Tissue-type plasminogen activator-primed human iPSC-derived neural progenitor cells promote motor recovery after severe spinal cord injury

Abstract

The goal of stem cell therapy for spinal cord injury (SCI) is to restore motor function without exacerbating pain. Induced pluripotent stem cells (iPSC) may be administered by autologous transplantation, avoiding immunologic challenges. Identifying strategies to optimize iPSC-derived neural progenitor cells (hiNPC) for cell transplantation is an important objective. Herein, we report a method that takes advantage of the growth factor-like and anti-inflammatory activities of the fibrinolysis protease, tissue plasminogen activator tPA, without effects on hemostasis. We demonstrate that conditioning hiNPC with enzymatically-inactive tissue-type plasminogen activator (EI-tPA), prior to grafting into a T3 lesion site in a clinically relevant severe SCI model, significantly improves motor outcomes. EI-tPA-primed hiNPC grafted into lesion sites survived, differentiated, acquired markers of motor neuron maturation, and extended βIII-tubulin-positive axons several spinal segments below the lesion. Importantly, only SCI rats that received EI-tPA primed hiNPC demonstrated significantly improved motor function, without exacerbating pain. When hiNPC were treated with EI-tPA in culture, NMDA-R-dependent cell signaling was initiated, expression of genes associated with stemness (Nestin, Sox2) was regulated, and thrombin-induced cell death was prevented. EI-tPA emerges as a novel agent capable of improving the efficacy of stem cell therapy in SCI.

Apelin alleviated neuroinflammation and promoted endogenous neural stem cell proliferation and differentiation after spinal cord injury in rats

“…Stem cell therapy is considered an effective method for treating SCI [ 51 ]. However, some reports suggest that stem cells transplanted after SCI survive only 1–2 weeks.…”

Plasminogen activator receptor assemblies in cell signaling, innate immunity, and inflammation

“…The activity of EI-tPA in a mouse model of IBD was discussed (180). In a second study, using a mouse model of spinal cord injury, EI-tPA again demonstrated efficacy, improving the ability of induced pluripotent stem cells to restore motor function (188). Although the activity of EI-tPA in this study was attributed to direct effects of EI-tPA on the stem cells, EI-tPA was administered into the spinal cord injury site with the stem cells.…”

Pluripotent Stem Cells for Spinal Cord Injury Repair

“…Notably, they found that the cells differentiated, acquired markers of motor neuron maturation, and extended βIII-tubulin-positive axons several spinal segments below the lesion. Furthermore, they observed a decrease in muscle atrophy, and animals had significantly improved motor function, without exacerbating pain [ 55 ]. Bonilla and coworkers combined human iPSC–NSC, MSC and a pH-responsive polyacetal–curcumin nanoconjugate (PA-C) that allowed the sustained release of curcumin to treat thoracic SCI in a rat subacute model.…”