membrane to the genome. Hepatospecific
deletion of STAT-3 decreases the cyclin D1 and E1, both
required for the cell cycle entry (72,191,192).
Besides STAT-3, there are two other transcription
pathways mediated by Tyr-kinase receptors, the nuclear
factor kb (NF-Kb) and the activating protein 1 (AP1). The
NF-Kb factor usually remains inactive in the cytoplasm
by the inhibitory protein IkbKb. The cytokine binding
to the transmembrane receptor triggers IkbKb degradation, releasing the NF-Kb factor which translocates to
the nucleus and stimulates the acute phase protein syn-
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thesis and the mentioned pro-proliferative and antiapoptototic genes. A rapid increase in TNF-a and IL-6 levels
takes place after a 70 % PHx, or secondary to liver injury
(ischemic, Cl4C, LPS administration). KO mice for IL-6
(IL-6 –/–) suffered hepatic failure following PHx, which
was reversed upon previous administration of IL-6 (225).
STAT-3 activation was almost absent in IL-6 –/– animals.
The STAT-3 protective effect on tissue injury was confirmed in KO conditional models, following adenovirus
exposure (otherwise STAT-3 model is lethal in the embryo
period) (198). The IL-6 cytoprotective effect was reported
in diverse murine models of hepatotoxicity as ischemic-reperfusion injury or severe cholestatic. The IL-6 antiapoptotic effect was recently proved in extreme hepatectomies
(87 % parenchyma resected) as well as in the rapid regeneration of “small-for-size” syndrome model (226-229).
The AP-1 transcription factor promotes the immediatelyearly genes expression during the first five posthepatectomy hours; particularly the Jun oncoprotein which facilitates the G0-G1 transition of the cell cycle (72).
One of the IL-6 family cytokines, which has concerned
particular interest is the cariotrophin-1 (CT-1). Prieto´s
group has described its protector effect in apoptosis as
well as a regenerative inducer in ischemic-reperfusion injury, in an extreme PHx (92 % resection) and in fulminant
hepatic failure experimental model (230-232).
Metabolic and xenobiotic signaling receptors
In addition to the extraordinary capability of the hepatocytes for entering into the cell cycle, meanwhile the
specific metabolic functions ought to be performed by the
remnant liver along the process (2,4,5,42,72). The related
metabolic gene expressions are initially supplanted by the
genes involved in the cytoskeletum formation, the mitotic spindle assembly and mitosis. Transcriptional studies
have shown a temporary silencing of the metabolic genes
(first 40 post-hepatectomy hours) and a posterior recovering towards the end of mitosis (42,233).
It has been previously described that the bile acids,
drugs detoxification and carbohydrates metabolism take
part in the early priming phase. The tightly regulation
of bile acids pool by the liver through the enterohepatic
circulation is very well known (234). This pool is maintained in the human between 2 and 4 g, circulating about
12 times per day; in the mouse is kept in 4 mg (235). The
bile acid increasing damages the cell membranes and mitochondrial too, promoting cell apoptosis and necrosis
(236,237).
The bile acids homeostasis, is regulated by nuclear receptors, through “Farnesoid X-receptor” (FXR). Free and
conjugated bile acids binding with FXR, stimulates the
transcription factors involved in early regeneration process (G1-S transition) as FoxM1b and proliferative genes
(Cdc 25) (166,180).
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At the time of a 70 % PHx an abrupt increase in the
portal flow to the remnant liver (1/3 of original mass)
undergoes increasing by three fold the nutrients, bile acids and all contents present in the splachnic circulation
(2,3,4,180,238-240).
Deficient mice in FXR suffer a delay in LR and higher
mortality rate following PHx (180). These animals are
unable to activate the early response genes c-myc, c-fos
and c-jun. On the other hand the bile acids administration
stimulated LR in previously hepatectomized mice and
was delayed after cholesteramine administration.
The bile acids stimulate the pro-inflammatory cytokines as TNF-a and IL-1 by the kupffer cells with prosurvival, anti-apoptotic and proliferative effects (240).
Bile acids and xenobiotics could behave as true DANGER
molecules triggering the priming phase in addition to their
mitogen effect, particularly the hydrophobic.
There is evidence that the administration of FXR receptor agonist enhance LR in old animals. These findings
as their cytoprotective properties have raised its likely
clinical application (241,242).
