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Current Signal Transduction Therapy, 2011, 6, 156-167
Hepatocyte Growth Factor (HGF): Neurotrophic Functions and Therapeutic
Implications for Neuronal Injury/Diseases
Hiroshi Funakoshi1,2,#,* and Toshikazu Nakamura3,*
1
Division of Molecular Regenerative Medicine, Department of Biochemistry and Molecular Biology, Osaka University
Graduate School of Medicine and 2Department of Microbiology and Immunology, Osaka University Graduate School of
Medicine, Osaka 565-0871, Japan, 3Kringle Pharma Joint Research Division for Regenerative Drug Discovery, Center
for Advanced Science and Innovation, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
Abstract: Hepatocyte growth factor (HGF), which was originally identified and molecularly cloned as a potent mitogen
for primary hepatocytes, exhibits multiple biological effects, such as mitogenic, motogenic, morphogenic, and antiapoptotic activities, in the liver and other organs throughout the body by binding to the c-Met/HGF receptor tyrosine
kinase (c-Met). In addition to hepatotrophic activities, HGF and c-Met are expressed in both developing and adult mature
brains and nerves, and plays functional roles in the central as well as peripheral nervous systems. A large number of studies have accumulated evidence showing that HGF is a multipotent growth factor that functions as a novel neurotrophic
factor for a variety of neurons, including the hippocampal, cerebral cortical, midbrain dopaminergic, motor, sensory,
sympathetic, parasympathetic and cerebellar granule neurons in vitro. In vivo, HGF exerts neuroprotective effects in the
animal model of cerebrovascular diseases, spinal cord injury, neurodegenerative diseases including amyotrophic lateral
sclerosis (ALS), and neuroimmune diseases, preventing neuronal cell death and functioning on glial, vascular and immune
cells. The multiple activities of HGF, in addition to highly potent neurotrophic activities, suggest that HGF is a potential
therapeutic agent for the treatment of various diseases of the nervous system. Furthermore, the anxiolytic activity of HGF
and an association of c-met with autism, as well as neurorecognition and schizophrenia, have been reported, suggesting
a role for HGF in emotional and psychiatric status. This review describes the role of HGF in the nervous systems during
development and focuses on the therapeutic potential of HGF for a variety of neurological, neuroimmunological and
psychiatric diseases among adults.
Keywords: HGF, c-Met, neurotrophic, amyotrophic lateral sclerosis (ALS), spinal cord injury (SCI), autophagy.
1. INTRODUCTION
Neurological diseases are disorders of brain, spinal cord
and peripheral nerves throughout the body, which evoke
abnormality of neurological functions such as the inability to
speak, decreased sensation, loss of balance, weakness, mental
function problems, visual changes, abnormal reflexes, and
walking problems. These diseases are caused by faulty genes,
problems with the way the nervous system develops, degeneration of neuronal cells, diseases of the blood vessels that
supply the brain, injuries to the spinal cord and brain, seizure
disorders, cancer, and infections. Although neurological disorders have been recognized as important diseases, their
treatment with available medications has many limitations.
The diseases are characterized by dysregulation/ disruption of a variety of neurological functions, such as the survival, proliferation, differentiation, maturation, and activitydependent modulation of neurons during development and in
*Address correspondence to these authors at the Department of Biochemistry and Molecular Biology, and Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Osaka 565-0871,
Japan; Tel: +81 6 6879 3781; Fax: +81 6 6879 3789;
E-mail: [email protected] and Kringle Pharma Joint Research
Division for Regenerative Drug Discovery, Center for Advanced Science
and Innovation, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871,
Japan; Tel:/ Fax: +81 6 6879 4130; E-mail: [email protected];
#Present Address: Research Center for Brain Function and Medical
Engineering, Asahikawa Medical University, Midorigaoka, Asahikawa
078-8510, Japan. E-mail: [email protected]
1574-3624/11 $58.00+.00
adults. The factors affecting these functions include neurotrophic factors such as neurotrophins (NGF, BDNF, NT-3
and NT-4) [1-4], the glial cell line-derived neurotrophic factor (GDNF) family (GDNF, Nerturin, Persephin and
Artemin) [5], and the ciliary neurotrophic factor (CNTF)/
interleukin (IL)-6 family (CNTF, LIF, cardiotrophin and IL6) [6, 7]. However, neurological, neuroimmunological and
psychiatric diseases are not simply dependent on the disruption of neuronal functions, but are sometimes dependent on
extraneuronal activities by glial, vascular and immunological
cells. For example, multiple sclerosis (MS) and animal models of inflammatory demyelination are characterized by a
complex interplay between degenerative and regenerative
processes, many of which are regulated and mediated by
various types of cells, including glial cells. Cellular communication between neurons, glial cells and immune cells is
critical and is controlled to a large extent by the activity of
cytokines/growth factors. Therefore, in addition to the classical neurotrophic factors, mounting evidence suggests that
multipotent growth factors with neurotrophic activity play a
pivotal role in the nervous system, during development and
for maintenance in adults, and may have advantages for the
treatments of individuals with diseases of the nervous system. In addition to direct neurotrophic functions in neurons,
such extraneuronal potential of these factors may be important in the development of therapeutic agents against neurological, neuroimmunological and psychiatric diseases.
Hepatocyte growth factor (HGF) was initially identified
as a mitogen for primary hepatocytes and was molecularly
©2011 Bentham Science Publishers Ltd.
