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Tissue-type plasminogen activator-primed human iPSC-derived neural progenitor cells promote motor recovery after severe spinal cord injury.
- Source :
-
Scientific reports [Sci Rep] 2019 Dec 17; Vol. 9 (1), pp. 19291. Date of Electronic Publication: 2019 Dec 17. - Publication Year :
- 2019
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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.
- Subjects :
- Animals
Cell Differentiation drug effects
Humans
Induced Pluripotent Stem Cells drug effects
Motor Neurons drug effects
Motor Neurons physiology
Rats
Recovery of Function
Spinal Cord drug effects
Spinal Cord pathology
Spinal Cord Injuries genetics
Spinal Cord Injuries physiopathology
Stem Cell Transplantation
Stem Cells drug effects
Tissue Plasminogen Activator chemistry
Tissue Plasminogen Activator genetics
Neural Stem Cells drug effects
Neurogenesis drug effects
Spinal Cord Injuries therapy
Tissue Plasminogen Activator pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 9
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 31848365
- Full Text :
- https://doi.org/10.1038/s41598-019-55132-8