The relationship between the metabolic pathways and
regeneration is complex given that the metabolic variations could be a consequence of the silencing of metabolic
genes process without implying a direct mitogen effect.
By the way, some authors have reported that persistent
hypoglycemia in hepatectomized mice stimulates regeneration, meanwhile the glucose addition inhibits LR
(42,243). Those findings seem to be contradictory with
Fissette (244,245), who reported that glucose and insulin
infusion previous to a major resection improved the liver
dysfunction and regeneration.
Liver ability to response to endogen stimuli –bile acids– and xenobiotics is an exclusively feature of the liver
which could explain its almost unlimited capability for a
“robust” response to a wide range of stimuli as liver resection, ischemia or bile acid overload (4,42,240).
PROGRESSION PHASE
Mitogenic signal transduction
Although there is not a clear limit between the LR phases; the progression phase takes place since the end of the
G1 phase to the cellular division or cytokinesis (2,4,5,9).
Besides the chromatine, other cytoplasm organelles –mitochondria, Golgi apparatus, lysosome, endoplasmic reticulum– ought to duplicate during this period in order to
maintain the ratio between the cytoplasm and nucleus size
in advance of accomplishing the metabolic functions of
the liver (69,73,109,110).
The progression phase is regulated by the previous mentioned growth factors –HGF, EGF, VEGF, and
TGF-a– which as well their mitogen effects, exert trophic
and pro-survival functions.
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The primary growth factors role is to activate the Cdkscyclin complex which evokes a wide variety of cell cycle
changes: Mitotic spindle duplication and DNA replication
in the S phase. The majority of the growth factors convey
the mitogen signal to the nucleus through the membrane
and cytoplasmic tyrosine-kinase receptors (RTK) promoting the downstream kinase cascade. The MAP-kinase cascade induces the immediately-early genes expression (cfos, c-jun, c-myc), which is the first transcriptional event
(two hours post-PHx). Among the factors codified by the
pro-mitotic genes highlight FosM1b and Myc factors (16,42,43,246).
The FosM1b factor increases in the first post-PHx
hour and evokes the activation of a large family of
transcription factors termed AP-1, which stimulates
the late response genes expression (two-days postPHx). These genes regulate G1 cyclins (D1, D2, D3)
required for the entry in the cell cycle (42). KO mice
for c-jun, show 50 % mortality after PHx. The regeneration impairment is associated with an increase in
cell necrosis and hepatocyte lipid accumulation. An
increasing in the inhibitory G1-S transition protein has
been described.
The Fos M1b factor promotes the late response genes
expression (2nd post-PHx day) and the G2-M transition.
The role of this factor in the entry into mitosis and in the
chromosome segregation was confirmed in hepato-specific FosM1b KO mice (247). It has been reported that hepatocyte over-expression of FosM1b restored the injured
liver, more efficiently than control hepatocytes (wild
type), suggesting eventual therapeutic applications in old
patients with liver diseases (248).
The Myc factor remains elevated throughout the entire cycle and promotes the “R” control point transition as well as the gene expression involved in the cellular size and metabolism (108). The Cyclin D levels
remains elevated throughout the cycle meanwhile the
mitogen is present with independence of the cell cycle
phase (108).
Growth factors and hormones such as insulin signalize
through the Ras kinase cascade –MAP–, which phosphorylates and inhibits the glycogen synthase kinase (GSK3b)
activity, allowing glycogen synthesis and also the activation of the preformed factors –AP-1, Myc– which stimulate cellular proliferation.
Hassanain et al. (244,245) has recently described the
benefit effect of insulin and dextrose infusion in patients
submitted to a major hepatectomy. These authors have assessed glycogen liver increasing as well as an improvement in the early postoperative liver function. Besides
the glycogen protector effect as energy source for cellular
division, GSK3b inhibition enhances the gene expression required for the regenerative response. The trophic
effect of pancreatic hormones on liver parenchyma and
liver regeneration was described by Starzl et al. in 1967
(249-252).
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Hepatocyte growth factor (HGF)
The HGF was discovered in 1984 as a plasma protein
with mitogenic effect in hepatocytes “in vitro”, from hepatectomized rats and initially denominated “hepatopoietin”
(235). Given its mitogen effects “in vivo” and “in vitro” is
the growth factor, which has raised more attention. In addition to the mitogenic effect have been reported diverse
effects as: Mitogenic (enhancement of cell motility), trophic, antiapoptotic, angiogenic and morphogenic effect
on liver, brain, placenta, lungs, intestines, myocardium
and reproductive system (211,253,254).