Hepatocyte Growth Factor (HGF): Neurotrophic Functions
cloned in humans in 1989 (see review [8-10]). In addition to
classical neurotrophic factors, hepatocyte growth factor
(HGF) has been implicated in neurotrophic activities with
various extraneuronal functions, including angiogenic activity as well as functions in glial and immune cells, via binding
to its specific receptor the c-Met/HGF receptor (c-Met) [810]. Studies of c-met using knock-out/in mice strategies and
anti-HGF treatment revealed that the HGF-c-Met system is
crucial for the development of motor, sensory, sympathetic,
cerebellar, and cerebral cortical development, as well as oligodendrocyte development in vivo [11, 12]. Here, recent
findings of a wide variety of biological functions of HGF in
the nervous systems are described with a special focus on
potential therapeutic effects on neurological, neuroimmunological and psychiatric pathologies, as a highly potent neurotrophic factor with pleiotrophic activities on various types
of cells, which is crucial for neuroregenerative medicine.
2. IDENTIFICATION OF HGF AS A NEUROTROPHIC FACTOR
2.1. Activities of HGF on Various Cells in the Nervous
System In Vitro
In addition to the role of HGF in the regeneration and
protection of a variety of organs, including liver, kidney and
lung, it has the ability to exert multipotent activities under
pathophysiological conditions [8, 13]. In the nervous system,
for example, c-Met/HGF signaling plays an essential role in
development and maintenance [8, 11, 14]. In brief, c-Met is
widely expressed in various regions of both developing and
Table 1.
Current Signal Transduction Therapy, 2011, Vol. 6, No. 2
157
adult brains in vivo, including neurons of the cerebral cortex
[15-19], hippocampus [15-18, 20], cerebellum [15-17],
brainstem motor nucleus [16, 21], retina [22] and sensory
ganglia [23, 24], and the spinal cord [25, 26], as well as
non-neuronal cells such as reactive astrocytes [25, 26],
oligodendrocytes progenitors [12], oligodendrocytes [12,
27], and microglia [28, 29]. Combined with the expression
and regulation of HGF during development and in adult
nervous systems, these findings suggest a functional coupling
of HGF and c-Met in both the central and peripheral nervous
systems.
Consistent with the expression profiles, in 1995, Honda
et al. used primary cultured rat hippocampal neurons to find
the first indication that HGF functioned as a neurotrophic
factor [16]. The Honda study found that HGF dosedependently increased the numbers of surviving hippocampal neurons after serum starvation [16]. Combined with the
notion that HGF and c-Met are expressed in various regions
of the nervous system during development and in adults,
these results led to the recognition that HGF also functions
as a neurotrophic factor for other types of neurons.
In neurons, HGF also promotes not only survival but also
neurite expression and branching. For example, HGF enhances survival, promotes neurite outgrowth, and stimulates
dendrite growth in a variety of neurons such as hippocampal,
midbrain dopaminergic, cerebral cortical, motor, sensory,
sympathetic, parasympathetic, and cerebral granular neurons.
HGF also guides axons to targets in vitro, as summarized in
Table 1 [8, 16, 19, 30, 31]. HGF promotes cellular migration
Neurotrophic and Non-Neurotrophic Activities of HGF in the Nervous Systems In Vitro
Target Cells
Function
References
Hippocampal neurons
Survival, dendritic maturation, differentiation, modulation of NMDA receptor and
PSD-95 localization
[16, 20, 32, 33, 96]
Midbrain dopaminergic neurons
Neurite extension, increased Tyrosine Hydroxylase (TH) activity
[31]
Cerebral cortical neurons
Survival, neurite extension, migration, numbers of dendritic arbors
[19, 30, 97]
Cerebellar granular neurons
Survival
[98, 99]
Thalamic neurons
Neurite extension
[100]
Motor neurons
Survival, neurite extension (chemoattractant)
[68-70]
Sensory neurons
Survival, neurite extension, migration
[23, 24]
Sympathetic neurons
Survival (postnatal), neurite extension, branching
[101-103]
Sympathetic neuroblasts
Survival, differentiation (but not proliferation)
[101]
Parasympathetic neurons
Survival
[104]
Olfactory interneuron precursors
Migration by Met-Grb2 coupling (slice culture)
[105]
Astrocytes
Migration, EAAT2/GLT-1 expression
[25, 106]
Schwann cells
Proliferation (mitogenic)
[107]
Oligodendrocyte progenitor cells
Proliferation, migration
[34]
Olfactory enseathing cells (OEC)
Proliferation (mitogenic)
[108]
SVZ neural stem-like cells
Growth and self-renewal
[109]
158 Current Signal Transduction Therapy, 2011, Vol. 6, No. 2
Funakoshi and Nakamura
and the synthesis of neurotransmitter synthesizing enzymes,
such as Tyrosine Hydroxylase (TH) [31]. Furthermore, HGF
modifies the localization of PSD-95 clusters and NMDA
receptors in primary hippocampal neurons [32, 33].
such as autism, schizophrenia and nonsyndromic hearing
loss, as summarized in Table 3.
In non-neuronal cells, HGF promotes chemokinesis [34]
and modulates the expression levels of glial specific glutamate
transporter EAAT2/GLT-1 of primary astrocytes [25]. In addition, HGF promotes the proliferation of oligodendrocyte progenitor cells (OPCs) in vitro [34] and in vivo [12], and modulates differentiation into oligodendrocytes [12]. Furthermore,
HGF modulates cytokine production in immune cells [35].
