Interferon-β Delivery via Human Neural Stem Cell Abates Glial Scar Formation in Spinal Cord Injury

Abstract

Glial scar formation is the major impedance to axonal regrowth after spinal cord injury (SCI), and scar-modulating treatments have become a leading therapeutic goal for SCI treatment. In this study, human neural stem cells (NSCs) encoding interferon-β (INF-β) gene were administered intravenously to mice 1 week after SCI. Animals receiving NSCs encoding IFN-β exhibited significant neurobehavioral improvement, electrophysiological recovery, suppressed glial scar formation, and preservation of nerve fibers in lesioned spinal cord. Systemic evaluation of SCI gliosis lesion site with lesion-specific microdissection, genome-wide microarray, and MetaCore pathway analysis identified upregulation of toll-like receptor 4 (TLR4) in SCI gliosis lesion site, and this led us to focus on TLR4 signaling in reactive astrocytes. Examination of primary astrocytes from TLR4 knockout mice, and in vivo inhibition of TLR4, revealed that the effect of IFN-β on the suppression of glial scar formation in SCI requires TLR4 stimulation. These results suggest that IFN-β delivery via intravenous injection of NSCs following SCI inhibits glial scar formation in spinal cord through stimulation of TLR4 signaling.

TLR3 ligand Poly IC Attenuates Reactive Astrogliosis and Improves Recovery of Rats after Focal Cerebral Ischemia

“…It has shown neuroprotective effects that are associated with reduced pro-inflammatory cytokine expression and increased anti-inflammatory cytokine expression in sites of injury. Recently, it was reported that IFN-b gene delivery suppresses astrocyte activation and glial scar formation after spinal cord injury [45,46]. In contrast to IFN-b, IL-6 is thought to contribute to astrogliosis in response to brain injuries [34,35].…”

“…TLR3 activation can modulate the TLR4/NF-kB signaling pathway and thus may inhibit generation of proinflammatory cytokines such as TNF-a and IL-6 [6,13,19,48]. Studies in experimental spinal cord injury models showed that TLR4 expression is increased in the gliosis lesion site and that TLR4 mutant mice exhibit sustained locomotor deficits and increased demyelination, astrogliosis, and macrophage activation [45,49]. In addition, it was suggested that TLR4 signaling in the spinal cord is required for exogenous IFN-b to suppress glial scar formation [45,49].…”

“…Studies in experimental spinal cord injury models showed that TLR4 expression is increased in the gliosis lesion site and that TLR4 mutant mice exhibit sustained locomotor deficits and increased demyelination, astrogliosis, and macrophage activation [45,49]. In addition, it was suggested that TLR4 signaling in the spinal cord is required for exogenous IFN-b to suppress glial scar formation [45,49]. These data suggest that TLR4 is important for regulating gliosis as well as inflammatory processes after CNS injury.…”

Stem cell therapy for central nerve system injuries: glial cells hold the key

“…In vivo treatment with peptide amphiphile could reduce glial scar formation, increase the number of oligodendroglia at the site of spinal cord injury and resulted in significant behavioral improvements (Tysseling-Mattiace et al, 2008). IFN-β-encoding could help transplanted NSCs to inhibit glial scar formation in spinal cord injury through the stimulation of TLR4 signaling (Nishimura et al, 2013). However, as we described before, glial scar can offer wound healing, limits the inflammation and protects the healthy tissue.…”

Blockade of Gap Junction Hemichannel Protects Secondary Spinal Cord Injury from Activated Microglia-Mediated Glutamate Exitoneurotoxicity

“…This was accomplished using a liposome-mediated interferon (IFN)-b gene delivery method, or by IFN-b delivery with intravenous injection of genetically engineered neural stem cells. 38,39 Inhibition of glial scar formation is a potential strategy for treating SCI. Whether reactive astrocytes are beneficial is still controversial.…”