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Hidenori Horie

Publications and source records attributed to Hidenori Horie.

At least 19 recordsLinked to original sources
PubMed2006

A carbohydrate-binding protein, Galectin-1, promotes proliferation of adult neural stem cells.

In the subventricular zone of the adult mammalian forebrain, neural stem cells (NSCs) reside and proliferate to generate young neurons. We screened factors that promoted the proliferation of NSCs in vitro by a recently developed proteomics technique, the ProteinChip system. In this screen, we identified a soluble carbohydrate-binding protein, Galectin-1, as a candidate. We show herein that Galectin-1 is expressed in a subset of slowly dividing subventricular zone astrocytes, which includes the NSCs. Based on results from intraventricular infusion experiments and phenotypic analyses of knockout mice, we demonstrate that Galectin-1 is an endogenous factor that promotes the proliferation of NSCs in the adult brain.

Animals↗
PubMed2005

Intravitreal macrophage activation enables cat retinal ganglion cells to regenerate injured axons into the mature optic nerve.

In mature mammals, retinal ganglion cells (RGCs) are generally unable to regenerate injured axons into the optic nerve. Here, we report that an intravitreal injection of either of two macrophage activators, oxidized galectin-1 or zymosan, strongly enhanced the regeneration of transected RGC axons beyond an optic nerve crush site in adult cats. Using WGA-HRP as an anterograde tracer, we found that injection of either macrophage activator caused many axons to grow into the distal optic nerve when evaluated 14 days later, with the strongest effects seen after injecting 100 ng of galectin-1. Elongation continued for at least another 2 weeks. Control eyes injected with saline contained very few labeled axons extending across the crush site. Elevation of intracellular cAMP levels using forskolin also enhanced regeneration beyond the crush site to some extent, but this treatment did not augment the effect of galectin-1 any further. These results indicate that RGCs of adult cats are capable of reverting to an active growth state and at least partially overcoming an inhibitory CNS environment as a result of intravitreal macrophage activation.

Animals↗
PubMed2005

Oxidized galectin-1 advances the functional recovery after peripheral nerve injury.

Oxidized galectin-1 has been shown to promote axonal regeneration from transected-nerve sites in an in vitro dorsal root ganglion (DRG) explant model as well as in in vivo peripheral nerve axotomy models. The present study provides evidence that oxidized galectin-1 advances the restoration of nerve function after peripheral nerve injury. The sciatic nerve of adult rats was transected and the distal nerve was frozen after being sutured into a proximal site with four epineurial stitches. An osmotic pump delivered oxidized galectin-1 peripherally to the surgical site. Functional recovery was assessed by measurement of the degree of toe spread of the hind paw for 3 months after the sciatic nerve lesion. The recovery curves of toe spread in the test group showed a statistically significant improvement of functional recovery after day 21 by the application of oxidized recombinant human galectin-1 (rhGAL-1/Ox) compared to the control group. This functional recovery was supported by histological analysis performed by light microscopic examination. The regenerating myelinated fibers at the site 21 mm distal to the nerve-transected site were quantitatively examined at 100 days after the operation. The frequency distribution of myelinated fiber diameters showed that exogenous rhGAL-1/Ox increased the number and diameter of regenerating myelinated fibers; the number of medium-sized (6-11 microm in diameter) fibers increased significantly (P<0.05). These results indicate that oxidized galectin-1 promotes the restoration of nerve function after peripheral nerve injury. Thus, rhGAL-1/Ox may be a factor for functional restoration of injured peripheral nerves.

Animals↗
PubMed2005

Impaired neurite outgrowth in the retina of a murine model of Sandhoff disease.