The association of mutation in the Met with autism was
first described in 2006 by Campbell et al. [36]. They showed
the genetic association of a common C allele in the promoter
region of the MET gene in 204 families with autism. The
allelic association at this MET variant was confirmed in a
replication sample of 539 families with autism and in a combined sample. They also showed that MET protein levels
were significantly decreased in autism spectrum disorder
(ASD) cases, compared with control subjects. This was accompanied in ASD brains by increased messenger RNA expression of proteins involved in regulating MET signaling
activity. Analyses of the coexpression of MET and HGF
demonstrated a positive correlation in control subjects that
was disrupted in ASD cases [37]. Their most recent study
supported the association of the MET promoter variant
rs1858830 C allele with ASD, implying a promoter mutation
in ASD [38].
This accumulating evidence indicates that HGF is a multipotent growth factor with highly potent neurotrophic activity. In comparison with classical neurotrophic factors, the
extraneuronal activity of HGF, in addition to its neurotrophic
activity, may increase the therapeutic advantage of HGF for
the treatment of several neurological diseases. Many researchers have reported the successful application of HGF in
various animal models of neurological conditions, including
cerebrovascular, neurodegenerative and psychiatric diseases.
3. DEVELOPMENTAL ROLES OF THE HGF-C-MET
SYSTEM IN THE NERVOUS SYSTEMS
Knock-out/in studies as well as sterotaxic injections of
HGF and anti-HGF antibody into the striatum reveal the
critical role of HGF in the nervous systems, as summarized
in Table 2. HGF plays important roles in motor (including
muscles), sensory, sympathetic, parasympathetic, and cortical neuronal development [11] & Table 2. In addition to the
neuronal development, intrastrial injections of HGF or antiHGF IgG demonstrated the critical role of HGF in the proliferation of oligodendrocyte progenitor cells and their differentiation into oligodendrocytes [12]. HGF is thus implicated
in neuronal as well as glial development, in an orchestrated
manner [12].
4. MUTATION(S) OF HGF-C-MET ASSOCIATED
WITH NEURAL DISEASES/SYMPTOMS
Recent studies have demonstrated the involvement of
mutation(s) in the HGF and c-Met genes in several disorders,
Table 2.
4.1. Autism
Sousa et al. reported new mutation(s) in autism, in both
single locus and haplotype approaches, with a single nucleotide polymorphism in intron 1 (rs38845) and with one intronic haplotype (AAGTG), in 325 multiplex International
Molecular Genetics of Autism Consortium (IMGSAC) families and 10 IMGSAC trios. Although another study with an
independent sample of 82 Italian trios failed to replicate
these results, the association itself was confirmed by a casecontrol analysis performed using the Italian cohort (P<0.02)
[39].
4.2. Schizophrenia and General Cognitive Ability
Comparison of 21 Single Nucleotide Polymorphisms
(SNPs) in the MET with schizophrenia status in 173 Caucasian patients and 137 controls revealed an association between genetic variation in the MET and schizophrenia [40].
It was also reported that genetic variations of the MET are
associated with general cognitive ability [40]. These findings
Developmental Roles of HGF in The Nervous Systems In Vivo
Target System
Function
References
Motor nervous system
Survival, Neurite extension, migration
[110, 111]
Sensory nervous system
Survival, axonal growth
[23]
Sympathetic nervous system
Survival of sympathetic neuroblasts
[101]
Cortical interneuron
Migration
[112, 113]
Cerebellar development
Proliferation of granule precursors in vivo was 25% lower than in controls. Behavioral tests indicated
a balance impairment in Met(grb2/grb2neo-) miceMet signaling knockdown disrupts specification of
VZ-derived cell types, and also reduces granule cell numbers, due to an early effect on cerebellar
proliferation and/or as an indirect consequence of the loss of signals from VZ-derived cells later in
development. These patterning defects preclude the analysis of cerebellar neuronal migration, but it
was found that Met signaling is necessary for migration of hindbrain facial motor neurons.
[111, 114]
Forebrain development
Motogen and guidance signal for gonadotropin hormone-releasing hormone-1 neuronal migration.
[115]
Oligodendrocyte development
Modification of oligodendrocyte progenitor cell proliferation and its differentiation
[12]
Hepatocyte Growth Factor (HGF): Neurotrophic Functions
Table 3.
Current Signal Transduction Therapy, 2011, Vol. 6, No. 2
159
Mutations of the HGF and c-Met Genes in Mental/Psychiatric Diseases/Status
(I) Autism
a. c-met
[36]
mutation in promoter region of c-met
b. c-met
[37, 116]
mutation in promoter region of c-met
c. c-met
[38]
mutation in promoter region of c-met
d. c-met
[39]
mutation in promoter region of c-met
(II) Schizophrenia and General Cognitive Ability
a. c-met
[40]
SNPs in the MET
b. c-met
[41]
(Editorial comments)
[42]
Two intron 4 deletions occur in a highly conserved sequence that is part of the 3' untranslated
region of a previously undescribed short isoform of HGF
(III) Nonsyndromic hearing loss
a. HGF
suggested the implication of HGF-c-Met axis in psychiatric
status and diseases [41].
4.3. Nonsyndromic Hearing Loss
Three mutations in HGF were found in patients with
nonsyndromic hearing loss, at the autosomal-recessive NSHI
locus DFNB39 [42]. Two of the mutations occurred in a region contained in the 3’ UTR of an alternate splice form of
HGF that had not been previously discovered. The third mutation, a third-position nucleotide change predicted to make a
synonymous amino acid substitution, altered splicing by affecting the relative strengths of the spliced forms of HGF.
The conditional deletion of exon 5 of HGF in the cochlea,
and apparently no other phenotype, resulted in a profound,
nonprogressive hearing loss associated with extensive morphometric pathology [42]. Conversely, the ubiquitous overexpression of HGF in a transgenic mouse resulted in progressive hearing loss associated with degeneration of the
outer hair cells, so dysregulation of HGF might be involved
in nonsyndromic hearing loss [42].
