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Remyelination Rules for Stem Cell Spinal Cord Injury Repair

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Review of “Transplantation of iPSC-Derived NSCs Mediate Functional Recovery Following Thoracic Spinal Cord Injury through Remyelination” from Stem Cells Translational Medicine by Stuart P. Atkinson

Neural stem cell (NSC)-based therapies have the potential to attenuate or repair the tissue damage observed after spinal cord injury (SCI) in order to preserve/repair central nervous system (CNS) function. However, the exact function of NSCs after transplant is relatively unknown. Potential mechanisms include the replacement of neurons lost following SCI [1], the promotion of host repair through the creation of a regenerative environment [2], the provision of trophic factor support [3], or modulation of the inflammatory response [4], although the remyelination of damaged host axons is thought to play the most significant role. To investigate these different elements, researchers from the laboratory of Michael G. Fehlings (Institute of Medical Science University of Toronto, Canada) have differentiated piggyBac transposon reprogrammed induced pluripotent stem cells (iPSCs) [5] into definitive NSCs (dNSCs) for subacute intraspinal transplantation following thoracic SCI. Using this method, they have highlighted the importance of remyelination by pluripotent-sourced NSCs in SCI repair and regeneration [6].

The study utilized two different types of iPSC-derived dNSCs; wild type (wt)-iPS-dNSCs and Shiverer (shi)-iPSC-dNSCs, which are generated from mouse embryonic fibroblasts containing a mutation in the myelin basic protein (MBP) gene which causes an inability to generate compact myelin [7]. Both iPSC lines demonstrated similar pluripotent characteristics, and dNSCs generated from both iPSC lines had the ability to differentiate into neural cells and expressed similar patterns of neurotrophic gene markers. Transplantation of dNSCs into the thoracic spinal cord of Shiverer mice found that, as expected, wt-iPS-dNSC mediated axonal myelination whereas the sh-iPS-dNSCs did not.

Following this validation step, the researchers then transplanted dNSCs intraspinally 7 days after clip-compression SCI and assessed spinal tissue 8 weeks later. Both dNSC types integrated into spinal tissue in similar cell number, graft length, and transplantation volume observed, with 80% of cells expressing a neuronal marker (OLIG2-, GFAP-, or NeuN-positive cells) and no sign of neoplastic growth. Assessment of functional recovery demonstrated significant improvement in locomotor function in the wt-iPS-dNSC recipients compared to the shi-iPS-dNSC and media control groups. Furthermore, wt-iPS-dNSC-grafted mice displayed improved action potential conduction in the injured spinal cord, and this was not associated with any worsening in neuropathic pain measures.

Histologically, spinal cords transplanted with the different dNSC types also displayed some obvious differences, with wt-iPS-dNSC treatment leading to a significantly greater amount of white matter (as measured by Luxol Fast Blue staining which identifies lipoprotein-rich myelin sheath) than treatment with shi-iPS-dNSCs. Further co-staining in wt-iPS-dNSC-implanted mice found that exogenous cells overlapped with MBP labelling, and electron microscopy found compacted multilayered myelin along with peroxidase deposition, indicating an exogenous origin. The adjoined figure shows GFP labelling of exogenous cells co-staining with MBP and NF200, providing support for axonal radial regrowth.

This study strongly suggests that graft-derived axonal remyelination drives the functional recovery observed upon dNSC transplantation, and neuroprotection via the excretion of various neurotrophins is a secondary mechanism. Furthermore, this study also provides a rational for the safe use of iPSC-derived NSCs in various therapeutic avenues, as the researchers observed no problematic side-effects within the time limits of the current study, and the generation, characterization, and in vivo application of shiverer mouse iPSC lines for the first time may prove useful for many related studies.

References

  1. Yan J, Xu L, Welsh AM, et al. Extensive neuronal differentiation of human neural stem cell grafts in adult rat spinal cord. PLoS Med 2007;4:e39.
  2. Qiu J, Cai D, Dai H, et al. Spinal axon regeneration induced by elevation of cyclic AMP. Neuron 2002;34:895-903.
  3. Romero MI, Rangappa N, Garry MG, et al. Functional regeneration of chronically injured sensory afferents into adult spinal cord after neurotrophin gene therapy. The Journal of neuroscience : the official journal of the Society for Neuroscience 2001;21:8408-8416.
  4. Pluchino S, Zanotti L, Rossi B, et al. Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism. Nature 2005;436:266-271.
  5. Woltjen K, Michael IP, Mohseni P, et al. piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature 2009;458:766-770.
  6. Salewski RP, Mitchell RA, Li L, et al. Transplantation of Induced Pluripotent Stem Cell-Derived Neural Stem Cells Mediate Functional Recovery Following Thoracic Spinal Cord Injury Through Remyelination of Axons. Stem Cells Transl Med 2015;4:743-754.
  7. Nave KA Neurological mouse mutants and the genes of myelin. Journal of neuroscience research 1994;38:607-612.