Department of Pathology, University of Washington School of Medicine, Seattle, Washington 98195-7470
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ABSTRACT |
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Studies utilizing knockout mice have contributed important new knowledge about the mechanisms that initiate liver regeneration. New mouse lines need to be established to address major questions about these mechanisms, targeting genes for which there is experimental evidence of their involvement in important pathways. Development of conditional, liver-specific knockout mice would be of great value for these studies.
hepatocytes; cytokines; growth factors; transcription factors
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INTRODUCTION |
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IT HAS BEEN ESTIMATED THAT ~70 genes increase their expression in the immediate early phase response after partial hepatectomy (18). This number is bound to grow when DNA arrays that can measure the expression of 5,000-25,000 genes come into use for the analysis of liver regeneration. However, only a fraction, perhaps a very small fraction, of these genes may be directly related to hepatocyte proliferation. During liver regeneration, hepatocytes retain their differentiated phenotype and compensate for the loss of cells or whole tissue. Thus differential expression of genes at the start of the process may be mostly related to the maintenance and enhancement of hepatic metabolic functions needed for homeostasis and survival. How then is it possible to learn which of these many genes plays a crucial role in hepatocyte replication?
The most direct way to determine whether a particular gene is essential for liver regeneration is to modify its expression: overexpression in transgenic mice and functional inactivation or deletion in knockout animals. Many of the advances of present day biomedical research are due in no small part to the use of gene manipulation in mice and the analysis of morphological and functional alterations created as a consequence of gene expression changes. For pathologists for whom the understanding of normal and abnormal physiology cannot be dissociated from the knowledge of cell, tissue, and organ morphology, the "discovery" of morphology by molecular biologists analyzing gene function is both gratifying and to some extent amusing because of its obvious nature. Transgenic and knockout technologies also have their pitfalls. For transgenics, overexpression of the transgene is generally many times higher than that which occurs in physiological or even pathological conditions. Often the transgene is driven by a potent promoter that may not be normally expressed in the cells that are being examined or the transgene itself is a viral product that may be harmful to the cells. Moreover, overexpression of the transgene throughout the life of the animal may modify the expression of other genes, which may themselves be suppressed or overexpressed to compensate for the high and nonphysiological expression of the transgene. For knockouts, one of the major problems that complicates data analysis is the existence of redundant or interactive pathways, particularly for critical cell functions. Thus the lack of an abnormal phenotype in a knockout mouse does not necessarily mean that the gene in question is not important. Its role might only become apparent by functional inactivation of another gene in a double knockout. Moreover, development and growth can be normal in some knockouts, but they may fail to respond to or survive certain types of stresses such as partial hepatectomy, carcinogen application, or toxic injury.
In any case, gene manipulation in mice will gain even more prominence in the near future, as the physiological roles of thousands of genes sequenced in the human genome project beg identification. New technology that permits conditional and tissue-specific expression of genes will go a long way to minimize many existing problems. Will it then be wise to create knockout models to study every immediate early gene whose expression is altered after partial hepatectomy? Such a quest would be a costly and relatively unrewarding fishing expedition, although admittedly a sophisticated fishing trip, which with some luck could yield a big fish. It would be much more appropriate, however, to limit the development of knockout mouse models for genes that have been well characterized as to function and patterns of expression and that have been shown by other types of experimental evidence (for instance, antibody or antisense blockage, effects on DNA replication in hepatocyte cultures under well controlled conditions, and so forth) to fit into pathways that are important for hepatocyte replication. To perform this task in a systematic rather than haphazard way, it is necessary to develop a model of how liver regeneration works. This model may even be wrong, but, if it is consistently tested, proving it wrong by actual experiments could be as important as demonstrating the correctness of the hypothesis. The main advantage of this type of strategy is that it forces investigators to make a distinction between central and peripheral issues and to focus on important questions about the mechanisms of liver regeneration.