The HGF is synthesized by mesenchymal cells as a precursor (pro-HGF) molecule and stored in the extracellular
matrix (ECM). HGF is a glycoprotein very similar to the
blood coagulation cascade factors and fibrinolysis as well
(plasminogen). Pro-HGF activation involves urokinasetype plasminogen activator (U-PA) (2,4,69,255-261).
Following a hepatic injury the plasma levels of HGF
increase very rapidly by 10 to 20-fold. The HGF plasma
raising is derived from the stored HGF and the releasing
by the macrophage synthesis upon IL-6 and TNF-a stimulation. In addition HGF transcription increases in the mesenchymal cells of lung, kidney and spleen confirming its
endocrine function (2,4,259,260,262-265). HGF binds to
the tyrosine kinase receptor –C-met– which its phosphorylation is assessed during the first 1 to 15 minutes postPHx, with the largest increase at 60 minutes. Following
hepatic resection prolonged increasing in HGF plasma
levels were observed, and remained elevated up to two
weeks after liver resection. The higher HGF increasing
has been reported in fulminant hepatic failure; this finding has questioned its therapeutic role in this condition.
This paradoxical phenomenon -inability to stimulate cell
proliferation with very high levels-, has been attributed
to the C-met receptor inhibition by competitive effect by
others ligands such as: IL-6, TGF-b1 or to the mentioned
“hyperproliferative stress response” by which an excessive mitogen stimulus provokes an apoptotic response by
p53 activation (61,266-270).
The HGF systemic and portal infusion in rodents increases DNA synthesis in the hepatocytes of zone 1. The
infusion of human HGF into the portal vein in rodents
resulted in hepatocyte proliferation and increase in relative liver mass (2,4).
The human HGF gene transfection by the hydrodynamic injection of plasmid DNA induces hepatomegaly
in mouse via b-catenine activation, and the infusion of
large amount of HGF increases the liver weight/body
weight ratio associated with the mitogenic stimuli. The
HGF withdrawal promoted apoptosis and the restoration
of the basal DNA level (2,4,255,271).
The collagenase pretreatment in rats resulted in a higher response to HGF. Furthermore, isolated hepatocytes
obtained by collagenase tissue digestion showed cell cycle initiating markers. This “pre-proliferative” pattern is
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according with the competence acquisition phenomenon
described by Pardee in 1989; by which the competent hepatocytes response steadfast to a posterior regenerative
stimulus (1,4,73).
It has been proposed that the releasing of remodeling
metalloproteinases from the extracellular matrix would
contribute to the initial regeneration phase, sensitizing
hepatocytes to the HGF stored in the liver. Likely the extracellular matrix remodeling by the urokinase and metalloproteinases, would generate a sterile inflammatory
response by releasing DAMPs from tissue injury and consequently the binding to Toll-like receptors and activation
of the transcription factors –NF-Kb, AP-1 and STAT-3–
involved in cell cycle entry (54,55,59).
The C-met membrane Tyrosine-Kinase receptor is
present in epithelial and in mesenchymal cells. The C-met
receptor binding with its ligand leads to down-stream
kinase cascade activation by mitogens (MAP kinase);
which stimulates the cytosolic transcription factors (AP1) related with proliferation and cell survival.
In addition HGF also activates the Janus Kinase (JAK)
pathway which activates the transcription factors such
as STAT-3, nuclear factor Kb (NF-Kb) and b-catenin.
The HGF binding with C-met receptor phosphorylates
b-catenin giving rise to its nuclear translocation and upregulation of target genes such as cyclin D required for
the G0-G1 transition of cell cycle (2,4,188,264,267,268).
The role of HGF and its receptor in the regenerative
response was also investigated using transgenic models.
Mice lacking HGF and C-met receptor (null mice) die
during gestation and express a reduced live size and extensive loss of parenchymal cells (270). Two independent
groups have investigated liver regeneration using conditional C-met KO mice. In these animals a reduction in
DNA synthesis associated with an absent of kinase mitogen activated (MAP) signaling was observed following a
partial hepatectomy. Also Cl4C administration impaired
regeneration and the inflammatory changes were more severe in these animals (197,271).
