Effects Of Remodeling Of Gliogenic Niche On Spinal Cord Injury

BACKGROUND CONTEXT: In contrast to the peripheral nervous system which shows good regrowth of neuritis after axotomy, the injured spinal cord of adult mammals has only limited ability. However, more recent observations implicate the inherent capacity for self-repair of the adult mammalian spinal cord in partial functional recovery. These studies suggest that the spared and/or regenerated spinal functions after injury may be attributed to the spontaneous formation or rearrangement of intraspinal circuits that are able to partially compensate for functional loss. In mammalian CNS, endogenous neural precursor cells (NPCs) residing in germinal niches might be instructive to spontaneous self-repair due to their ability to support neurogenesis and gliogenesis during adulthood. However, self-renewal, proliferation, differentiation and migration of these cells vary based on the territory they occupy. Correlative evidence has suggested NPCs might be present not only around the central canal, but throughout the parenchyma of intact adult spinal cord. Furthermore, recent studies have expanded our conception of the role of astrocytes in the cellular homeostasis of the nervous system, by proposing that glia might not only regulate neurogenesis and gliogenesis but also themselves be neural progenitor cells. Reactive astrocytes are a prominent feature of the cellular response to SCI. Astrocytes exhibit a gradated response to injury that includes changes in gene expression, hypertrophy and process extension. Scar tissue formed in part by reactive astrocytes has long been implicated as a major impediment to axon regeneration. Nevertheless, the basic phenomena of reactive astrocytosis after CNS injury appear conserved throughout vertebrate evolution, suggesting that fundamental aspects of the process of reactive astrocytosis convey survival advantage. Galectin-1 is the first identified member of the galectin family of carbohydrate-binding proteins that has been implicated in neural repair. Accumulating evidence indicates that galectin-l is a potential candidate molecule that contributes to neuroprotective functions and has a tight correlation with astrocytes. However, localization and functional roles of Galectin-l in the adult spinal cord, as well as reciprocal mechanisms between Galectin-l protein and reactive astrocytes, have not been clarified.PURPOSE: Given the interest in utilizing synergistic effects of Galectin-l and reactive astrocytes on functional recovery after SCI, there is considerable motivation to understand the dynamic mechanisms that regulate remodeling of reactive astrocytes and to explore influential components of altered gliogenic niche following SCI.METHODS: Here we investigated the spatio-temporal profile of endogenous Galectin-l expression by in situ hybridization before and after experimental adult spinal cord injury and examined the conelation of Galectin-l with the fate of dividing cells in vivo, using double-labeling methods. Furthermore, for detection of in vivo function of exogenous Gal-1 in response to SCI, we used recombinant Gal-1 by intrathecal injection of Gal-1. Finally, to explore further whether Gal-1 and reactive astrocytes provide a synergistic effect on neurological recovery following SCI, we investigated the differences in two behavioral evaluations, open field locomotor test and rotorod test, between wild-type (WT) and reactive astrocyte-deficient transgenic mice after injury.RESULTS: Galectin-1 mRNA was detectable at a relatively low level in uninjured spinal cord, but was markedly increased in the grey matter and/or white matter and in the ependyma rostral and caudal to the lesion site after injury. Co-localization results revealed that Galectin-1 was expressed predominantly by GFAP-positive reactive astrocytes. In addition, intrathecal infusion of recombinant Galectin-1 enhanced cell division and reactive astrocytosis in the adult spinal cord. To explore further whether Gal-1 and reactive astrocytes provide a synergistic effect on neurological recovery following SCI, we investigated the differences in behavioral analysis between wild-type (WT) and reactive astrocyte-deficient transgenic mice after injury, and found neuroprotective effects of Galectin-1 appeared to be specifically mediated through reactive astrocytes.CONCLUSIONS: This study demonstrated that Galectin-1 plays a crucial role in long-period plasticity after SCI. Our study also suggests a molecular interpretation for intraspinal spontaneous functional self-repair through the recapitulation of certain features characteristic of glial derived remodeling during developmental period. This phenomenon of synergism between Galectin-1 and reactive astrocytes opens new perspectives in the design of therapeutic strategies aimed at enhancing functional recovery following SCI.