Intralesion Injection of Basic Fibroblast Growth Factor Alters Glial Reactivity to Neural Trauma

Menon, V. K.; Landerholm, Thomas E.

doi:10.1006/exnr.1994.1155

Cited by 31 publications

(19 citation statements)

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“…2A. The majority of these cells were likely invading macrophages and resident microglia (10,28,29); this conclusion was consistent with the labeling results described below. Astrocytes in the area of the lesion were detected by S100 and GFAP antibody staining.…”

Section: Resultssupporting

confidence: 87%

“…bFGF is a potent mitogen for astrocytes in vitro (21,31), and after a lesion in vivo, production of bFGF and its receptor is dramatically upregulated in glia (12). However, other studies showed little or no increase in the number of dividing astrocytes in response to a single infusion of bFGF in vivo in the adult rat (29). To confirm this and to determine whether the addition of bFGF could counteract the ability of N-CAM to inhibit astrocyte division, we added the growth factor with and without N-CAM.…”

Section: Resultsmentioning

confidence: 99%

“…4A), suggesting increased recruitment or cell division. These cells were likely blood-borne macrophages or resident microglia (10,28,29 Data are presented as mean ± SEM (n = 3 for each condition). All comparisons of the labeling indices between the N-CAM or N-CAM-related molecules and the random peptide within each brain region were found to be significant (P < 0.05; paired sample Student's t test).…”

Section: Resultsmentioning

confidence: 99%

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Neural cell adhesion molecule (N-CAM) inhibits astrocyte proliferation after injury to different regions of the adult rat brain.

Krushel

Sporns

Cunningham

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

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N-CAM or one of the N-CAM-related molecules was infused than on the opposite side. The inhibition was greatest in the cortical lesion sites ('50%) and was less pronounced in the hippocampus (-25%) and striatum ("20%). Two weeks after the lesion, the cerebral cortical sites infused with N-CAM continued to exhibit a significantly smaller population of dividing astrocytes than the sites on the opposite side. When N-CAM and basic fibroblast growth factor, which is known to stimulate astrocyte division in vitro, were coinfused into cortical lesion sites, astrocyte proliferation was still inhibited. These results suggest the hypothesis that, by reducing glial proliferation, N-CAM or its peptides may help create an environment that is more suitable for neuronal regeneration.

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Section: Resultssupporting

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Neural cell adhesion molecule (N-CAM) inhibits astrocyte proliferation after injury to different regions of the adult rat brain.

Krushel

Sporns

Cunningham

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

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“…The nature of the experimental approaches previously used to study the damage response in vivo, which, in most cases, have not been manipulations that target a specific cell type but affect the response as a whole, have made it difficult to tease apart functionally relevant cell-cell interactions. A good example of this is the infusion of FGF2 into the sites of injury, which led to the hypothesis that FGFs promote astrogliosis (13)(14)(15). Here, by specifically targeting astrocytes in the adult, we demonstrate that the FGF pathway directly inhibits the activation of protoplasmic astrocytes in the normal brain and after traumatic injury.…”

Section: Discussionmentioning

confidence: 82%

“…11, 12) and based on increased proliferation and GFAP expression upon injections of high concentrations of FGF2 in different brain areas (e.g., refs. [13][14][15]. However, the role FGF signaling may play in directly regulating astrocyte activation in these experiments is difficult to interpret given the high concentrations of exogenous ligand that was administered and the potential for indirect effects through other cell types affected by FGFs.…”

Section: Significancementioning

confidence: 99%

Astrocyte activation is suppressed in both normal and injured brain by FGF signaling