5. ROLE OF HGF IN ANXIETY-RELATED BEHAVIOR
When HGF was infused at a constant rate into the cerebral lateral ventricles and its effect on anxiety in rats was
monitored, the elevated plus-maze test and the black-andwhite box test revealed that HGF administration caused all
indicators of anxiety to increase. No significant effect on
general locomotor activity was seen [43]. Whereas HGF
antisense infusion into the cerebral lateral ventricles showed
that, in a forced-swimming test, rats that received antisense
DNA increased the length of time that they were immobile in
the water. Results from the elevated plus-maze test, the
black-and-white box test and the conditioned-fear test clearly
demonstrated that HGF antisense administration caused all
indicators of anxiety to increase [44]. Furthermore, Kaneshita et al. suggested a possible relationship between increased serum HGF levels and the efficacy of antidepressant
therapy in patients with panic disorder [45]. These reports
support the notion that HGF plays a role in both physiological anxiety states and in the efficacy of treating them with
antidepressants.
6. POTENTIAL IMPLICATIONS OF HEPATOCYTE
GROWTH FACTOR FOR DISEASE MODELS IN THE
NERVOUS SYSTEM
6.1. Ischemic Diseases in the Nervous System (Cerebrovascular Diseases)
Ischemic stroke in the brain (brain ischemia) is associated with cerebrovascular disease characterized by a sudden
loss of function due to the loss of blood supply to an area of
the brain that controls that function. The biochemical
changes of brain ischemia result in neuronal cell death and
endothelial cell damage. Brain ischemic neuronal cell death
can cause dysfunction of the central nervous system such as
permanent paralysis, loss of vision, and impairments of
speech, cognition or learning and memory. Furthermore,
endothelial cell damage can cause disruption of the bloodbrain barrier (BBB), resulting in the extravasation of plasma
components and the formation of edema (ischemic cerebral
edema), resulting in secondary damage to neurons [46]. Gliosis may modulate the progression of the disease.
The most popular classes of drugs used to prevent or treat
stroke are anti-thrombotics and thrombolytics. However,
there is no specific treatment to prevent neuronal and endothelial cell death and improve functional recovery after
ischemic stroke.
Many studies have demonstrated that HGF has the ability
to act as a potent cerebroprotective agent for functional
recovery after ischemic brain injuries, by preventing several
pathophysiological alterations caused by brain ischemia, as
follows Table 4 and Fig. (1).
6.1.1. Prevention of neuronal cell death
Continuous post-ischemic administration of recombinant
human HGF protein (rhHGF) effectively prevented the
delayed neuronal cell death in the hippocampus, which is
one of the brain regions most vulnerable to ischemia [4752]. Gene transfer of HGF into the subarachnoid space
using Hemagglutinating virus of Japan (HVJ)-Liposome
prevented delayed neuronal cell death in the hippocampus by
increasing HGF protein in the cerebrospinal fluid [53].
160 Current Signal Transduction Therapy, 2011, Vol. 6, No. 2
Table 4.
Funakoshi and Nakamura
Therapeutic Potential of HGF for Neurological Diseases in the Animal Model
Neurological Disorders
Application
Molecular Mechanisms
References
Ischemic brain injury
Recombinant human HGF (rhHGF)
protein
Prevention of neuronal cell death
[47-51, 58, 60, 63]
Bcl-2 protein Bcl-xL protein Bax translocation from cytoplasm to nucleus Caspase-3 activation AIF translocation (via preventing PARP formation and p53 expression)
Prevention of endothelial cell death
Bcl-2 protein Tight-junction proteins (occluding/ZO-1) Spongel soaked with rhHGF protein
Modulation of apoptosis and autophagy
[57]
HGF gene
Angiogenesis [53, 117]
(HJV-Liposome)
Cerebral blood flow HGF gene
Neurite extension (HJV-Envelope)
Synapses [64]
Inhibition of gliosis (astrocytosis and glial scar formation)
Alzheimer’s disease
Transplantation of bone marrow
mesenchaymal cells (MSCs) with
ex vivo HGF gene transfer using HSV-1
Anti-apoptosis
[118]
HGF gene
Recovery of vessel density
[80]
(naked plasmid)
Blood flow BDNF protein Parkinson’s disease
HGF gene
Prevention of neuronal cell death
[86]
Prevention of motor neuronal cell death
[21, 25, 77]
(naked plasmid)
Amyotrophic lateral
sclerosis (ALS)
HGF gene
(transgenic mouse)
Caspase-1, -3 and -9 activation XIAP protein iNOS protein rhHGF protein
Spinal cord injury (SCI)
EAAT2 protein in astrocytes
(intrathecal administration)
Inhibition of gliosis (astrocytosis and microgliosis)
[74]
HGF gene
Prevention of motor neuronal cell death
[27]
(HSV-1 viral vector)
Prevention of oligodendrocyte death
Caspase-3 activation Multiple sclerosis (MS)
HGF gene
Modulation of neuroimmune system
[35]
(Transgenic mouse)
Seizure
HGF gene
Modulation of GABAergic inhibition and seizure susceptibility [91]
(Transgenic mouse) rhHGF protein
Hydrocephalus
rhHGF protein
Retinal injury
rhHGF protein
TGFbeta inhibition
[90]
Anti-fibrosis
Anti-apoptosis
[92, 119]
Neuroprotection of the Photoreceptor and retinal pigment
epithelium (RPE)
Hearing impairment
Peripheral nerve injury
and neuropathy
rhHGF protein (gelatin hydrogels)
Neuroprotection of outer hair cells (OHC)
[120]
HGF gene
Prevention of loss of hair cells (HC)
[93]
(HVJ-E)
apoptosis of spinal ganglion cells
Recombinant rat HGF protein
[71-73, 121-124]
HGF gene
(adenoviral vector)
Neuropahic pain
HGF gene (HVJ)
[94]
Fig. (1). Pleiotrophic functions of HGF during development and in the animal model of neurological and neuroimmunological diseases. HGF
acts on neuronal cells to attenuate neuronal cell death by preventing caspase-dependent and -independent apoptosis and by inhibiting gliosis
(microgliosis and astrocytosis), and by acting on glial cells, such as astrocytes, to retain (or even incease) the levels of glial-specific glutamate
transporter 1 (GLT-1)/exitatory amino acid transporter 2 (EAAT2), which might be favorable to reduce glutamatergic neurotoxicity. The
possibility that HGF directly functions on microglia cannot be excluded, since c-Met is expressed in the subpopulation of microglia in ALS
model mice and in primary culture (Ohya-Shimada and Funakoshi, unpublished results). HGF also attenuates down-regulation of tight junctional proteins (occludin and ZO-1) and promotes angiogenesis that is beneficial for ischemic conditions. Under development and demyelinating conditions, such as MS, HGF may promote OPC (reservoir cells of oligodendrocytes) proliferation and migration into demyelinated regions and modulate remyelination. Further, HGF modulates immune cell functions, such as tolerization of DCs. This figure is a modified
version of Fig. (1) of [95].
