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Treating Spinal Cord Injury with Potentiated iPSC-derived Neural Progenitor Cells

Review of “Tissue-type plasminogen activator-primed human iPSC-derived neural progenitor cells promote motor recovery after severe spinal cord injury” from Scientific Reports by Stuart P. Atkinson

The grafting of neural progenitor cells derived from human induced pluripotent stem cells (hiNPCs) as a treatment for spinal cord injury (SCI) represents a safe and potentially effective strategy in animal models of moderate injury; however, evaluations in more severe disease models have failed to provide significant recovery of motor function [1]. 

In a recent Scientific Reports article [2], researchers led by Wendy M. Campana (University of California San Diego, La Jolla, CA, USA) explored means to potentiate hiNPC therapy for severe SCI with a specific focus on the neuroprotective functions and growth factor-like activities [3-5] of tissue-type plasminogen activator (tPA), an activator of fibrinolysis global approved for the treatment of non-hemorrhagic stroke through its inherent protease activity [6]. 

Fascinatingly, Shiga et al. now report that the grafting of hiNPCs pretreated with a proteolytically-inactive form of tPA represents a safe and effective means to promote significant motor function improvements in a severe SCI rat model.

The authors discovered that pretreated hiNPCs survived, differentiated, displayed markers of motor neuron maturation, and extended βIII-tubulin-positive axons several spinal segments below the lesion following grafting into immunodeficient rats one week following a spinal cord compression injury. Rats subjected to such an injury exhibit complete hindlimb paralysis within a day after injury; however, the administration of pretreated hiNPCs but not control hiNPCs also fostered a significant improvement in locomotor function and decreased muscle atrophy without exacerbating pain responses. 

Moving in vitro to decipher the mechanisms involved, the authors established that the treatment of hiNPCs with the proteolytically-inactive form of tPA led to the activation of N-methyl-D-aspartate receptor (NMDA-R, a known cell-signaling receptor for tPA [7])-dependent cell signaling, the elevated expression of stemness-associated gene expression, and protection from the microenvironmental challenges normally associated with spinal cord injury.

Overall, the authors provide evidence that enzymatically-inactive tPA may represent a safe and effective means to potentiate the therapeutic effect of hiNPCs following grafting into the injured spinal cord. 

For more on this exciting finding, and all the advances in this area, stay tuned to the Stem Cells Portal!

References

  1. Lu P, Woodruff G, Wang Y, et al., Long-Distance Axonal Growth from Human Induced Pluripotent Stem Cells after Spinal Cord Injury. Neuron 2014;83:789-796.
  2. Shiga Y, Shiga A, Mesci P, et al., Tissue-type plasminogen activator-primed human iPSC-derived neural progenitor cells promote motor recovery after severe spinal cord injury. Scientific Reports 2019;9:19291.
  3. Kim Y-H, Park J-H, Hong SH, et al., Nonproteolytic Neuroprotection by Human Recombinant Tissue Plasminogen Activator. Science 1999;284:647.
  4. Minor KH and Seeds NW, Plasminogen activator induction facilitates recovery of respiratory function following spinal cord injury. Molecular and Cellular Neuroscience 2008;37:143-152.
  5. Seeds NW, Williams BL, and Bickford PC, Tissue Plasminogen Activator Induction in Purkinje Neurons After Cerebellar Motor Learning. Science 1995;270:1992.
  6. Castellino FJ and Ploplis VA, Structure and function of the plasminogen/plasmin system. Thrombosis and Haemostasis 2005;93:647-654.
  7. Nicole O, Docagne F, Ali C, et al., The proteolytic activity of tissue-plasminogen activator enhances NMDA receptor-mediated signaling. Nature Medicine 2001;7:59-64.