PURPOSE: To investigate the effects of lysosomal storage on the morphologic appearance and the neurite outgrowth capability of the retina in a mouse model of G(M2) gangliosidosis (Sandhoff disease). METHODS: Histopathologic appearances of retinas in Sandhoff (SD) mice at 3 and 4 months of age were examined by light and electron microscopy. Retinas of SD mice and wild-type (WT) mice at 1, 2, and 4 months of age were cultured in collagen gel in the presence or absence of brain-derived neurotrophic factor (BDNF), and neurite outgrowth was examined. RESULTS: Morphologic studies revealed accumulation of G(M2) ganglioside in the retinal ganglion cells of SD mice in a time-dependent manner. The number of neurites from the retinal explants after 7 and 10 days in culture were significantly lower in 2- and 4-month-old SD mice than in the age-matched WT mice. The application of BDNF significantly improved neurite outgrowth from the retina in both SD and WT mice at 2 months of age. At 4 months of age, BDNF was much less effective at stimulating neurite outgrowth in the retina of SD mice than in retina of WT mice. CONCLUSIONS: These results indicate that lysosomal storage of G(M2) ganglioside impairs the capability of neurite outgrowth in retinal ganglion cells in culture and that BDNF is effective at diminishing this impairment during the early stage of the disease.

Animals↗
PubMed2005

Oxidized galectin-1 is an essential factor for peripheral nerve regeneration.

Although many factors have been implicated in the regenerative response of peripheral axons to nerve injury, the signals that prompt neurons to extend processes in peripheral nerves after axotomy are not well-understood. As shown in the first chapter, oxidized recombinant human galectin-1 (rhGAL-1/Ox), which lacks lectin activity, promotes initial axonal growth in an in vitro peripheral nerve regeneration model at low concentrations (pg/ml). At a similarly low concentration, rhGAL-1/Ox has also been shown to be effective in enhancing axonal regeneration using in vivo experiments. Moreover, the application of functional anti-rhGAL-1 antibody strongly inhibited axonal regeneration in vivo as well as in vitro. Since galectin-1 (GAL-1) is expressed in the regenerating sciatic nerves as well as in both sensory and motoneurons, these results indicate that GAL-1, which is secreted into the extracellular space, is subsequently oxidized and then may regulate initial repair after axotomy. This possibility was confirmed by Western blot analysis, which revealed that both reduced and oxidized forms of GAL-1 are present in culture media of DRG neurons and immortalized adult mouse Schwann cells (IMS32). Externalized GAL-1/Ox has been found to stimulate macrophages to secrete an axonal regeneration-promoting factor. From these results, we propose that axonal regeneration occurs in axotomized peripheral nerves as a result of cytosolic reduced GAL-1 being released from Schwann cells and injured axons, which then becomes oxidized in the extracellular space. GAL-1/Ox in the extracellular space stimulates macrophages to secrete a factor that promotes axonal growth and Schwann cell migration, thus enhancing peripheral nerve regeneration and functional recovery. These results suggest that rhGAL-1/Ox may be a novel factor for functional restoration of injured peripheral nerves.

Animals↗
PubMed2005

Regulation of the neuronal fate by DeltaFosB and its downstream target, galectin-1.

In mammals, the regulation of the cell fate to either proliferate, differentiate, arrest cell growth, or initiate programmed cell death is the most fundamental mechanism for maintaining normal cell function and tissue homeostasis. Under multiple signaling pathways, Jun and Fos family proteins are known to play important roles as components of an AP-1 (activator protein-1) complex, to regulate the transcription of various genes involved in cell proliferation, differentiation and programmed cell death. DeltaFosB, one of the AP-1 subunits encoded by alternatively spliced fosB mRNA, triggers one round of proliferation in quiescent rat embryo cell lines, followed by a different cell fate such as morphological alteration or delayed cell death. As one of the downstream targets of the DeltaFosB in rat3Y1 cell line, we identified rat galectin-1 and its novel variant, galectin-1beta, and demonstrated that the expression of galectin-1 is required for the proliferative activation of quiescent rat1A cells by DeltaFosB, thus indicating that galectin-1 is one of functional targets of DeltaFosB. The expression of DeltaFosB is highly inducible in the adult brain in response to various insults such as ischemic reperfusion injury, seizure induced by electric stimulation or cocaine administration. On the other hand, galectin-1 has also been shown to be involved in the regeneration of damaged axons in the peripheral nerve, as well as in neurite outgrowth or synaptic connectivity in the olfactory system during development. We herein propose that DeltaFosB together with galectin-1, may therefore mediate neuroprotection and neurogenesis in response to brain damage.

Animals↗
PubMed2005

Structural and functional studies of galectin-1: a novel axonal regeneration-promoting activity for oxidized galectin-1.