Hepatocyte Growth Factor (HGF): Neurotrophic Functions
Current Signal Transduction Therapy, 2011, Vol. 6, No. 2
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162 Current Signal Transduction Therapy, 2011, Vol. 6, No. 2
Overexpression of HGF using HVJ envelope vector in the
brain enhanced the neurite extension, increased synapses and
prevented gliosis and glial scar formation, which inhibits
neuronal survival or regeneration in the peri-infarct region of
the neocortex [64].
The molecular mechanisms by which HGF prevents neuronal cell death are the inhibition of apoptosis through
upregulation of the production of anti-apoptotic Bcl-2 [48,
49] and Bcl-xL proteins, stimulation of increased extracellular signal-regulated kinase phosphorylation [50, 54], and
blockage of Bax translocation from the cytoplasm to the
nucleus [53]. Furthermore, HGF also plays a role in the prevention of primary oxidative DNA damage after ischemia
via an independent pathway to the caspase. In brief, HGF
prevents primary oxidative DNA damage after ischemia by
attenuating the activation of poly(ADP-ribose) polymerase
(PARP) and the expression of p53, which prevents an increase in the expression of apoptosis-inducing factor protein
(AIF) in the nucleus [51]. AIF has been shown to act as a
main molecular effector of caspase-independent apoptosislike program cell death via mitochondrial release and nuclear
translocation, which leads to characteristic non-nucleosomal
secondary DNA damage (DNA fragmentation) [55, 56].
Furthermore, recent findings reveal that HGF modulates not
only apoptosis but also autophagy after transient middle
cerebral artery occlusion in rats [57]. This evidence suggests
that HGF exerts neuroprotective effects against brain
ischemic neuronal cell death by preventing caspasedependent and -independent cell death signals.
6.1.2. Reduction of Infarction Volume
The infarction volume was significantly reduced by
the administration of rhHGF into the ventricle, by Spongel,
or gene transfer of HGF with HVJ envelop vector into
the cerebrospinal fluid via the cisterna magna or transplantation of bone marrow stromal cells (MSC) with
expression of the HGF gene by ex vivo gene transfer using
HSV-1 [47-49, 57-59].
6.1.2. Prevention of Disruption of the Blood-Brain
Barrier (BBB)
Treatment with rhHGF attenuated the disruption of the
BBB after microsphere embolism-induced sustained cerebral
ischemia [60]. The molecular mechanisms by which HGF
prevents the disruption of the BBB are as follows: 1) prevention of the apoptotic endothelial cell death through attenuating the decrease in the level of Bcl-2 [60]: and 2) a decrease
in the expression of the tight-junction proteins, occludin and
zonula occludens (ZO)-1 in cerebrovascular endothelial cells
[61]. Therefore, HGF-mediated prevention of endothelial
cell injury and maintenance of tight junctional proteins in
endothelial cells may be a possible mechanism for the protective effect of HGF against the disruption of the BBB after
ischemia.
6.1.3. Prevention of Ischemic Cerebral Edema
Treatment with rhHGF suppressed the microsphere
embolism (ME)-induced increase in tissue water. Although
an ME-induced increase in water content was associated
with increases in tissue Na+ and Ca2+ content and decreases
in tissue K+ and Mg2+ content, HGF suppressed the increases
Funakoshi and Nakamura
in Na+ and Ca2+ content, but not the decreases in K+ and
Mg2+ content [62].
6.1.4. Prevention of Dysfunction of Learning and Memory
Administration of rhHGF into the ventricle prevented
learning and memory dysfunction in the water maze task by
protecting against injury to the endothelial cells [58, 63].
rhHGF and gene transfer of HGF using HVJ envelope vector
significantly improved learning and memory after cerebral
ischemia [64]. Therefore, HGF promotes the recovery of
cognitive function in the chronic stage of ischemia through
reconstitution of the neuronal network.
