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Improved functional recovery after spinal cord injury by transplantation of induced pluripotent stem cell-derived neural stem/progenitor cells (iPSC-NPCs) has been reported. However, beneficial effects of iPSC-based therapy have so far been produced mostly using genetically immunodeficient rodents. Because of the long time required for generation and characterization of iPSCs, the use of autologous iPSCs for treating patients with acute spinal cord injury (SCI) is not feasible. Therefore, it is of utmost importance to investigate the effect of iPSC-based therapy on functional recovery after SCI using pharmacologically immunosuppressed, immunocompetent animal models. Here we studied the functional outcome following subacute transplantation of human iPSC-derived NPCs into contused mouse spinal cord when tacrolimus was used as an immunosuppressive agent. We show that human iPSC-derived NPCs transplanted into pharmacologically immunosuppressed C57BL/6J mice exhibited poor long-term survival and failed to improve functional recovery after SCI as measured by Basso Mouse Scale (BMS) for locomotion and CatWalk gait analysis when compared to vehicle-treated animals. The scarce effect of iPSC-based therapy observed in the current study may be attributable to insufficient immunosuppressive effect, provided by monotherapy with tacrolimus in combination with immunogenicity of transplanted cells and complex microenvironment of the injured spinal cord. Our results highlight the importance of extensive preclinical studies of transplanted cells before the clinical application of iPSC-based cell therapy is achieved.

Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) modulates gene expression in response to oxidative damage in neurodegenerative diseases, including spinal cord injury (SCI). We noticed that activation of Nrf2 pathway persists for an extended time after clinically relevant contusion model of SCI. Injured Nrf2(-/-) mice were impaired in hindlimb function, exhibited increased atrophy, demyelination, and astrogliosis of the SC concomitant with altered expression of genes controlling apoptosis, inflammation, and neurotrophic factors suggesting the importance of Nrf2 for recovery. We used lentiviral gene transfer to increase Nrf2 expression and improve functional recovery after SCI. Although the transferred Nrf2 was expressed in neurons and astrocytes, we noticed hindlimb function impairment and elevated expression of pro-inflammatory cytokines as an adverse effect. These toxic effects were not reduced by including Nrf2 in the lentiviral vector. Augmenting the amount of delivered Nrf2 gene diminished toxic effects of the lentivirus, yet was not sufficient to improve functional recovery. Results of this study lead to the hypothesis that Nrf2 plays a crucial and multifaceted role in recovery from SCI, but even high overexpression of Nrf2 in injured SC may not offer extra benefit, providing protection only against lentivirus-induced toxicity that is manifested in the SC.

BackgroundA disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) proteoglycanases are specialized in the degradation of chondroitin sulfate proteoglycans and participate in mechanisms mediating neuroplasticity. Despite the beneficial effect of ADAMTS-4 on neurorepair after spinal cord injury, the functions of ADAMTS proteoglycanases in other CNS disease states have not been studied. Therefore, we investigated the expression, effects and associated mechanisms of ADAMTS-4 during amyotrophic lateral sclerosis (ALS) in the SOD1G93A mouse model.ResultsADAMTS-4 expression and activity were reduced in the spinal cord of SOD1G93A mice at disease end-stage when compared to WT littermates. To counteract the loss of ADAMTS-4, SOD1G93A and WT mice were treated with saline or a recombinant ADAMTS-4 before symptom onset. Administration of ADAMTS-4 worsened the prognosis of SOD1G93A mice by accelerating clinical signs of neuromuscular dysfunctions. The worsened prognosis of ADAMTS-4-treated SOD1G93A mice was accompanied by increased degradation of perineuronal nets enwrapping motoneurons and increased motoneuron degeneration in the lumbar spinal cord. Motoneurons of ADAMTS-4-treated SOD1G93A mice were more vulnerable to degeneration most likely due to the loss of their extracellular matrix envelopes. The decrease of neurotrophic factor production induced by ADAMTS-4 in vitro and in vivo may also contribute to a hostile environment for motoneuron especially when devoid of a net.ConclusionsThis study suggests that the reduction of ADAMTS-4 activity during the progression of ALS pathology may be an adaptive change to mitigate its neurodegenerative impact in CNS tissues. Therapies compensating the compromized ADAMTS-4 activity are likely not promising approaches for treating ALS.

Unfortunately, after publication of this article [1], an error was discovered in Fig. 12 (Fig. 1 here) that was introduced during the Production process. The corrected figure can be seen below and the original article has also been updated to reflect this change.