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LIVER REGENERATION AS A MULTISTEP PROCESS |
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A simplified view of liver regeneration is that it is a multistep
process that starts with gene expression changes that prime quiescent
(G0) hepatocytes to enter the
cell cycle (6). This phase, which involves the activation of the
transcription factors nuclear factor for -chain in B cells
(NF
B), signal transducer and activator of
transcription-3 (STAT3), activator protein-1, and CCAAT enhancer
binding protein (C/EBP
) as well as the expression of immediate early
genes, is reversible and is neither sufficient by itself to cause DNA
replication nor specific for proliferation. Priming is, however,
required to make hepatocytes respond fully to at least two growth
factors, hepatocyte growth factor (HGF) and transforming growth
factor-
(TGF-
), which are highly expressed during liver
regeneration (19). Once hepatocytes progress through the cell cycle and
go over a G1 restriction point,
the cells are irreversibly committed to replication. Expression of
cyclin D1 during liver regeneration is a good marker to indicate when
hepatocytes become mostly autonomous in their replication capacity and
no longer require growth factors (2). From that point on, the cell
cycle machinery takes over and the hepatocyte functions as other cell
types do when reaching the G1/S
stage of cell cycle progression. Thus, to look at liver regeneration as
a unique biological process, it is logical to focus on its mechanisms
of initiation and the activation of pathways that lead from
proliferation competence to replication autonomy. However, liver
regeneration as a unique phenomenon does not end there. One of the more
fascinating and least understood features of the process is why it
stops when it does. There are no descriptions in the literature of
livers that, at the end of the regenerative process, become
significantly larger than the original size (the regenerated liver mass
is ±10% of the original hepatic mass). There must be mechanisms
that link the replicative activity of hepatocytes in the regenerating
liver with body functional demands, but the nature of these mechanisms is not known.
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KNOCKOUT MOUSE MODELS USED IN STUDIES OF LIVER REGENERATION |
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The most productive applications of knockout mice to studies of liver
regeneration have been directed at the analysis of genes believed to
participate in the initiation of the process (Table 1). Studies with tumor necrosis factor
(TNF) receptor type 1 (TNFR-1) and type 2 (TNFR-2) knockout mice
(23-25) were based on previous data on the effect of anti-TNF
antibodies (1). Data generated from these animals fit well with those
obtained with interleukin (IL)-6 and inducible nitric oxide synthase
(iNOS) knockouts (3, 14). The combined data from these experiments demonstrated that cytokines participate in the initiation of liver regeneration and that TNF is essential for liver regeneration after
partial hepatectomy and necessary for optimal growth after CCl4 injury (23-25). TNF
proliferative signaling depends on TNFR-1 and involves the sequential
activation of NFB, IL-6, and STAT3. IL-6 may be a key element in
this sequence and has both proliferative and anti-apoptotic effects
(3). Partial hepatectomy causes liver injury rather than regeneration
in iNOS knockout mice, despite the induction of TNF, NF
B, IL-6, and
STAT3 (14). This suggests that nitric oxide induction after partial
hepatectomy protects against cytokine injury.
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The TNFR-1-mediated pathway is certainly not the only one involved in
the initiation of liver regeneration. C/EBP is a leucine zipper
transcription factor that transactivates several genes involved in the
acute phase response. C/EBP
-deficient mice have defective liver
regeneration (7). In these animals, DNA synthesis was 25% of normal
and the expression of cyclins B and E but not D1 was reduced. C/EBP
effects do not depend on IL-6 because IL-6 knockout mice showed no
alteration in C/EBP activity.
The analysis of liver regeneration in urokinase type plasminogen activator (uPA)- and uPA receptor (uPAR)-deficient mice examines another aspect of the initiation of liver regeneration. It tested the hypothesis that uPA plays an essential role in the initiation of liver regeneration by converting HGF into the active double-chain form capable of receptor binding (11). Lack of uPA activity in the knockout mice inhibited liver regeneration (15). However, uPAR deficiency had no effect on the growth process, indicating that whatever role uPA may play in liver regeneration it does not require binding to the receptor. It remains to be determined whether uPA deficiency prevented activation of HGF after partial hepatectomy.
cAMP-responsive promoter element modulator (CREM) is a transcription factor activated by phosphorylation of a serine residue by kinases stimulated by cAMP. Servillo et al. (17) showed that CREM activity is greatly increased after partial hepatectomy. Its deficiency in knockout mice delayed entry of hepatocytes into the S phase and disrupted the synchronization of hepatocyte replication. It has not yet been established whether increased CREM activity after partial hepatectomy is a cytokine-mediated event or by what specific mechanisms synchronization is lost. In any case, the work of Servillo et al. (17) uncovered a cAMP-dependent regulatory pathway that is important for liver regeneration.
The knockout animal models described so far do not involve deficiency of hepatocyte structural components. Hepatocytes contain cytokeratins (CK) 8 and 18 as their only cytokeratins (bile duct cells have CK7 and CK19). Mice deficient in CK8 develop colon hyperplasia and inflammation, but their liver structure and function are apparently normal (10). Nevertheless, all mice died shortly after partial hepatectomy if anesthetized with phenobarbital. Animals survive 1-2 days after the operation if ether is the anesthetic. This rather intriguing finding shows that CK8 is essential for hepatocyte structural integrity but its deficiency is harmful only when hepatocytes are preparing for replication. Presumably, the cell shape changes required for replication do not take place in these animals and prevent the cells from dividing.
