Transplantation of neural precursors generated from spinal progenitor cells reduces inflammation in spinal cord injury via NF-κB pathway inhibition

Abstract

BackgroundTraumatic spinal cord injury (SCI) triggers a chain of events that is accompanied by an inflammatory reaction leading to necrotic cell death at the core of the injury site, which is restricted by astrogliosis and apoptotic cell death in the surrounding areas. Activation of nuclear factor-κB (NF-κB) signaling pathway has been shown to be associated with inflammatory response induced by SCI. Here, we elucidate the pattern of activation of NF-κB in the pathology of SCI in rats and investigate the effect of transplantation of spinal neural precursors (SPC-01) on its activity and related astrogliosis.MethodsUsing a rat compression model of SCI, we transplanted SPC-01 cells or injected saline into the lesion 7 days after SCI induction. Paraffin-embedded sections were used to assess p65 NF-κB nuclear translocation at days 1, 3, 7, 10, 14, and 28 and to determine levels of glial scaring, white and gray matter preservation, and cavity size at day 28 after SCI. Additionally, levels of p65 phosphorylated at Serine536 were determined 10, 14, and 28 days after SCI as well as levels of locally secreted TNF-α.ResultsWe determined a bimodal activation pattern of canonical p65 NF-κB signaling pathway in the pathology of SCI with peaks at 3 and 28 days after injury induction. Transplantation of SCI-01 cells resulted in significant downregulation of TNF-α production at 10 and 14 days after SCI and in strong inhibition of p65 NF-κB activity at 28 days after SCI, mainly in the gray matter. Moreover, reduced formation of glial scar was found in SPC-01-transplanted rats along with enhanced gray matter preservation and reduced cavity size.ConclusionsThe results of this study demonstrate strong immunomodulatory properties of SPC-01 cells based on inhibition of a major signaling pathway. Canonical NF-κB pathway activation underlines much of the immune response after SCI including cytokine, chemokine, and apoptosis-related factor production as well as immune cell activation and infiltration. Reduced inflammation may have led to observed tissue sparing. Additionally, such immune response modulation could have impacted astrocyte activation resulting in a reduced glial scar.Electronic supplementary materialThe online version of this article (10.1186/s12974-019-1394-7) contains supplementary material, which is available to authorized users.

Geniposide protects PC12 cells from lipopolysaccharide-evoked inflammatory injury via up-regulation of miR-145-5p

“…Inflammation is a main contributor of the secondary injury of SCI, in which lots of signalling pathways are involved. In central nervous system, several stimuli such as LPS can induce the activation of NF-jB and JNK pathways [30,31]. The activated signalling triggers the production of proinflammatory cytokines and thereby induces inflammatory response and increases vulnerability to apoptosis [32,33].…”

Filling the Gap: Neural Stem Cells as A Promising Therapy for Spinal Cord Injury

“…Furthermore, preclinical studies have been conducted, approaching different cell sources, to better comprehend better the cellular response after transplantation namely immune rejection, tumor risk formation, and grafts survival. Using a human primary source of neural precursors from the fetal spinal cord (SPC-01) it was showed strong immunomodulatory properties through astroglial p65 NF-κB inhibition which significantly impacted the reduction of the glial scar and the cavity size [147]. Moreover, the well-defined human H9 ESC-derived NSC line has also been commonly addressed as a cellular source with high reproducibility.…”

Deficiency of the microglial Hv1 proton channel attenuates neuronal pyroptosis and inhibits inflammatory reaction after spinal cord injury

“…The inflammatory reaction begins at the lesion site and then expands to surrounding tissue during the secondary phase [3]. A persistent inflammatory microenvironment and the presence of reactive oxygen species (ROS) are potential factors that impede injury repair following SCI [4,5].…”