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From Rodents to Non-Human Primates - NSPCs aid Functional Recovery after Spinal Cord Injury

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Review of “Allogeneic Neural Stem/Progenitor Cells Derived From Embryonic Stem Cells Promote Functional Recovery After Transplantation Into Injured Spinal Cord of Nonhuman Primates” from Stem Cells Translational Medicine by Stuart P. Atkinson

Investigations using neural stem/progenitor cells (NSPCs) to promote functional recovery following spinal cord injury (SCI) have mainly used rodent models and this research has led to the start of some human clinical trials. However, some believe that differences in rodent neuroanatomy and immunological responses are grounds for further basic research in more appropriate models [1, 2]. To this end, researchers from the laboratories of Hideyuki Okano and Masaya Nakamura (Keio University School of Medicine, Tokyo, Japan) have assessed the effectiveness of allogeneic embryonic stem cell (ESC)-derived NSPC transplantation for SCI in adult common marmosets (non-human primates) in a preclinical study. Their new findings describe functional recovery after NSPC transplantation into the injured spinal cord, promoting their proposed clinical use in humans [3].

The fluorescently labelled ESC-derived marmoset NSPCs used in the study, as expected, had the ability to differentiate into neurons, astrocytes, and oligodendrocytes in vitro, and expressed high levels of various neurotrophic factors (VEGF-A, IGF-1, FGF-1, and PDGF-C). Eight marmosets received a moderate contusive SCI and following this, half received NSPC grafts into the lesion site and half received only vehicle (control) 14 days after injury. Cells grafted well and migrated into both gray and white matter at the lesion epicenter, with evidence of neuron, astrocyte, oligodendrocyte and oligodendrocyte progenitor cell differentiation. Additionally the researchers found myelin binding protein (MBP) positive cells and higher levels of myelin in the NSPC-treated marmosets, suggesting that the grafted cells contributed to the remyelination of axons after SCI. NSPC transplant was also associated with the prevention of spinal atrophy and cavity formation which occurs after a contusive injury, a lack of tumorigenic or unwanted growth, and increased angiogenesis at the lesion epicenter.

Assessment at later time points found that NSPC transplantation mediated the sparing of neuronal fibers in the injured spinal cord and axonal regrowth, while the group also observed evidence of transplanted cells forming synaptic connections with host axons. NSPC transplantation also led to significant improvements in two different measures of motor function at 4 and 9 weeks after transplantation respectively (See figure), with no evidence of an immunological response.

This suggests that NSPCs can improve functional recovery through remyelination of host axons and neurotrophic support mechanisms without any unwanted side effects in the time period studied, and strongly supports the use of allogeneic multipotent stem cell derived-NSPCs for the treatment of SCI in human patients. However, the authors do note that studies to determine the optimal therapeutic window for cell transplantation are necessary, alongside validation in allograft and autograft models in the absence of an immunosuppressant [4].

References

  1. Iwanami A, Kaneko S, Nakamura M, et al. Transplantation of human neural stem cells for spinal cord injury in primates. Journal of Neuroscience Research 2005;80:182-190.
  2. Iwanami A, Yamane J, Katoh H, et al. Establishment of graded spinal cord injury model in a nonhuman primate: the common marmoset. Journal of Neuroscience Research 2005;80:172-181.
  3. Iwai H, Shimada H, Nishimura S, et al. Allogeneic Neural Stem/Progenitor Cells Derived From Embryonic Stem Cells Promote Functional Recovery After Transplantation Into Injured Spinal Cord of Nonhuman Primates. Stem Cells Translational Medicine 2015;4:708-719.
  4. Morizane A, Doi D, Kikuchi T, et al. Direct comparison of autologous and allogeneic transplantation of iPSC-derived neural cells in the brain of a non-human primate. Stem Cell Reports 2013;1:283-292.