The effective treatment for cerebral ischemia has not yet been established. Hepatocyte growth factor (HGF) is a potent pleiotropic cytokine that is involved in cell and tissue regeneration, including in the central nervous system. Studies have demonstrated that an exogenous administration of HGF protects brain tissue from ischemic damage. In response to binding to the receptor c-Met, HGF activates the downstream signaling pathways (including the phosphatidylinositol 3-kinase/Akt, Ras/MAPK and signal transducer and activator of transcription pathways) which leads to various cellular responses involved in angiogenesis, glial scar formation, anti-apoptosis and neurogenesis. The purpose of this review is to summarize the present understanding of the therapeutic potential of HGF in cerebral ischemia.
Cerebral ischemia causes an irreversible and neurodegenerative disorder that may lead to progressive dementia and cognitive deterioration. However, no effective treatment has been established yet to prevent brain injury following ischemia.Hepatocyte growth factor (HGF), also referred to as Scatter factor, was first identified and purified from plasma and serum as a potent mitogen for hepatocytes in 1984 by Nakamura
HGF was first identified as a mitogenic protein for rat hepatocytes in 1984 (
The proto-oncogene product receptor tyrosine kinase c-Met is the only known receptor for HGF. The human Met (HGF receptor) gene is located on chromosome 7q21-q31. c-Met is synthesized as a 170-kDa glycosylated precursor protein that is cleaved into a 50-kDa α-chain and a 140-kDa β-chain that are linked by disulfide bonds (
In response to ligand (HGF) binding, c-Met undergoes autophosphorylation on two tyrosine residues (Y1234 and Y1235) within the activation loop of the tyrosine kinase domain, which regulate the intrinsic kinase activity of c-Met. Phosphorylation of Y1349 and Y1356 near the C-terminus of c-Met forms a multifunctional signal transducer docking site (Y1349VHVX3Y1356VNV) that binds a number of substrates containing Src homology-2 (SH2) domains, including growth factor receptor-bound protein 2 (Grb2), Gab1, phosphatidylinositol 3-kinase (PI3K), phospholipase C-γ (PLC-γ), Shp2 and Scr (
Angiogenesis was first described as a vital factor in tumor growth in 1971 (
For a long time, attempts to alleviate ischemic cerebral injuries and ameliorate the prognosis have focused on ensuring or improving the survival of neurons, while ignoring the role of angiogenesis. However, the latter might be closely correlated with the survival of neurons following the ischemic insults. Krupinski
As a potent angiogenic molecule, HGF mediates angiogenesis primarily through direct actions on vascular endothelial cells. Studies have demonstrated that HGF and c-Met are expressed and functional in vascular endothelial cells of various origins, including neuromicrovascular endothelial cells (
The molecular mechanisms of the angiogenic activity of HGF may be strongly associated with the E-twenty-six (ETS) pathway, since the ETS family plays a significant role in regulating gene expression in response to the multiple developmental and mitogenic signals (
In addition to the proliferative effects, HGF also protects endothelial cells against apoptosis or cell death induced by various detrimental insults, including hypoxia and serum deprivation. However, the signal pathways that mediate the protective effects are not fully known. Ma
It is known that matrix degradation and remodeling are indispensable in angiogenesis, and allow endothelial cell migration and invasion (
In addition, HGF regulates angiogenesis through interacting with other well-known angiogenic regulators. It has been shown that HGF induces VEGF expression at both the mRNA and protein levels, which might be regulated by MAKP, PI3K, PKC and Sp1, a modulator of the VEGF promoter (
Furthermore, compared with other angiogenic regulators including VEGF, HGF has noted advantages in promoting angiogenesis, as follows: a) it does not disrupt the blood brain barrier (BBB); b) it does not increase cerebral edema; c) it does not cause vascular inflammation; and d) it has anti-thrombosis ability (
Since mature neurons cannot duplicate, it is essential to maintain their survival to improve the outcome of cerebral ischemia. The roles of excitatory amino acid receptor activation, calcium overload, nitric oxide and oxidative stress are well established in the pathogenesis of ischemic brain damage (
In recent years, there has been a growing interest in the therapeutic potential of stem cells. Stem cells are multipotent and self-renewing cells, so it is believed that they may be beneficial to the outcome of cerebral stroke. There is evidence revealing that transplantation of neural stem cells (NSCs) or mesenchymal stem cells (MSCs) decreases the infarcted area and improves functional outcomes (
Ischemia induces tissue damage to the CNS and activates astrocytes, leading to reactive gliosis, which causes glial scar formation (
As a multifunctional cytokine, it was suggested by Ha
Aside from the proliferation and activation of astrocytes, several other factors are also associated with the formation of glial scarring, including transforming growth factor-β (TGF-β) and extracellular matrix components. Previous studies suggest that HGF plays antifibrotic roles by regulating proteoglycan synthesis. When astrocytes are activated, four classes of proteoglycans are produced by astrocytes, which are closely related to glial scar formation (
The clinical use of HGF is quite limited at present for a number of reasons, including lack of effective administration methods and adverse effects. We will discuss these below.
A notable breakthrough has been made in using HGF in the therapy for limb ischemia, which is at the clinical trial stage (
Gene therapy may solve the issue of degradation, but the safety and efficiency of the gene carrier must be ensured. Retroviruses are one of the widely used gene carriers, and can integrate the gene into the chromosomes of the target cells (
Considering the safety of gene therapies, certain scientists have proposed a new solution: transferring the virus vector into the host cells (e.g., MSCs) and then transferring the cells into the injured organs (
Previous studies have demonstrated that HGF plays a role in tumorigenesis through its capability to promote angiogenesis and mitogenesis (
Overall, as a growth factor, HGF has therapeutic potential against cerebral ischemia. Binding to the receptor c-Met, downstream signaling pathways are phosphorylated and activated, including the PI3K/Akt, Ras/MAPK and STAT pathways, then HGF is capable of regulating angiogenesis, glial scar formation, neurogenesis and anti-apoptosis, protecting the brain from ischemic insults. Although certain obstacles remain before clinical application of HGF can be achieved, we are of the opinion that through the deepening research these issues will be overcome, bringing benefit to patients with cerebral ischemia.