6.2. Neurodegenerative Diseases
Neurodegenerative diseases such as Alzheimer’s disease,
Parkinson’s disease and amyotrophic lateral sclerosis are
characterized by neuronal degeneration, resulting in severe
nervous system dysfunction. Although several hypotheses
have been proposed, the actual pathogenic mechanisms that
lead to selective neuronal degeneration are largely unknown,
and no effective treatment is currently available to arrest or
reverse neuronal cell death and to improve the functional
recovery at each stage of neurodegenerative diseases. Molecules with neurotrophic activity have long been thought of as
beneficial agents for the treatment of neurodegenerative diseases, not only because of their survival-promoting activity,
but also because of their neurite-promoting activity, which
may assist in the reorganization of neural networks [62]. The
role of HGF in neurodegenerative diseases is summarized in
Table 4.
6.2.1. Amyotrophic Lateral Sclerosis
Amyotrophic lateral sclerosis (ALS) is increasingly considered to be a disorder of multiple etiologies, which have in
common the progressive degeneration of both upper and
lower motor neurons and their axons, accompanied by intense gliosis in lesioned areas of the brainstem, motor cortex,
and spinal cord. These ultimately give rise to a relentless loss
of muscle function, such as spasticity, hyper-reflexia, generalized weakness of the limbs, and muscle atrophy and
paralysis [65]. However, the actual pathogenic mechanisms
that lead to the selective motor neuronal degeneration are
largely unknown. Riluzole is a currently available drug that
prolongs survival by several months. Riluzole protects
against motor neuronal injury by inhibiting glutamate release, inactivating voltage-dependent sodium channels and
interfering with intracellular events that follow transmitter
binding at excitatory amino acid receptors [66]. However, no
other effective treatment against ALS is currently available
[67], and a large worldwide effort and challenges are in progress to find new therapeutic intervention(s).
The beneficial effects of HGF on motor neurons in vitro
and in vivo have been reported. For example, HGF promotes
survival of embryonic spinal motor neurons in vitro and in
vivo [68-70]. Recombinant HGF application and adenoviral
gene transfer of HGF prevent the death of injured adult motoneurons after peripheral nerve avulsion, such as hypoglossal, facial and spinal nerves in vivo [71-73]. Consistent with
these findings, beneficial effects of HGF application have
been shown in animal models of ALS. For example,
overexpression of HGF in the nervous system has attenuated
Hepatocyte Growth Factor (HGF): Neurotrophic Functions
spinal and brainstem (facial and hypoglossal) motor neuronal
cell death and prolonged the lifespan in a mouse model
of ALS in which mutated Cu2+/Zn2+ superoxide dismutase
1 was overexpressed [21, 25]. Continuous intrathecal
administration of rhHGF attenuates motor neuron degeneration, improves motor performance and has prolonged
survival even with treatment beginning around the onset of
paralysis [74]. The molecular mechanisms by which HGF
attenuates neuronal cell death are as follows: 1) inhibition of
apoptosis by preventing the induction of pro-apoptotic
proteins, including caspase-1, -3 and -9: and 2) enhancement
of the induction of inhibitors of apoptosis family proteins,
including X chromosome-linked inhibition of apoptosis
protein (XIAP), in the motor neurons of ALS model mice
[21, 25, 74]. In addition, HGF retained the levels of the glialspecific glutamate transporter (excitatory amino acid
transporter 2/glutamate transporter 1) in reactive astrocytes,
thereby reducing the glutamate neurotoxicity of motor
neurons [25, 74], and reduced both microgliosis (accumulation of activated microglia) and astrocytosis in ALS model
mice [21, 25]. Gliosis in the vicinity of degenerating motor
neurons may contribute to ALS disease progression, raising
the possibility that gliosis might be a good target for curative
efforts. The regulation of the HGF-c-Met system in the
spinal cords of sporadic and familial patients with ALS is
very similar to that in the transgenic mouse model of ALS,
which overexpresses mutant SOD1G93A [26]. Thus, HGF is
an endogenous neurotrophic/ neuroregenerative factor that is
regulated in ALS, and supplementation of HGF exerts
neuroprotective effects by acting on motor neurons and glial
cells, which might be valuable for ALS therapy for both
familial and sporadic patients. The direct role of HGF in
microglia/macrophage in the disease progression of ALS is
the next issue to be studied, since c-Met is expressed in the
subpopulation of microglia/macrophage in ALS model mice
and in primary cuture (Ohya-Shimada and Funakoshi,
unpublished results). Previous in vitro studies demonstrated
that phosphorylation status of the serine residue at position
985 of c-Met is associated with decreased HGF-induced
phosphorylation of the tyrosine residue and its phosphorylation state is regulated in vitro through protein phosphatase
2A (PP2A), a serine/threonine protein phosphatase, and protein kinase C (PKC), a serine/threonine protein kinase [75,
76]. Furthermore, reciprocal phosphorylation of serine and
tyrosine residue(s) of c-Met is shown in motor neurons of a
transgenic mouse model of amyotrophic lateral sclerosis
(ALS), suggesting the potential contribution of reciprocal
phosphorylation in vivo [77]. Such reciprocal regulation of
the phosphorylation states of serine and tyrosine residues of
c-Met supports the notion that HGF functions more
efficiently when animals are affected by mutant SOD1G93A
(under ALS-stress) and this mechanism might be beneficial
in avoiding the non-essential activation of c-Met in non-ALS
mice in the presence of a certain amount of HGF, suggesting
that HGF could be a safe and effective therapeutic agent for
the treatment of ALS and related disorders [77].
