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In addition to hepatotrophic activities, HGF and c-Met are expressed in both ... Keywords: HGF, c-Met, neurotrophic, amyotrophic lateral sclerosis (ALS), spinal ...
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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.

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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]

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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