Epidermal growth factor (EGF)
The EGF represents a family factors, from which highlight: Epidermal growth factor (EGF), amphiregulin (AR),
heparin-binding EGF (HB-EGF) and transforming growth
factor-a (TGF-a). These factors are over-expressed during a liver injury. They signalize through the tyrosine kinase receptors (RTK): EFFR/ErbB1, HER2/ErbB2, HER3/
ErbB3 and HER/ErbB4, that are collectively called EbbB14, which upon ligand binding promote downstream the mitogen activated cascade (MAPK kinase) (4,73,272).
Mouse lacking EGFR die between midgestation and
postnatal day 20 with severe defects in the placenta,
brain, skin and lung (273). In animals in which EGF was
blocked and a partial hepatectomy was carried out; 1/3
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183
died and the survivors showed a delay in hepatocyte division (274). However the liver regeneration was accomplished, suggesting that EGF signaling is important but
not crucial for LR (61,274).
The rest of the EGF family are also synthesized as profactors that remain attached to the hepatocyte membrane
and released by proteolysis. After PHx, the plasma levels
of EGF rise, resulting in an increased EGF/EGFR ratio,
confirming that EGFR plays a mitogenic role in the initial
phase of LR (4).
The HB-EGF role was investigated in KO models
and in transgenic animals as well. A delay in hepatocyte
proliferation was observed in the first case and by contrast liver regeneration was stimulated in the second one.
Animals lacking amphiregulin showed an impaired regenerative response, following a PHx (275,276).
The TGF-a is produced by the own hepatocytes –autocrine effect– and furthermore exerts paracrine effects on
the endothelial and biliary cells. After HPx the TGF-a
levels increases in the first 24-48 hours. The TGF-a addition to hepatocytes “in culture” and “in vivo” induces
DNA synthesis and stimulates the transition through the
control “R” point of cell cycle (279-281).
TERMINATION PHASE AND LIVER SIZE
REGULATION
Liver regeneration ends when the initial liver mass
is restored and enabling it to carry out the liver functions (liver index ~ 2.5 %). The strict liver index regulation is one of the most intriguing feature of LR, because underlies a strict control at the end of the cell cycle
and in the “neoformed” tissue remodeling process too
(2,4,5,42,61,72,73).
The regeneration termination phase has been related
with anti-inflammatory and pro-apoptotic cytokines as
well as “hepatostat” factors such as IL-10, signaling cytokine suppressor proteins (SOCS-3), plasminogen activator
inhibitor PAI-I and particularly the TGF-b (5,6,61,282).
Elegant studies using microarrays techniques in mouse
and also in pigs have provided that the initial pro-mitotic gen over-expression is later supplanted by metabolic
genes activation and afterwards by the cessation of proliferation and the returning to the previous quiescent state
(34,41,61,72,73).
The transforming growth factor b family (TGF-b 1-3)
comprises a number of cytokines related with cell differentiation and healing. They signalize through two receptors (type I and type II) which activate transcription regulators known as SMAD proteins (Small Mothers Against
Decapentaplegic) which are translocated to the nucleus.
In most of the tissues TGF-b inhibits proliferation at the
G1 cell cycle phase (283-285).
Following a PHx an early increase in TGF-b ARNm
has been described though a TGF-b transitory “resis-
184
J.A.-Cienfuegos ET AL.
Mitógenos
Fact.
crecimiento
citocinas
RTK
Membrana celular
Ras Myc
E2F1
NÚCLEO
p16INK4a ARF
División celular
p53
Apoptosis
Muerte celular
Fig. 7. Representation of the hyperproliferation stress response. The
excessive mitogenic signal elicits increased expression of ARF and the
Cdk inhibitor p16INK4a. ARF activates p53 giving rise to a permanent cellcycle arrest. modified from Morgan DO. RTK: Tyrosine-kinase receptor.
E2F: Protein, whose concentration increases in response to excessive
mitogenic stimuli, reducing the rate of p53 ubiquitination. p16INK4a: Cdk
inhibitor protein: Cdk4, Cdk6).
tance” has been reported as consequence of a diminishing
in the hepatocyte receptors as well as inhibitors over-expression. This temporarily resistance resolves after DNA
synthesis, restoring the TGF-b capability for inhibiting
the cellular proliferation, and promoting the regeneration
cessation (5-7 post-PHx days in the rat, three weeks in
pigs) (286-288).
