JNK/ERK/FAK Mediate Promigratory Actions of Basic Fibroblast Growth Factor in Astrocytes via CCL2 and COX2 (original) (raw)
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Frontiers in Molecular Neuroscience, 2020
Astrocytes are the most abundant type of glial cells in the brain, and they play a key role in Alzheimer's disease (AD). Fibroblast Growth Factor-2 (FGF-2) has been implicated as a potential therapeutic agent for treating AD. In the present study, we investigated the protective effects of low molecular weight (LMW; 17 KDa) and high molecular weight (HMW; 23 KDa) forms of FGF-2 on Aβ 1-42-induced toxicity, and proliferation in astrocytes. We show that both isoforms of FGF-2 have similar protective effects against Aβ 1-42-induced cytotoxicity in primary cultured cortical astrocytes as measured by Lactate Dehydrogenase (LDH) release assay. Additionally, 17 KDa FGF-2 significantly promoted astrocyte proliferation as measured by Trypan Blue, DRAQ5 and 5-ethynyl-2'-deoxyuridine (EdU) staining, but not 23 kDa FGF-2. Furthermore, our results demonstrated that AKT signaling pathway was required for the protective and proliferative effects of FGF-2. Downstream effector studies indicated that 17 kDa FGF-2 promoted astrocyte proliferation by enhanced expression of c-Myc, Cyclin D1, Cyclin E. Furthermore, our data suggested that Cyclin D1 was required for the proliferative effect of LMW FGF2 in astrocytes. Taken together, our findings provide important information for the similarities and differences between 23 kDa and17 kDa isoforms of FGF-2 on astrocyte survival and proliferation.
Astrocyte activation is suppressed in both normal and injured brain by FGF signaling
Proceedings of the National Academy of Sciences of the United States of America, 2014
In the brain, astrocytes are multifunctional cells that react to insults and contain damage. However, excessive or sustained reactive astrocytes can be deleterious to functional recovery or contribute to chronic inflammation and neuronal dysfunction. Therefore, astrocyte activation in response to damage is likely to be tightly regulated. Although factors that activate astrocytes have been identified, whether factors also exist that maintain astrocytes as nonreactive or reestablish their nonreactive state after containing damage remains unclear. By using loss- and gain-of-function genetic approaches, we show that, in the unperturbed adult neocortex, FGF signaling is required in astrocytes to maintain their nonreactive state. Similarly, after injury, FGF signaling delays the response of astrocytes and accelerates their deactivation. In addition, disrupting astrocytic FGF receptors results in reduced scar size without affecting neuronal survival. Overall, this study reveals that the ac...
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2003
Multiple evidence suggests that fibroblast growth factors (FGFs), most prominently FGF-2, affect astroglial proliferation, maturation, and transition to a reactive phenotype in vitro, and after exogenous administration, in vivo. Whether this reflects a physiological role of endogenous FGF is unknown. Using FGF-2 and FGF-5 single- and double mutant mice we show now a region-specific reduction of glial fibrillary acidic protein (GFAP), but not of S100 in gray matter astrocytes. FGF-2 is apparently the major regulator of GFAP, because in mice deficient for FGF-2, GFAP is distinctly reduced in cortex and striatum, whereas in FGF-5-/- animals only a reduction in the midbrain tegmentum can be observed. In FGF-2-/-/FGF-5-/- double mutant animals, GFAP-immunoreactivity is reduced in all three brain regions. Cortical astrocytes cultured from FGF-2-/-/FGF-5-/- double mutant mice revealed reduced levels of GFAP, but not S100 as compared with wild-type littermates. This phenotype could be rescu...
Molecular Brain Research, 1996
Fractionation of human astrocytes revealed the presence of 103, 118, and 145 kDa forms of FGF receptor 1 (FGFR1) in isolated nuclei. Only trace amounts of FGFR1 proteins were detected in the cell membrane or cytoplasmic fractions. Nuclear FGFR1 is found in the nucleoplasm and nuclear matrix but not in chromatin. Immuno-confocal microscopy further demonstrates the intranuclear presence of FGFR1 and its colocalization with FGF-2. Nuclear FGFR1 binds to FGF-2 and has tyrosine kinase activity. Translocation of functional growth factor receptors into the cell nucleus offers a novel mechanism for growth factor action.
Fibroblast growth factor-2 induces astroglial and microglial reactivity in vivo
Journal of Anatomy, 2002
A role for fibroblast growth factor-2 (FGF-2) has been proposed in mediating the glial response to injury in the central nervous system (CNS). We have tested this possibility in vivo , by injecting FGF-2 into the cerebrospinal fluid (CSF) of the brain ventricles of young rats and analysing glial cells in the anterior medullary velum (AMV), which partly roofs the IVth ventricle. FGF-2 was administered at two different doses, low FGF-2 (500 ng mL -1 CSF) and high FGF-2 (10 µ g mL -1 CSF), and saline vehicle was injected in controls. Injections were performed twice daily for three days, commencing at postnatal day (P) 6, and AMV were analysed at P9, using immunohistochemistry and Western blotting. Glial cells were unaffected by treatment with saline or low FGF-2, whereas high FGF-2 induced reactive changes in glial cell types: (1) there was increased GFAP expression in astrocytes, demonstrated by Western blot and immunohistochemistry, and astrocytes appeared hypertrophic, with increased process thickness and number;
Experimental Neurology, 2008
Following trauma to the brain significant changes occur in both the astroglial and vascular components of the neuropil. Angiogenesis is required to re-establish metabolic support and astrocyte activation encompasses several functions including scar formation and the production of growth factors. VEGF has seminal involvement in the process of brain repair and is upregulated during many pathological events. VEGF signaling is regulated mainly through its two primary receptors: flk-1 (KDR/VEGF-R2) is expressed on vascular endothelium and some neurons and flt-1 (VEGF-R1) in the CNS, is expressed predominantly by activated astrocytes. Using an injury model of chronic minipump infusion of neutralizing antibodies (NA) to block VEGF receptor signaling, this study takes advantage of these differences in VEGF receptor distribution in order to understand the role the cytokine plays after brain injury. Infusion of NA to flk-1 caused a significant decrease in vascular proliferation and increased endothelial cell degeneration compared to control IgG infusions but had no effect on astrogliosis. By contrast infusion of NA to flt-1 significantly decreased astroglial mitogenicity and scar formation and caused some increase in endothelial degeneration. Neutralization of the flt-1 receptor function, but not flk-1, caused significant reduction in the astroglial expression of the growth factors, CNTF and FGF by seven days. These data suggest that after CNS injury, endogenous VEGF upregulation (by astrocytes) induces angiogenesis and, by autocrine signaling, increases both astrocyte proliferation and facilitates expression of growth factors. It is likely that VEGF plays an important role in aspects of astroglial scar formation.
