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Human iPSC-Derived Neural Cells Form Extensive Neural Networks in Rodents

Review of “Long-Distance Axonal Growth from Human Induced Pluripotent Stem Cells after Spinal Cord Injury” from Neuron by Stuart P. Atkinson

The transplantation of neural stem/progenitor cells (NSPCs) derived from embryonic spinal cord or embryonic stem cells (ESCs) is a potentially useful strategy for the treatment of spinal cord injury (SCI) due to the ability of these cells to form extensive axonal networks after transplantation [1], in addition to their remyelination capacity and neuroprotective properties [2-4]. However, this has not been shown in the more clinically relevant case of patient-specific human induced pluripotent stem cells (iPSCs), which may not require immunosuppression. Now, in a study published in Neuron, researchers from the laboratory of Mark H. Tuszynski (UC San Diego School of Medicine) explore this strategy, discovering that human iPSC-derived NSCs transplantation can also give rise to an extensive axonal network in rodents [5].

The researchers first derived hiPSCs and redifferentiated these cells towards an NSC fate, followed by embedding into growth factor-laden fibrin matrices to aid graft survival and retention in a spinal cord lesion (C5 spinal cord hemisection). At three months, grafted cells had survived and were distributed throughout the lesion. The vast majority of grafted cells had differentiated into neuronal and astrocytic cell types, with a small percentage of neurons expressing choline acetyltransferase (ChAT), which is characteristic of spinal motor neurons. Large numbers of graft-derived immunoreactive axons extended out of the lesion site and into the host spinal column, to a level 41% higher than the number of axons emerging from grafts of rat-derived neural progenitor cells per hemicord in a previous study by the same group [1], equivalent to that of rodent host axons in some regions of white matter, and extending huge distances in both rostral and caudal directions. Graft-derived axons reached as far as the lumbar spinal cord, the frontal cortex and olfactory bulb – essentially the entire length of the rat, although axon density did diminish as a function of distance from the graft. Furthermore, the researchers observed no unwanted growths or teratomas, suggesting that iPSC-derived cells were safe in this context.

Vast numbers of hiPSC-derived axons extended through adult white matter, frequently directly contacting host myelin membranes, although graft-derived human axons were not detectably myelinated by rat host oligodendrocytes. In grey matter, hiPSC-derived axons formed bouton-like terminals (chemical synapse formations) at all levels of the rat spinal cord in close proximity to host neurons and dendrites, suggesting contact between exogenous axons and host dendrites. Interestingly, host axons also grew into human iPSC-derived NSC grafts with evidence of synapse formation. This strongly suggests that transplantation of iPSC-derived NSCs is sufficient to generate structures which can bridge a lesion site and support functional recovery. 

These findings suggest that iPSC-derived cells permit extensive and long-distance axonal growth. Notably, the group generated iPSCs from the cells of an 86 year old subject, suggesting that age is not a barrier to the functionality of these cells. However, collagenous rifts, occurring within most grafts prevented the passage of axons, and in grafts lacking rifts, the core presented with regions of low cell density also inhibiting axonal passage and neural linkage. Indeed, in these rats, assessments of behavioral outcomes found no functional recovery. Further work will look at additional distinct iPSC lines to assess heterogeneity across donor cells, methods of cell preparation, and optimal cell source, as well as potential ways round the confounding factors to boost the chances of functional recovery in SCI.

References

  1. Lu P, Wang Y, Graham L, et al. Long-distance growth and connectivity of neural stem cells after severe spinal cord injury. Cell 2012;150:1264-1273.
  2. Cummings BJ, Uchida N, Tamaki SJ, et al. Human neural stem cells differentiate and promote locomotor recovery in spinal cord-injured mice. Proceedings of the National Academy of Sciences of the United States of America 2005;102:14069-14074.
  3. Keirstead HS, Nistor G, Bernal G, et al. Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. The Journal of neuroscience : the official journal of the Society for Neuroscience 2005;25:4694-4705.
  4. Plemel JR, Chojnacki A, Sparling JS, et al. Platelet-derived growth factor-responsive neural precursors give rise to myelinating oligodendrocytes after transplantation into the spinal cords of contused rats and dysmyelinated mice. Glia 2011;59:1891-1910.
  5. 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.