It may be hard to believe, but according to a paper in the August 7 issue of the journal Neuron, neural stem cells grown from an old man underwent dramatic rebirth when grafted into injured rat spinal cords. Reportedly, the cells generated neurons, which sprouted axons that extended up or down the length of the spine. Researchers led by Mark Tuszynski at the University of California, San Diego, developed the neural transplants from induced pluripotent stem cells (iPSCs). The cells set up shop within rat spinal-cord lesions and established a more extensive neural network than has ever been reported for such transplants. The axons did not extend across the damage site, nor did the animals regain the motor functions they had lost as a result of the lesions. Even so, the researchers see the vigorous growth of the transplanted cells as a sign that these important steps can be achieved, as well.

“The amount of outgrowth is amazing. That they achieved these results with iPS cells from a very old patient is important, especially if we are ever going to consider iPS-derived therapies for Alzheimer’s disease,” commented Mathew Blurton-James of the University of California, Irvine. Other researchers contacted by Alzforum declined to comment or were unavailable.

Healing spinal-cord injuries with stem cells is a holy grail, but many barriers stand in the way. Confronting a hostile, damaged environment in the host, transplanted cells must forge functional connections with in-house neurons and survive attack from the host’s immune system. In 2012, Tuszynski’s group reported that transplanted neural stem cells—either derived from rat embryo spinal cords or from human fetal spinal cords—sprouted long axons when grafted into spinal-cord lesions of rats severed at the thoracic position. The injured rats regained movement in their hind limbs (see Lu et al., 2012). Now, the group has tried a more ambitious test: They partially severed rat spinal cords much higher up than they had done previously, and sought to fill in the lesions with iPSCs (rather than primary neural stem cells) from an adult human. If iPSC-derived neural precursors from an 86 year-old man could populate the spinal cord, Tuszynski reasoned, it could mean that people of any age could use their own cells as seeds to repair damage.

First author Paul Lu and colleagues converted skin fibroblasts from the donor into iPSCs and then into neural stem cells (NSCs). The researchers transduced these NSCs with green fluorescent protein (GFP) for tracking and grafted them directly into rats’ lesions two weeks after injury. Three months later, not only were the transplanted cells thriving in the lesion, they had developed into full-fledged neurons with axons running the entire length of the spinal cord in both directions. 

Bridging the Gap?

Transplanted neural stem cells (GFP, green) filled in a partial spinal cord lesion. The graft’s center was less populated than its outskirts. [Image courtesy of Lu et al., Cell 2014.]

One major issue marred the transplants: Bundles of collagen formed in the middle of the grafts in four of the seven rats used in this study, which likely prevented axons from crossing from one side of the injury to the other, the authors suggested. The other three rats had no collagen-filled rifts, but few neurons populated the center of their grafts. While axons did not traverse the lesions, they spread out toward the head and tail. The number of axons—more than 20,000 in the caudal direction—was nearly double that observed when rats were transplanted with primary NSCs in the previous study. The axons also extended twice as far, reaching into the frontal cortex and olfactory bulb in one direction, and to the lumbar region in the other. The axons followed organized tracts along the spinal cord, and branched off into the host’s gray matter along the way.

The vigor with which the newbie axons propagated could have something to do with their developmental stage, Tuszynski told Alzforum. Interestingly, while the cell bodies of the transplanted neurons expressed mature neuronal markers, the axons appeared to be developmentally young, as they expressed no neurofilament and were unmyelinated by host oligodendrocytes. Maturation tends to prevent neurons from branching out into new territory, so this odd developmental dichotomy between the cells’ soma and axons could have allowed them to reach further than other types of stem cells, which are often inhibited by host factors, Tuszynski speculated. “These early-stage axons don’t seem to be repelled,” he said. “This was the most interesting aspect of our findings.”

The transplanted neurons formed boutonesque terminals with host neurons, and expressed synaptic markers such as synaptophysin and the vesicular glutamate transporter vGlut1. The rat’s own serotonergic axons, which are important for controlling motor function, extended into grafted lesions but not into lesions of control rats that received no NSCs.

None of the rats recovered from paralysis. The collagen barriers were likely to blame in the animals that had them, and the early developmental stage of the transplanted axons may have prevented them from functioning properly, Tuszynski said. Given more time, perhaps the iPS-derived neurons might have developed into more functional cells. The collagen blockades did not form in similar, ongoing experiments in monkeys, nor in rats whose spinal cord was injured by contusion (the most common way humans are injured) rather than slicing, Tuszynski said. —Jessica Shugart

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References

Paper Citations

  1. . Long-distance growth and connectivity of neural stem cells after severe spinal cord injury. Cell. 2012 Sep 14;150(6):1264-73. PubMed.

Further Reading

Papers

  1. . Axonal growth and connectivity from neural stem cell grafts in models of spinal cord injury. Curr Opin Neurobiol. 2014 Aug;27C:103-109. Epub 2014 Apr 5 PubMed.
  2. . A re-assessment of long distance growth and connectivity of neural stem cells after severe spinal cord injury. Exp Neurol. 2014 Jul;257:186-204. Epub 2014 Apr 18 PubMed.
  3. . Neural stem cells in models of spinal cord injury. Exp Neurol. 2014 Jul 28; PubMed.

Primary Papers

  1. . Long-Distance Axonal Growth from Human Induced Pluripotent Stem Cells after Spinal Cord Injury. Neuron. 2014 Aug 6; PubMed.