FGF-2 in Astroglial Cells during Vertebrate Spinal Cord Recovery
Frontiers in Neuroscience, 1970
Fibroblast growth factor-2 is a pleiotrophic cytokine with neurotrophic and gliogenic properties. It is known to regulate CNS injury responses, which include transformation of reactive astrocytes, neurogenesis, and promotion of neurotrophic activities. In the brain, it is localized in astrocytes and discrete neuronal populations. Following both central and peripheral nervous system injury, astrocytes become reactive. These activated cells undergo hypertrophy. A key indicator of astrocyte activation is the increased accumulation of intermediate filaments composed of glial fibrillary acidic protein (GFAP). Following physical insult of brain or spinal cord, reactive astrocytes show increased FGF-2 immunoreactivity. Thus, FGF-2 appears to participate in astrocytic differentiation and proliferation and a good candidate for astrocytic function regulation in healthy, injured, or diseased CNS. To further investigate the cellular mechanisms underlying FGF-2 restorative actions and to analyze the changes within astroglial cells, we studied the localization of GFAP and FGF-2 in adult intact and injured Pleurodeles CNS. Our results show that spinal cord injury triggers a significant increase in FGF-2 immunoreactivity in reactive astrocytes at sites of insult. In addition, these results were time-dependent. Increase in FGF-2 immunoreactivity along the CNS axis, starting 1-week post-injury, was long-lasting extending to 6 weeks. This increase was accompanied by an increase in GFAP immunoreactivity in the same spatial pattern except in SC3 where its level was almost similar to sham-operated animals. Therefore, we suggest that FGF-2 may be involved in cell proliferation and/or astroglial cells differentiation after body spinal cord transection, and could thus play an important role in locomotion recovery.
Scientific Reports
The glutamate transporter 1 (GLT1) is upregulated during astrocyte development and maturation in vivo and is vital for astrocyte function. Yet it is expressed at low levels by most cultured astrocytes. We previously showed that maturation of human and mouse stem cell-derived astrocytes-including functional glutamate uptake-could be enhanced by fibroblast growth factor (FGF)1 or FGF2. Here, we examined the specificity and mechanism of action of FGF2 and other FGF family members, as well as neurotrophic and differentiation factors, on mouse embryonic stem cell-derived astrocytes. We found that some FGFs-including FGF2, strongly increased GLT1 expression and enhanced astrocyte proliferation, while others (FGF16 and FGF18) mainly affected maturation. Interestingly, BMP4 increased astrocytic GFAP expression, and BMP4-treated astrocytes failed to promote the survival of motor neurons in vitro. Whole transcriptome analysis showed that FGF2 treatment regulated multiple genes linked to cell division, and that the mRNA encoding GLT1 was one of the most strongly upregulated of all astrocyte canonical markers. Since GLT1 is expressed at reduced levels in many neurodegenerative diseases, activation of this pathway is of potential therapeutic interest. Furthermore, treatment with FGFs provides a robust means for expansion of functionally mature stem cell-derived astrocytes for preclinical investigation.
Journal of Neurochemistry, 2013
Heparin-binding epidermal growth factor-like growth factor (HB-EGF), a vascular-derived trophic factor, belongs to the epidermal growth factor (EGF) family of neuroprotective, hypoxia-inducible proteins released by astrocytes in CNS injuries. It was suggested that HB-EGF can replace fetal calf serum (FCS) in astrocyte cultures. We previously demonstrated that in contrast to standard 2D cell culture systems, Bioactive3D culture system, when used with FCS, minimizes the baseline activation of astrocytes and preserves their complex morphology. Here, we show that HB-EGF induced EGF receptor (EGFR) activation by Y1068 phosphorylation, Mapk/Erk pathway activation, and led to an increase in cell proliferation, more prominent in Bioactive3D than in 2D cultures. HB-EGF changed morphology of 2D and Bioactive3D cultured astrocytes toward a radial glia-like phenotype and induced the expression of intermediate filament and progenitor cell marker protein nestin. Glial fibrillary acidic protein (GFAP) and vimentin protein expression was unaffected. RT-qPCR analysis demonstrated that HB-EGF affected the expression of Notch signaling pathway genes, implying a role for the Notch signaling in HB-EGFmediated astrocyte response. HB-EGF can be used as a FCS replacement for astrocyte expansion and in vitro experimentation both in 2D and Bioactive3D culture systems; however, caution should be exercised since it appears to induce partial de-differentiation of astrocytes.