In transgenic animals and in those in which TGF-b
was infused the anti-proliferative effects on different regeneration phases have been assessed, though no major
changes were observed due to its pleomorphic feature.
A delay in cellular proliferation was shown in transgenic
mouse overexpressing TGF-b receptors (61,289,290).
Significantly the knock-out mice for TGF-b receptor II
(TGFBR2 –/–) showed and earlier and increased DNA
synthesis in the first 120 h post-PHx, however no difference in the regeneration cessation was found with respect
to control animals (wild type), suggesting that another
DNA inhibitory pathways could be involved (291).
Other members of the TGF-b family are the activins,
from which activin A is the most common. It was isolated
in 1993 as a pro-apoptotic factor of hepatocytes “in vitro”. The activin A promotes the intracellular Smad activation, like TGF-b, having been suggested that both share
complementary functions. The injection of follistatin –an
activin receptor antagonist– following PHx, induced an
Rev Esp Enferm Dig (Madrid)
increasing in the liver weight and in the hepatocyte proliferation, supporting that activin A inhibits the proliferation
and takes part in regulating liver regeneration termination
(5,61,73,292).
In hepatocyte culture and in “bioartificial” models, the
extracellular matrix plays a significant role in hepatocyte
differentiation and proliferation (60,61,73). In spite of
representing only 0.5 % of liver weight, the ECM plays
an active role in the tissue injury response and regeneration. Besides storing growth factors –PDGF, TGF-b,
VEGF, HGF– the ECM contains cytokines, metalloproteinases (collagenase, gellatinase), and macromolecules
as fibronectine, laminine and collagen (type I, II, and
VI) very reactive whenever the endothelial-sinusoidal
barrier is damaged (184,185,293-298). After liver damage –surgical trauma, ischemia, toxic– the type urokinase plaminogen activator (m-PA) and metalloproteinase
are released, stimulating the growth factors liberation as
well as the macromolecules degradation (fibrinogen, fibronectin, laminin) and eventually the DAMPs expression (DANGER theory) and promoting the sterile inflammation response and the hepatocyte priming phase
(60,156,157,185).
The initial post-PHx proliferation associated with ECM
degradation has been reported; giving rise to assembling
nests of hepatocytes with deficient access to endocrine
and paracrine factors, which in basal conditions inhibit
cell division. The hypertrophic compiled hepatocytes require a posterior remodeling process up to get the initial
hepatic index (72).
Michalopoulos group has corroborated the inhibitory
effect of an integrin linked kinase (ILK) upon hepatocyte
proliferation “in vitro” (ILK). Hepatoespecific KO animals for this integrin acquire hepatomegaly and enhanced
hepatocyte proliferation (42,299). The hepatoespecific ablation of ILK impairs the regeneration termination. When
these animals are submitted to a PHx the deficient livers
in ILK reach a 58 % higher weight than the initial at 14
days post-HPx. The HGF and its C-met receptor expression increasing and the cell cycle inhibitor p27 diminution
were observed (299-302).
Given the great interest in developing “bio-artificial
livers” through the re-populating of previous decellularized matrix scaffold with hepatocytes and pluripotential
cells, its development exploitation has been stimulated
keeping in mind the increasing demand of other solid organs than the liver for transplantation as kidney, lung and
heart (293-298,303,304).
p53 and regeneration control
Multicellular organisms contain cell cycle control
mechanisms which react to stress situations –lack of nutrients, hypoxia, DNA damage– arresting the cell cycle or
inducing cellular apoptosis (305,306).
Rev Esp Enferm Dig 2014; 106 (3): 171-194
Vol. 106, N.º 3, 2014
Liver regeneration – The best kept secret. A model of tissue injury response
The most prevalent system is the gen regulatory protein
p53, also known as the “genome gatekeeper” by which
cell responses to DNA damage or another stress conditions (307-311). Even though p53 is known as a tumor
suppressor factor (more than 25,000 mutations have been
reported in human tumors), p53 has recently raised great
interest as regulator of LR ending (312).
Kurinna et al. has described that the gen p53 is necessary for the high grade ploidy and aneuploidy reverting,
reported in basal conditions likewise during LR. Mouse
with p53 lacking (p53 –/–) were associated with a higher
ploydia grade (8n and 16 n) as a result of failures in the
cell cycle final phase or cytokinesis. The same authors
described for the first time that p53 regulates the expression of genes involved in the three cell division phases:
Initiation-progression, division and restoration to the quiescent G0 state after PHx (117).