6.2.2. Alzheimer’s Disease
Alzheimer’s disease (AD) is a progressive, age-related
dementia of unknown etiology characterized by neuronal
degeneration, synaptic loss and cholinergic deficits, leading
to cognitive, behavioral and psychological impairment.
Current Signal Transduction Therapy, 2011, Vol. 6, No. 2
163
Histologically, AD neurodegeneration is distinguished by
neuropathological changes and deposits of misfolded
proteins, mainly consisting of amyloid (A) and hyperphosphorylated Tau in neurofibrillary tangles in the form of
senile plaques and deposits in the neocortex, hippocampus
and cerebral blood vessels [78]. Current drugs improve
symptoms, but have no profound disease-modifying effects
[79].
Beneficial effects of HGF on AD therapy have been
reported. Takeuchi et al. have reported that overexpression
of human HGF plasmid DNA injected into the cerebral ventricle improved A-induced memory impairment in A (140)-injected mice by increasing HGF protein in the injection
site and around the cerebral ventricles [80]. This effect is
associated with significant recovery of vessel density in the
dentate gyrus of the hippocampus, recovery of blood flow,
upregulation of brain-derived neurotrophic factor (BDNF)
(which enhances long-term potentiation (LTP) in the hippocampus [81]), a significant decrease in oxidative stress, and
synaptic enhancement in mice treated with A [80]. In vitro
studies have shown that HGF increased the expression of
synaptic proteins including the NR2B subunit of the NMDA
receptor, calcium/calmodulin-dependent protein kinase II,
and the GluR1 subunit of the AMPA receptor [82], rapidly
enhanced induction of synaptic transmission and synaptic
LTP in the CA1 region of the hippocampus, and augmented
NMDA receptor-mediated currents [83]. Furthermore, HGF
attenuated the decreased synaptic localization of NR2B and
PSD-95 [33]. HGF increased the number of puncta of PSD95 in young hippocampal neurons [32]. Since functional
localization of the NMDA receptor at synapses depends on
PSD-95 [84], HGF might modulate the synaptic expression
of the NMDA receptor by regulating the localization of
PSD-95, leading to the modification of cognitive impairment
in AD.
6.2.3. Parkinson’s Disease
Parkinson’s disease (PD) is characterized by dopaminergic striatal insufficiency, secondary to a progressive loss of
dopaminergic neurons in the substantia nigra and intracellular inclusions called Lewy bodies. At present, available
therapies, such as treatment of levodopa combined with carbidopa, aim to replace dopamine in the brain to restore motor
function [85]. These drugs provide dramatic relief from the
symptoms, but do not seem to stop or reverse the progression
of PD.
Neurotrophic effects of HGF in primary midbrain dopaminergic neurons and beneficial effects of HGF on PD
therapy have been reported [31, 86]. Koike et al. reported
that gene transfer of human HGF plasmid DNA by direct
injection into the rat striatum inhibited dopaminergic neuronal cell death in 6-hydroxydopamine (OHDA)-induced PD
model rats by increasing HGF protein in the injection site
[86]. 6-OHDA is a neurotoxin used to selectively degenerate
dopaminergic neurons and induce Parkinsonism in laboratory animals [87]. Furthermore, HGF significantly inhibited
amphetamine-induced abnormal rotation in rats [86]. These
results demonstrate that HGF inhibits the loss of dopaminergic neurons in the substantia nigra in a rat PD model, providing a potential novel therapy for PD
164 Current Signal Transduction Therapy, 2011, Vol. 6, No. 2
6.3. Injuries of the Nervous Systems
6.3.1. Spinal Cord Injury
Spinal cord injuries (SCI) are classified as partial or
complete, depending on how much of the cord width is damaged. In general, injuries that are higher in the spinal cord
produce more paralysis. For example, a spinal cord injury at
the neck level may cause paralysis in both arms and legs and
make it impossible to breathe without a respirator, while a
lower injury may affect only your legs and lower parts of the
body. Currently, there are no effective treatments, and the
mechanisms underlying these neuropathological changes are
not completely understood. Methylprednisolone is the presently available drug, and it appears to reduce the damage to
neuronal cells if it is given within the first 8 hours after injury. SCI is followed by secondary degeneration, which is
characterized by progressive tissue necrosis. Several experimental approaches have been employed to minimize tissue
damage and to enhance axonal growth and regeneration
throughout the lesion epicenter after SCI. Although several
neurotrophic factors that augment axonal pathfinding and
neuronal survival improve the neurological deficit after spinal cord injury, angiogenesis after SCI is also a critical factor
in the endogenous regenerative response to trauma [88].
Since HGF is widely known as a potent neurotrophic and
angiogenic factor, it might be more effective than other neurotrophic factors for treatment of spinal cord injury. Kitamura et al. demonstrated that the application of exogenous
HGF genes into the injured spinal cord, using a replicationincompetent herpes simplex virus-1 vector, prevented motor
neuronal loss by attenuating caspase-3 activation after SCI,
thereby promoting the survival of motor neurons and reducing the size of the damaged area [27]. HGF promoted the
survival of oligodendrocytes, as well as neurons, by reducing
caspase-3 activation after SCI, resulting in a significant reduction in the area of demyelination after SCI [27]. Taken
together, the antiapoptotic and neurotrophic effects of HGF
on the neurons and oligodendrocytes contributed to a significant reduction in the area of parenchymal damage after SCI.
Furthermore, the introduction of HGF into the injured spinal
cord increased the total area of endothelial cells and the
number of vessels with abnormally large lumina after SCI
[27]. HGF appears to exert significant neuroprotective and
antiapoptotic effects that promote the survival of neurons
and oligodendrocytes, and also enhances angiogenesis
around the lesion epicenter after SCI. These effects significantly reduced the area of damage and provided a better
scaffold for axonal regeneration.