Recently, we discovered oxidized galectin-1 as a factor that regulates initial axonal growth in the peripheral nerve after axotomy. Galectin-1 is a member of the galectins, a family of animal lectins ranging from Caenorhabditis elegans to humans, which is defined by their affinity for beta-galactosides and by significant sequence similarity in the carbohydrate-binding site. Galectin-1 is a homodimer with a subunit molecular mass of 14.5 kDa, which contains six cysteine residues per subunit. The cysteine residues should be in a free state in order to maintain a molecular structure that is capable of showing lectin activity. However, our structural analysis revealed that the axonal regeneration-promoting factor exists as an oxidized form of galectin-1, containing three intramolecular disulfide bonds. The oxidized galectin-1 exhibited marked peripheral nerve regeneration-promoting activity, although it showed no lectin activity. It was also revealed that oxidized galectin-1 exists as a monomer in a physiological solution. Galectin-1 seems to have a variety of biological functions. These functions could vary according to the time at which a biological function is taking place, as well as the site in which a biological function is taking place. In addition, these functions could vary according to the structure of galectin-1 by which a particular biological function is taking place. Disulfide bond formation alters the structure of galectin-1, so as to confer the novel ability to promote axonal regeneration. Oxidized galectin-1 likely acts as an autocrine or paracrine factor to promote axonal regeneration, functioning more like a cytokine than as a lectin.

Amino Acid Sequence↗
PubMed2004

Long-term induction of beta-CGRP mRNA in rat lungs by allergic inflammation.

Calcitonin gene-related peptide (CGRP) is one of the major neuropeptides released from sensory nerve endings and neuroendocrine cells of the lung. Two CGRP isoforms, alpha-and beta-CGRP, have been identified in rats and humans, but no studies have attempted to reveal direct evidence of differences in action or location of these isoforms in allergic inflammation (AI). We investigated mRNA expressions of alpha-and beta-CGRP in lungs, nodose ganglia (NG), and dorsal root ganglia (DRG) of an animal model for AI of the airways, utilizing a model created by sensitizing Brown Norway (BN) rats with ovalbumin (OVA). By semiquantitative RT-PCR analysis, long-lasting enhanced expression of the beta-CGRP mRNA was shown in the lungs of the AI rats (14.5-fold enhancement at 6 hr, 8.1-fold at 24 hr, and 3.7-fold at 120 hr after OVA-challenge compared to the level in the lungs of phosphate-buffered saline (PBS)-challenged control rats). In contrast, the mRNA expression of the alpha-CGRP in AI lungs showed only a transient increase after OVA-challenge (2.7-fold at 6 hr) followed by a lower level of expression (0.5-fold at 48 hr and 0.6-fold at 120 hr). The mRNA expressions of both isoforms in NG, but not in DRG, were transiently up-regulated at 6 hr after antigen challenge. In situ RT-PCR in combination with immunohistochemical analysis revealed that beta-CGRP was expressed in neuroendocrine cells in clusters (termed neuroepithelial bodies [NEBs]) in AI lungs. These results indicate that the long-term induction of beta-CGRP in NEBs may play an important role in pulmonary AI such as bronchial asthma.

Allergens↗
PubMed2004

Oxidized galectin-1 stimulates macrophages to promote axonal regeneration in peripheral nerves after axotomy.

Various neurotrophic factors that promote axonal regeneration have been investigated in vivo, but the signals that prompt neurons to send out processes in peripheral nerves after axotomy are not well understood. Previously, we have shown oxidized galectin-1 (GAL-1/Ox) promotes initial axonal growth after axotomy in peripheral nerves. However, the mechanism by which GAL-1/Ox promotes axonal regeneration remains unclear and is the subject of the present study. To identify possible target cells of GAL-1/Ox, a fluorescently labeled recombinant human GAL-1/Ox (rhGAL-1/Ox) was incubated with DRG neurons, Schwann cells, and intraperitoneal macrophages from adult rats. Only the cell surfaces of intraperitoneal macrophages bound the rhGAL-1/Ox, suggesting that these cells possess a receptor for GAL-1/Ox. Experiments examining tyrosine phosphorylation revealed that rhGAL-1/Ox stimulated changes in signal transduction pathways in these macrophages. These changes caused macrophages to secrete an axonal growth-promoting factor. This was demonstrated when conditioned media of macrophages stimulated with rhGAL-1/Ox in 48 hr culture strongly enhanced axonal regeneration from transected-nerve sites of DRG explants. Furthermore, activated macrophage-conditioned media also improved Schwann cell migration from the transected-nerve sites. From these results, we propose that axonal regeneration occurs in axotomized peripheral nerves as a result of cytosolic reduced galectin-1 being released from Schwann cells and injured axons, which then becomes oxidized in the extracellular space. Oxidized galectin-1 then stimulates macrophages to secrete a factor that promotes axonal growth and Schwann cell migration, thus enhancing peripheral nerve regeneration.