Two other animal models have been used for studying events of liver
regeneration other than its initiation. One of these involved TGF-
deficiency. TGF-
knockout mice grew normally and had no deficit in
liver regeneration (16). At face value, the results suggest that this
growth factor plays no role in liver regeneration, despite the strong
correlative evidence linking TGF-
expression and hepatocyte
proliferation. However, TGF-
is a member of the epidermal growth
factor (EGF) family of growth factors (which include EGF and
heparin-binding EGF as hepatocyte mitogens) that signals
through the EGF receptor. Thus a definitive answer for the role of
TGF-
in liver regeneration will not be forthcoming until mouse lines
are established in which more than one of the EGF family of ligands is
deleted. Another alternative is to produce lines in which the EGF
receptor can be conditionally inactivated because EGF knockout mice die
during embryonic development or during the neonatal period.
The introduction of a dominant negative gene (superrepressor) to block
NFB binding in rats is an excellent example of transient inhibition
of gene expression. This type of system can be adapted to permit
"knocking out" a gene in a regulatable manner. Iimuro et al. (8)
developed methods to inhibit NF
B activation after partial
hepatectomy by infecting livers of rats with an adenovirus expressing a
truncated form of I
B. This gene functions as a superrepressor of the
I
B dissociation from NF
B, thus preventing migration of the
heterodimer to the cell nucleus. Partially hepatectomized rats infected
with the adenovirus vector containing the gene had normal levels of DNA
replication but developed marked apoptosis after the peak of DNA
synthesis. Clearly, blockage of NF
B activity had a major apoptotic
effect in the regenerating liver. However, it is surprising that the
effect takes place after DNA replication, presumably in
G2 cells and not at the start of
liver regeneration when NF
B is transiently activated (5). It is a
good assumption that in the absence of NF
B activity TNF may cause
apoptosis rather than hepatocyte proliferation in the regenerating
liver. This notion is supported by data from cell cultures as well as
recent experiments with double transgenic mice that are deficient in both the relA (p65) component of NF
B as well as TNFR-1. In contrast to relA-deficient mice, which die during days
14-16 of development with massive liver apoptosis,
double knockouts survive development and are born with apparently
normal livers (Ref. 4 and M. Rosenfeld and N. Fausto, unpublished
observations). Thus, in the developing liver, deficiency
in TNFR-1 signaling removes an apoptotic signal that is normally
blocked by NF
B activity. If a similar mechanism exists in the
regenerating liver, it is even more puzzling that hepatocytes
expressing the I
B superrepressor did not die in the first few hours
after partial hepatectomy. At that time, TNF concentrations in blood
and liver are high and NF
B has maximal binding activity.
It is possible but unlikely that the protective effect of NFB in the
regenerating liver depends on a gene that is transcribed only after the
first peak of DNA replication has taken place (24 h or later after
partial hepatectomy). Another possibility is that mitogenesis is a
critical time for NF
B protective effects (8). Other issues need also
to be considered in explaining these results. The adenovirus used as
vector for the I
B gene can cause liver damage. Although control
experiments were performed, it would still be possible that the
adenovirus itself may have modified the expression of cytokines after
partial hepatectomy. Another question that bears directly into the
interpretation of these results is whether blockage of NF
B activity
in the infected livers occurred in both hepatocytes and nonparenchymal
cells. One interesting possibility is that inhibition of NF
B
activation in nonparenchymal cells after partial hepatectomy causes
effects that are earlier than and different from those caused by NF
B blockage in hepatocytes.
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WHERE ARE WE GOING? MORE QUESTIONS AND NEW MODELS |
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There are some "big" questions about the mechanisms of liver regeneration that can best be approached by using knockout mice. This list of questions is not comprehensive and is biased toward the model for liver regeneration outlined in this article.
The source of TNF to initiate liver regeneration.
A reasonable but unproven hypothesis is that it is generated from
lipopolysaccharides (LPS; endotoxin). Even if TNF originates from LPS,
why is there a surge in blood and liver TNF after partial hepatectomy?
LPS is continuously released by intestinal bacteria, but it remains to
be established how gut LPS may influence hepatic TNF levels. In mice
strains of low LPS sensitivity, liver regeneration is delayed for
several hours, suggesting that knockout mice with functional deficiency
of LPS receptors would be extremely useful for exploring these
questions. A different but related issue is whether both diffusible and
membrane-anchored TNF participate in signal transduction at the start
of liver regeneration. Knockout mice deficient in TACE (the protease
that cleaves anchored TNF) could be a good model for studying this
issue. However, the enzyme is not specific for TNF and also cleaves
other membrane-bound factors such as TGF-. TACE knockouts are
embryonic lethals with pathological changes that cannot be ascribed to
lack of cleavage of anchored TNF. Thus other types of strategies are
needed to separately analyze the role of anchored and diffusible TNF in liver regeneration.