It is well known that p53 activation arrests cell cycle
inducing apoptosis at the time of cellular stress conditions
as severe hypoxia, acidosis or an excessive mitogenic
stimulus. The latter is termed as “hyperproliferation stress
response” (307,308) (Fig. 7), p53 promotes the expression of the cell cycle inhibitor p21 and the pro-apoptotic
proteins (caspases), leading to a permanent cell cycle arrest and even cell death (307).
The Myc and Ras –oncoproteins– proliferative activity is only attainable whenever p53 is absent. The
hyperproliferation stress response is the “in vivo”
counterpart of the replicative senescence process described “in vitro”. Culture cells after several divisions
undergo a stable cell-cycle arrest induced by p53 rising. Cellular replicative senescence has been related
with hyperproliferation stress –overactive Myc and
Ras– or with non-physiological conditions given “in
vitro”: Deficient extracellular matrix components and
inadequate levels of oxygen. Additionally cells lacking
p53 proliferate endlessly and are therefore called “immortal” (313-317).
Although the hyperproliferative stress response has
been related with protective mechanisms against cancer
development, this physiologic response could be the underlying setting of clinical situations in which an excessive mitogenic stimuli takes place as “small-for-size syndrome”, fulminant hepatic failure, post-hepatectomy liver
failure or acute-on-chronic failure. In these conditions a
large mitogenic stimulus is provoked by the endothelial
damage, necrosis, parenchymal hemorrhage and hypoperfusion as a result of arterial vasospasm (150,151,318320).
Today is still unknown why the liver regenerates in
some cases and fails in others, developing an irreversible
hepatic failure; not yet there is a clear limit regarding the
minimal size remnant in liver resection or in liver-donor
procedure (10,151,321-324). In spite of the myriad of pa-
Rev Esp Enferm Dig 2014; 106 (3): 171-194
185
pers regarding liver regeneration, its regulatory mechanism still remains as an enigma (2,4-6,9).
CONCLUSIONS AND FUTURE PERSPECTIVES
Liver regeneration still endures as one of the most amazing an enigmatic paradox of adaptation and response to
keep the homeostasis. In the last decades has extensively
investigated given its therapeutic consequences. LR is an
extremely complex process, strictly regulated, which reproduces the tissue injury restoration, with an initial or priming
phase -G0-G1 progress of hepatocyte cell cycle- and a posterior phase of proliferation-phases S and M- that ends with
the hepatic mass restoration. This phenomenon has been related with hormones (insulin, glucagon), cytokines (TNF-a,
IL-1b, IL-10), growth factors (HGF, EGF, VEGF) and in
the last decade with the mesenchymal hematopoietic stem
cells (CD 133+, CD117+) and in addition with oval cells.
The current description of developing structures with
“hepatoid” phenotype derived from induced pluripotential
stem cells (iPS) in rodents, has raised great concern as a
future alternative to liver transplantation; although because
the liver complexity should be seen with caution (325,326).
LR rigorously accomplishes the characteristics of the
most regulated biological systems (robustness) –pleiomorfism, redundancy and feedback mechanisms– such
as the cell cycle, natural immune response or circadian
rhythm, which illustrates the difficulty in its guidance for
therapeutic goals.
Because the liver functions complexity, the intents of
definitive or temporarily supplying methods have been
elusive, with exception of liver transplantation. Perhaps
cell therapy development and acknowledge of liver regeneration molecular and physiological basis could get
near the expected dream of using the own liver regenerative capacity in the treatment of liver disease, which at
present only liver transplantation is a real option.
Santiago Ramon y Cajal aphorism, “It is fair to say
that, in general, no problems have been exhausted; instead, men have been exhausted by the problems” is very
opportune regarding liver regeneration unveiling efforts.
ACKNOWLEDGEMENTS
We gratefully acknowledge to Lydia Munarriz for
manuscript editing and transcription. We thank to Fabiola
de Goñi and Beatriz Urbelz for their contribution in researching data. The authors acknowledge to investigators from the Hepatology Division of CIMA (Center for
Medical and Applied Research). The authors apologize to
the many authors whose works have not been cited owing
to space limitations.
186
J.A.-Cienfuegos ET AL.
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