Animals↗
PubMed2004

Synthesis, localization and externalization of galectin-1 in mature dorsal root ganglion neurons and Schwann cells.

We recently confirmed that oxidized galectin-1 is a novel factor enhancing axonal growth in peripheral nerves after axotomy, but the process of extracellular release and oxidization of endogenous galectin-1 in the injured nervous tissue remains unknown. In the present study, we examined the distribution of galectin-1 in adult rat dorsal root ganglia (DRG) in vivo and in vitro. By RT-PCR analysis and in situ hybridization histochemistry, galectin-1 mRNA was detected in both DRG neurons and non-neuronal cells. Immunohistochemical analyses revealed that galectin-1 was distributed diffusely throughout the cytoplasm in smaller diameter neurons and Schwann cells in DRG sections. In contrast, the immunoreactivity for galectin-1 was detected in almost all DRG neurons from an early stage in culture (3 h after seeding) and was restricted to the surface and/or extracellular region of neurons and Schwann cells at later stages in culture. In a manner similar to the primary cultured cells, we also observed the surface and extracellular expression of this molecule in immortalized adult mouse Schwann cells (IMS32). Western blot analysis has revealed that both reduced and oxidized forms of galectin-1 were detected in culture media of DRG neurons and IMS32. These findings suggest that galectin-1 is externalized from DRG neurons and Schwann cells upon axonal injury. Some of the molecules in the extracellular milieu may be converted to the oxidized form, which lacks lectin activity but could act on neural tissue as a cytokine.

Animals↗
PubMed2003

Galectin-1 is involved in the potentiation of neuropathic pain in the dorsal horn.

Galectin-1 is one of the endogenous-galactoside-binding lectins, suggested to be involved in a variety of functions, such as neurite outgrowth, synaptic connectivity, cell proliferation and apoptosis. This protein is expressed in the dorsal root ganglion (DRG) and the spinal cord in the developing and adult rats, especially intensely in small DRG neurons. In the present study, we examined whether galectin-1 is colocalized with TrkA or c-Ret mRNA in small DRG neurons and the effect of axotomy on the expression of galectin-1 in the spinal cord. About 20% of the DRG neurons showed intense galectin-1-immunoreactivity (IR). Of the intensely galectin-1-IR DRG neurons, 93.9% displayed c-Ret mRNA positive signals. On the other hand, only 6.8% displayed TrkA mRNA positive signals. Galectin-1-IR was increased in the dorsal horn at 1 to 2 weeks after axotomy. Intrathecal administration of anti-recombinant human galectin-1 antibody (anti-rhGAL-1 Ab) partially but significantly attenuated the upregulation of substance P receptor (SPR) in the spinal dorsal horn and the mechanical hypersensitivity induced by the peripheral nerve injury. These data suggest that endogenous galectin-1 may potentiate neuropathic pain after the peripheral nerve injury at least partly by increasing SPR in the dorsal horn.

Animals↗
PubMed2003

Oxidized galectin-1 stimulates the migration of Schwann cells from both proximal and distal stumps of transected nerves and promotes axonal regeneration after peripheral nerve injury.

