The Extracellular Matrix Glycoprotein Tenascin-C Is Beneficial for Spinal Cord Regeneration

Abstract

Tenascin-C (TNC), a major component of the extracellular matrix, is strongly upregulated after injuries of the central nervous system (CNS) but its role in tissue repair is not understood. Both regeneration promoting and inhibiting roles of TNC have been proposed considering its abilities to both support and restrict neurite outgrowth in vitro. Here, we show that spontaneous recovery of locomotor functions after spinal cord injury is impaired in adult TNC-deficient (TNC(-/-)) mice in comparison to wild-type (TNC(+/+)) mice. The impaired recovery was associated with attenuated excitability of the plantar Hoffmann reflex (H-reflex), reduced glutamatergic input, reduced sprouting of monaminergic axons in the lumbar spinal cord and enhanced post-traumatic degeneration of corticospinal axons. The degeneration of corticospinal axons in TNC(-/-) mice was normalized to TNC(+/+) levels by application of the alternatively spliced TNC fibronectin type III homologous domain D (fnD). Finally, overexpression of TNC-fnD via adeno-associated virus in wild-type mice improved locomotor recovery, increased monaminergic axons sprouting, and reduced lesion scar volume after spinal cord injury. The functional efficacy of the viral-mediated TNC indicates a potentially useful approach for treatment of spinal cord injury.

The laser lesion of the mouse visual cortex as a model to study neural extracellular matrix remodeling during degeneration, regeneration and plasticity of the CNS

“…Thus, the strong injuryinduced increase of the expression of isoforms containing the TNfnBD or TNfnD6 domains may contribute to create an environment promoting axonal regrowth. This interpretation conforms with recent reports that Tnc retards retrograde degeneration in a spinal cord injury model, supposedly via the TNfnD-domain (Chen et al 2010;Yu et al 2011). On the other hand, Tnc deflects growth cones when presented as a sharp boundary next to conducive substrates such as laminins in a choice assay (Faissner and Kruse 1990;Götz et al 1996;Taylor et al 1993).…”

Astroglial-Derived Periostin Promotes Axonal Regeneration after Spinal Cord Injury

“…Although we did not observe a significant change in ED-1 ϩ monocyte infiltration after transplantation of POSTN knock-down GDAs BMP , it remains to be seen whether POSTN modulates the effect of tenascin-C on lymphocyte and neutrophil infiltration and neurite sprouting (Chen et al, 2010;Schreiber et al, 2013) or if POSTN is required for axonal growth in the presence of collagen (Soderblom et al, 2013). Loss of POSTN also did not appear to alter GDA BMP -transplantinduced organization of injured tissue, which may be attributable to the effect of GDNF expressed by GDAs BMP (Deng et al, 2011).…”

The extracellular matrix molecule tenascin C modulates expression levels and territories of key patterning genes during spinal cord astrocyte specification

“…Tnc becomes upregulated upon spinal cord lesion by reactive astrocytes and influences the regenerative capacity of the damaged tissue (Camand et al, 2004;Chen et al, 2010;Dobbertin et al, 2010). However, the functions of Tnc during spinal cord development so far remained elusive.…”

“…During CNS development Tnc is transiently expressed in the brain by radial glia cells (Gotz et al, 1998;Stoykova et al, 1997;von Holst et al, 2007). In the adult CNS, Tnc remains expressed by neurogenic subventricular zone astrocytes, but becomes strongly upregulated upon CNS lesions by reactive astrocytes, and it appears to affect the glial acidic fibrillary protein (GFAP) expression levels (Brodkey et al, 1995;Camand et al, 2004;Chen et al, 2010;Kazanis et al, 2007;Laywell et al, 1992;Robel et al, 2011;Robel et al, 2009;Steindler et al, 1995).…”