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

• Published in: Scientific reports Vol. 9; no. 1; pp. 19291 - 13
• Main Authors: Shiga, Yasuhiro, Shiga, Akina, Mesci, Pinar, Kwon, HyoJun, Brifault, Coralie, Kim, John H., Jeziorski, Jacob J., Nasamran, Chanond, Ohtori, Seiji, Muotri, Alysson R., Gonias, Steven L., Campana, Wendy M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17-12-2019; Nature Publishing Group
• Subjects: 13; 13/100; 13/105; 13/106; 14/19; 38/91; 631/378/1687/1825; 631/378/2183/2182; 692/617/375/1824; 96/2; Animals; Apoptosis; Biomarkers; Cell Differentiation - drug effects; Gene expression; Growth factors; Humanities and Social Sciences; Humans; Induced Pluripotent Stem Cells - drug effects; Kinases; Motor Neurons - drug effects; Motor Neurons - physiology; multidisciplinary; Neural stem cells; Neural Stem Cells - drug effects; Neurogenesis - drug effects; Neurons; Phosphorylation; Progenitor cells; Rats; Recovery of Function; Science; Science (multidisciplinary); Spinal Cord - drug effects; Spinal Cord - pathology; Spinal cord injuries; Spinal Cord Injuries - genetics; Spinal Cord Injuries - physiopathology; Spinal Cord Injuries - therapy; Stem Cell Transplantation; Stem cells; Stem Cells - drug effects; Tissue Plasminogen Activator - chemistry; Tissue Plasminogen Activator - genetics; Tissue Plasminogen Activator - pharmacology
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-55132-8

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 (
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NPC) 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
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NPC 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
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NPC 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
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NPC demonstrated significantly improved motor function, without exacerbating pain. When
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NPC 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.