Kang

Balordi

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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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 gainof-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 activation of astrocytes in the normal and injured neocortex is not only regulated by proinflammatory factors, but also by factors such as FGFs that suppress activation, providing alternative therapeutic targets.brain damage | astrogliosis A strocytes are the most abundant cell type in the mammalian brain. The thin processes of protoplasmic astrocytes (graymatter astrocytes) canvas the neural parenchyma and make contact with several other cell types. Protoplasmic astrocytes carry out a variety of functions, including maintaining the bloodbrain barrier, ion homeostasis, neurotransmitter turnover, and synapse formation (1). Another major function of these astrocytes involves their activation in response to damage. Astrocyte activation, or astrogliosis, plays a central role in the response to most or all neurological insults including trauma, infections, stroke, tumorigenesis, neurodegeneration, and epilepsy. The extent of astrogliosis can influence long-term recovery, and the response of astrocytes to different insults is likely to be graded and complex (2, 3). Nevertheless, in most cases, astrocytes transiently become hypertrophic and express high levels of intermediate filaments such as GFAP, vimentin, tenascin C, and nestin, and, in cases of severe damage, astrocytes can also become proliferative and form a scar.Astrogliosis can have beneficial and detrimental effects on recovery. Astrogliosis is essential for minimizing the spread of damage and inflammation, but it is also inhibitory for axonal and cellular regeneration. For example, in transgenic mice in which reactive astrocytes are ablated or disabled, traumatic injury leads to the lack of normal scar formation, prolonged and more widespread inflammation, and a failure to reconstruct the bloodbrain barrier and maintain tissue integrity (4, 5). However, ablation or impairment of reactive astrocytes also leads to increased nerve fiber growth in the immediate vicinity of the injury site, which could improve axonal regeneration and functional recovery (4, 5). Therefore, levels of astrocy...

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Influence of IN-1 antibody and acidic FGF-fibrin glue on the response of injured corticospinal tract axons to human Schwann cell grafts

et al. 1997

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Two strategies have been shown by others to improve CST regeneration following thoracic spinal cord injury: 1) the administration of a monoclonal antibody, IN-1, raised against a myelin-associated, neurite growth inhibitory protein, and 2) the delivery of acidic fibroblast growth factor (aFGF) in fibrin glue in association with peripheral nerve grafts. Because autologous transplantation of human Schwann cells (SCs) is a potential strategy for CNS repair, we evaluated the ability of these two molecular agents to induce CST regeneration into human SC grafts placed to span a midthoracic spinal cord transection in the adult nude rat, a xenograft tolerant strain. IN-1 or control (HRP) antibodies were delivered to the injury/graft region by encapsulated hybridoma cells ("IN-1 ravioli") or daily infusion of hybridoma culture supernatant; aFGF-fibrin glue was placed in the same region in other animals. Anterograde tracing from the motor cortex using the dextran amine tracers, Fluororuby (FR) and biotinylated dextran amine (BDA), was performed. Thirty-five days after grafting, the CST response was evaluated qualitatively by looking for regenerated CST fibers in or beyond grafts and quantitatively by constructing camera lucida composites to determine the sprouting index (SI), the position of the maximum termination density (MTD) rostral to the GFAP-defined host/graft interface, and the longitudinal spread (LS) of bulbous end terminals. The latter two measures provided information about axonal die-back. In control animals (graft only), the CST did not enter the SC graft and underwent axonal die-back [SI = 1.4 +/- 0.1, MTD = 2.0 +/- 0.2, LS = 1.3 +/- 0.3, (n = 3)]. Results of IN-1 delivery from ravioli did not differ from controls, but injections of IN-1-containing supernatant resulted in a significant degree of sprouting but did not prevent axonal die-back [SI = 1.9 +/- 0.1, MTD = 1.5 +/- 0.2, LS = 1.1 +/- 0.1, (n = 7)] and traced fibers did not enter grafts. Acidic FGF dramatically reduced axonal die-back and caused sprouting [SI = 2.0 +/- 0.1 (n = 5), MTD = 0.5 +/- 0.04 (n = 6), LS = 0.4 +/- 0.1 (n = 6)]. Some traced fibers entered SC grafts and in 2/6 cases entered the distal interface. We conclude that 1) human SC grafts alone do not support the regeneration of injured CST fibers and do not prevent die-back, 2) grafts plus IN-1 antibody-containing supernatant support some sprouting but die-back continues, and 3) grafts plus aFGF-fibrin glue support regeneration of some fibers into the grafts and reduce die-back.

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Intralesion Injection of Basic Fibroblast Growth Factor Alters Glial Reactivity to Neural Trauma

Cited by 31 publications

References 0 publications

Neural cell adhesion molecule (N-CAM) inhibits astrocyte proliferation after injury to different regions of the adult rat brain.

Neural cell adhesion molecule (N-CAM) inhibits astrocyte proliferation after injury to different regions of the adult rat brain.

Astrocyte activation is suppressed in both normal and injured brain by FGF signaling

Influence of IN-1 antibody and acidic FGF-fibrin glue on the response of injured corticospinal tract axons to human Schwann cell grafts

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