Oxidized galectin-1 has recently been identified as a key factor that plays important roles in initial axonal growth in injured peripheral nerves. The aim of this study was to investigate the effects of oxidized galectin-1 on regeneration of rat spinal nerves using acellular autografts (containing no viable cells) and allografts (containing no cell membranes) with special attention to the relationship between axonal regeneration and Schwann cell migration. Immunohistochemically, endogenous galectin-1 was expressed in dorsal root ganglion (DRG) neurons, spinal cord motoneurons, and axons and Schwann cells in normal sciatic nerves. Administration of oxidized recombinant human galectin-1 (rh-gal-lox, 5 ng/ml) in autograft model promoted axonal regeneration from motoneurons as well as from DRG neurons; this was confirmed by a fluorogold tracer study (p < 0.05). Anti-rh-gal-1 antibody (30 microg/ml) strongly inhibited axonal regrowth (p < 0.05). Pretreatment of allografts with rh-gal-lox stimulated the migration of Schwann cells not only from proximal stumps but also from distal stumps into the grafts, resulting in accelerated axonal regeneration (p < 0.05). Moreover, Schwann cell migration preceded the axonal growth in the presence of exogenous rh-gal-lox in the grafts. These results strongly suggest that local administration of exogenous rh-gal-lox promotes the migration of Schwann cells followed by axonal regeneration from both motor and sensory neurons, resulting in acceleration of neuronal repair. This technique may also be of value in the repair of human nerves.

Animals↗
PubMed2002

Diabetes is not a potent inducer of neuronal cell death in mouse sensory ganglia, but it enhances neurite regeneration in vitro.

We examined the effects of diabetes on the morphological features and regenerative capabilities of adult mouse nodose ganglia (NG) and dorsal root ganglia (DRG). By light and electron microscopy, no apoptotic cell death was detected in the ganglia obtained from either streptozotocin (STZ)-induced diabetic or normal C57BL/6J mice in vivo. Neurite regeneration from transected nerve terminals of NG and DRG explants in culture at normal (10 mM) and high (30 mM) glucose concentrations was significantly enhanced in the diabetic mice. Chromatolytic changes (i.e. swelling and migration of the nucleus to an eccentric position in the neurons, and a loss of Nissl substance in the neuronal perikarya) and apoptotic cell death (less than one-fifth of the neurons) in the cultured ganglia were present, but neither hyperglycemia in vivo nor high glucose conditions in vitro altered the morphological features of the ganglia or the ratios of apoptotic cells at 3 days in culture. By semiquantitative RT-PCR analysis, the mRNA expressions of ciliary neurotrophic factor (CNTF) in DRG from both mice were down-regulated at 1 day in culture. The expression in diabetic DRG, but not in control DRG, was significantly up-regulated at later stages (3 and 7 days) in culture. In summary, hyperglycemia is unlikely to induce cell death in the sensory ganglia, but enhances the regenerative capability of vagal and spinal sensory nerves in vitro. The up-regulation of CNTF mRNA expression during the culture of diabetic DRG may play a role in the enhanced neurite regeneration.

Animals↗
PubMed2002

Trachea enhances neurite regeneration from adult rat nodose ganglia in vitro.

Trachea is intensely innervated with vagal afferent nerve fibers, and may play an important role in vagus nerve regeneration after axonal injury caused by trauma and surgical operation. We investigated the effects of tracheal tissue on neuronal cell survival and neurite regeneration in adult rat nodose ganglia (NG) in vitro. Co-culture with trachea significantly increased the average number of neurites regenerated from transected nerve terminals of NG explants, from 73.7 to 154.2 after 3 days, from 68 to 186.7 after 5 days, and from 31 to 101.5 after 7 days in culture. Dissociated NG neurons could continue to survive and extend neurites only in the co-existence with satellite cells in collagen gel. Co-cultured trachea improved the ratios of survival and neurite-bearing cells of NG neurons, from 56.7% and 11.1% to 72.3% and 37.6% after 4 days, and from 41.1% and 20.3% to 56.4% and 47.2% after 7 days in culture, respectively. These results imply that tracheal tissue secretes a factor, which could enhance neuronal cell survival and neurite regeneration in NG in the presence of satellite cells in vitro.

Animals↗
PubMed2002

Brain-derived neurotrophic factor enhances neurite regeneration from retinal ganglion cells in aged human retina in vitro.