6.3.2. Peripheral Nerve Injury and Neuropathy
Peripheral nerve avulsion is an injury caused when the
nerve root is severed or cut from the spinal cord, causing
marked motor neuronal degeneration. The therapeutic effects
of HGF on motor neurons in vitro and in vivo have been reported, as described it in the “Amyotrophic Lateral Sclerosis” section. In animal models of peripheral nerve avulsion
(adult motor neuron injury), Okura et al. have demonstrated
that application of rat recombinant HGF protein prevents the
rapid decrease of choline acetyltransferase (ChAT) mRNA
and protein after axotomy [71]. In addition, Hayashi et al.
have reported that the treatment of an adenoviral vector
encoding HGF after facial nerve and spinal root avulsion
Funakoshi and Nakamura
significantly improved the survival of injured facial and
spinal motor neurons and ameliorated ChAT immunoreactivity in these neurons [72]. These lines of evidence
suggest that HGF may be a potential neuroprotective agent
against motor neuron injury in adult humans.
6.4. Neuroimmune Disease
Immune-mediated diseases of the CNS, for example multiple sclerosis (MS), is a devastating autoimmune disease
that affects more than 1 million people worldwide and severely compromises motor and sensory function through
demyelination and axonal loss. MS and its animal model,
experimental autoimmune encephalomyelitis (EAE), are
characterized by the activation of antigen-presenting cells
and the infiltration of autoreactive lymphocytes within the
CNS, leading to demyelination, axonal damage, and neurological deficits. Because HGF shows immunomodulatory
effects and neuroprotective effects, the effects of HGF on
animals of EAE were examined, using transgenic mice overexpressing rat HGF in a neuron-specific manner. The protein
produced was secreted into extracellular space in the nervous
system and functioned in an autocrine, as well as a paracrine,
fashion (HGF-Tg mice [25]) [35]. EAE induced either by
immunization with myelin oligodendrocyte glycoprotein
peptide or by adoptive transfer of T cells was inhibited in
HGF-Tg mice. Notably, the level of inflammatory cells infiltrating the CNS decreased, except for CD25(+)Foxp3(+)
regulatory T (T(reg)) cells, which increased. A strong Thelper cell type 2 cytokine bias was observed: IFN-gamma
and IL-12p70 decreased in the spinal cord of HGF-Tg mice,
whereas IL-4 and IL-10 increased. Antigen-specific response
assays showed that HGF was a potent immunomodulatory
factor that inhibited dendritic cell (DC) function and the differentiation of IL-10-producing T(reg) cells, decreased in IL17-producing T cells, and down-regulated surface markers of
T-cell activation. These effects were fully reversed when DC
were pretreated with anti-cMet (HGF receptor) antibodies.
These results suggest that, by combining both potentially
neuroprotective and immunomodulatory effects, HGF is a
promising candidate for the development of new treatments
for immune-mediated demyelinating diseases associated
with neurodegeneration such as multiple sclerosis.
Given that c-Met is expressed and phosphorylated in both
OPCs and oligodendrocytes [12], and that HGF promotes
proliferation of OPC [12] and promotes its chemotaxis [89],
and that HGF attenuates activation of caspase-3 in oligodendrocytes in the animal model of spinal cord injury [27], it
would be intriguing to examine whether HGF suppresses the
degeneration of oligodendrocytes in neuroimmune disease
model(s), and whether HGF promotes the proliferation
of oligodendrocyte precursor cells (OPCs) to increase the
numbers of reserve cells for oligodendrocytes, chemotaxis
of OPCs and subsequent remyelination [34]. Considering
that HGF attenuated gliosis, including astrocytosis and
microgliosis in the animal model of ALS [21, 25] and that cMet is expressed in reactive astrocytes [21, 25] and in the
subpopulation of microglia in primary culture and in the
animal model of ALS, the role of the HGF-c-Met system
in other types of cells including astrocytes, microglia and
macrophages is another interesting issue for future study
Fig. (1).
Hepatocyte Growth Factor (HGF): Neurotrophic Functions
6.5. Other Diseases
In addition to these animal models, therapeutic roles of
HGF have been shown in other neuronal and neuroimmune
diseases, such as hydrocephalus, seizures, retinal and hearing
impairment, and neuropathic pain (Table 4) [90-94].
7. CONCLUSIONS
Many studies have demonstrated that HGF is a powerful
neurotrophic factor with a great deal of extraneuronal activity that is beneficial in various animal disease models in the
nervous system (Table 4). These findings suggest the possibility of therapeutic application of HGF in neurological, neuroimmunological, and psychiatric diseases. Clinical trials of
recombinant HGF protein in subjects with ALS and spinal
cord injury have been designed and planned as collaborative
projects among Osaka University, Asahikawa Medical
University, Tohoku University and Keio University with
the support of the Japanese Ministry of Health Labor and
Welfare.
Current Signal Transduction Therapy, 2011, Vol. 6, No. 2
[15]
[16]
[17]
[18]
[19]
[20]
[21]
ACKNOWLEDGEMENTS
We are grateful to Ms. Kanai for the help with figure
preparation and Ms. Ikushima for secretarial assistance. This
work was supported by Research Grants from the Japanese
Ministry of Health Labor and Welfare to H.F. and by a
grant-in-aid from the Global Centers of Excellence (COE)
program of the Ministry of Education, Science, and Culture
of Japan to Osaka University.
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Received: June 29, 2010
Revised: July 07, 2010
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