Multiple TNF signaling pathways.
TNF signaling involves activation not only of NFB and STAT3 but also
of p38, c-Jun NH2-terminal kinase
(JNK), and ERK-1 and ERK-2 (22). Data on NF
B and STAT3 are
available, but less is known about other TNF-activated pathways in
liver regeneration. JNK activity increases after partial hepatectomy,
and, in contrast to c-fos (knockout
animals deficient in this gene have a normal regenerative response),
c-jun is likely to be important for
hepatocyte proliferation. However,
c-jun knockouts are embryonic lethals exhibiting a complex phenotype that includes hepatoblast apoptosis and
tissue destruction as well as hypoplastic hepatic cord formation. A
very worthwhile goal would be to develop mice in which
c-jun expression is normal but could
be shut off in a regulatable manner in the adult liver. The model would
be even more valuable if regulated c-jun expression were liver specific.
Cytokine-independent pathways. Cytokines play a prominent role in the initiation of liver regeneration, but there are other pathways that are not cytokine dependent. Not only do these pathways need to be clearly identified, but it is necessary to determine how these multiple pathways interact. Most importantly, it is essential to determine whether growth factors, particularly HGF, act in parallel with cytokines to initiate liver regeneration (12). To start with, there is still disagreement in the literature on whether HGF present in blood after partial hepatectomy is in the active (double chain) form or is an inactive single-chain molecule that does not bind to receptors (13). New strategies need to be devised to study the role of HGF in liver regeneration using mouse knockout models because HGF knockouts are embryonic lethals. Mice in which HGF expression or c-met activity is conditionally regulated in the liver would provide an exciting system for analysis of the role of HGF at the initiation of liver regeneration. They could be used to sort out growth factor-mediated cytokine-independent pathways and to study the mechanisms of HGF activation after partial hepatectomy. Other strategies may include developing lines of mice that carry HGF deletions specific for blockage of mitogenic activity, leaving intact HGF morphogenic and motogenic capacity.
Growth factor redundancy.
Many growth factors stimulate DNA synthesis in cultured hepatocytes,
and at least two of these, HGF and TGF-, participate in liver
regeneration (5, 6). It has not been established whether this
multiplicity of factors is a protective mechanism to ensure that
regeneration will not fail because of the redundancy of the effects of
the various factors or whether HGF and TGF-
have complementary
activities. In primary cultures of hepatocytes, these two factors act
at least partially in a complementary manner, since their combination
achieves a greater level of DNA replication than when either HGF or
TGF-
is exposed as a single agent (20). Despite compelling data
associating TGF-
expression with hepatocyte proliferation in liver
development, regeneration, and carcinogenesis as well as in cultured
cells (5, 6), TGF-
knockout mice have normal liver regeneration
(16). As mentioned, double knockout strategies (deficiency of TGF-
and EGF for instance) may provide information on the requirement for
EGF family growth factors in liver regeneration. More definitive data
to answer this question could be obtained in conditional expressors of
EGF receptors, particularly if regulation of EGF receptor activity was
restricted to the liver.
Termination of liver regeneration.
The cessation of liver regeneration might be dependent on the
extinction of positive signals or on an independent system of negative
regulators and repressors. Regardless of its mediators, hepatocyte
growth after partial hepatectomy is sensitive to metabolic demands
imposed on the liver, and there might be signals that sense when liver
mass has been restored. The key to explaining the precise regulation of
liver growth after partial hepatectomy may depend on the identification
of interactions between metabolic and mitogenic pathways. Oxidative
stress generated at the start of regeneration (9), which could cause
IB degradation and activation of NF
B, might be a signal that
links these processes. However, it is quite challenging to design a
mouse knockout model that would be useful for the analysis of the
termination of liver regeneration. The model needs to take into account
that in liver regeneration both positive (i.e., growth factors, cyclin
D1, mdm2, and so forth) and negative (p53, TGF-
, activin) cell cycle
effectors are stimulated. Furthermore, even in transgenic mice that
overexpress TGF-
, a strong hepatocyte mitogen, regeneration is more
efficient but it is still perfectly regulated (21). The major challenge is then to disrupt a mechanism that operates under strong selective pressure and is precisely regulated.
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FOOTNOTES |
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* Fifth in a series of invited articles on Lessons From Genetically Engineered Animal Models.
Address for reprint requests and other correspondence: N. Fausto, Dept. of Pathology, Box 357470, Univ. of Washington School of Medicine, C-516 Health Sciences Bldg., Seattle WA 98195-7470 (E-mail: nfausto{at}u.washington.edu).
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