To investigate the capability of neurite regeneration from retinal ganglion cells (RGCs) in an adult human retina and to evaluate the effect of neurotrophin on the neurite regeneration, an in vitro model for retinal explants was developed. A human retina was obtained from a 70 year old patient with retrobulbar carcinoma. The retina was excised and the retinal explants were cultured in serum-free medium with or without brain-derived neurotrophic factor. The capability of neurite regeneration was evaluated by counting the numbers of outgrowing neurites outside the retinal explants. In culture without brain-derived neurotrophic factor (control), there was no neurite outgrowth from the retinal explants after 2 days. And at 3 days in culture, a small number of outgrowing neurites were first observed outside the retinal explants. In contrast, within 24 hr in culture with brain-derived neurotrophic factor, there were a considerable number of elongating neurites with spread growth cones from the retinal explants. Immunohistochemical analysis revealed that these neurites were derived from RGCs. The addition of brain-derived neurotrophic factor increased the number of outgrowing neurites approximately 10-fold compared to that of the control at 3 days in culture. The enhancement of neurite regeneration induced by brain-derived neurotrophic factor continued for longer than 1 week in culture. In conclusion, an aged human retina can regenerate neurites from RGCs in vitro and brain-derived neurotrophic factor significantly promotes the regeneration.

Aged↗
PubMed2002

Galectin-1 plays essential roles in adult mammalian nervous tissues. Roles of oxidized galectin-1.

Previous data have suggested that galectin-1 is expressed widely in nervous tissues at embryonic stages but becomes restricted mainly to peripheral nervous tissues with maturation. Though the expression is intense in adult mammalian peripheral neurons, there had been no report about functions of galectin-1 there. Recently we discovered a factor that enhanced peripheral axonal regeneration. The factor was identified as oxidized galectin-1 with three intramolecular disulfide bonds and showed no lectin activity. Oxidized recombinant human galectin-1 (rhGAL-1/Ox) showed the same nerve growth promoting activity at very low concentrations (pg/ml). rhGAL-1/Ox at similarly low concentration was also effective in in vivo experiments of axonal regeneration. Moreover, the application of functional anti-rhGAL-1 antibody strongly inhibited the axonal regeneration in vivo as well as in vitro. Since galectin-1 is expressed in the regenerating sciatic nerves as well as in both sensory neurons and motor neurons, these results suggest that galectin-1 is secreted into the extracellular space to be oxidized, and then, in its oxidized form, to regulate initial repair after axotomy. The administration of oxidized galectin-1 effectively promoted functional recovery after sciatic nerve injury in vivo. Oxidized galectin-1, hence, appears to play an important role in promoting axonal regeneration, working as a kind of cytokine, not as a lectin. Recent reports indicated additional roles of cytosolic galectin-1 in neural diseases, such as ALS. Furthermore galectin-1 has been proved to be a downstream target of DeltaFosB. In hippocampus of rat brain, expression of DeltaFosB is induced immediately after ischemia-reperfusion, suggesting that galectin-1 may also play important roles in central nervous system after injury.

Animals↗
PubMed2002

FosB gene products trigger cell proliferation and morphological alteration with an increased expression of a novel processed form of galectin-1 in the rat 3Y1 embryo cell line.

In this study, we established rat 3Y1 embryo cell lines expressing FosB and DeltaFosB as fusion proteins (ER-FosB, ER-DeltaFosB) with the ligand-binding domain of human estrogen receptor (ER). The binding of estrogen to the fusion proteins resulted in their nuclear translocation. After estrogen administration, exponentially growing cells expressing ER-DeltaFosB, and to a lesser extent ER-FosB, underwent morphological alteration from the flat fibroblastic shape to an extended bipolar shape, and ceased proliferating. Such morphological alteration was also induced in quiescent cells expressing ER-DeltaFosB and ER-FosB after one round of cell division triggered by estrogen administration. The cells expressing ER-DeltaFosB changed shape frequently, and the content of F-actin in the cytoplasm detected by binding of Alexa 488-phalloidin significantly decreased after the morphological alteration. By two-dimensional gel electrophoresis analysis of cellular proteins from the cells expressing ER-DeltaFosB, we identified several proteins whose expression either increased or decreased after estrogen administration. Two of these proteins were identified from their amino acid sequences as novel processed form of galectin-1.

Actins↗