Stem Cells for Spinal Cord Injuries

The difficulty with treating spinal cord injuries arises from a number of factors. Firstly there is the primary damage to the axons of the spinal cord itself, resulting in mechanical damage that can inhibit neurotransmission and transport of cellular material to and from the distal cord. The damaged cord must also compensate for secondary damage such as the generation of free radicals, a lack of oxygen to the affected area (anoxia), glial scarring, and a host of other issues.

Your typical spinal neuron looks like this.

(Image snagged from http://www.steve.gb.com). The axon is a long process that extends from the cell body. Axons exit the central nervous system to innervate your muscles, relaying signals from your brain to the muscles and thus telling them when to contract. Your spinal cord is made up of bundles of these axons. Glial cells such as Schwann cells in the periphery or, within the cord itself, oligodendrocytes, wrap themselves around the axon, thus promoting faster transmission of electrical signals and also providing for general maintenance of the environment surrounding the cord, in part by shuttling different compounds around, responding to injury, etc.

Crush injuries to the spinal cord are common, as opposed to clean cuts that sever the cord without any damage to overlying tissue and bone. Crush injuries usually result in low blood flow to the affected area, producing an ischemic condition. Fluid buildup often results, leading to compression from swelling and secondary ischemia. This damage can exceed the amount produced from the primary injury. A whole host of toxic conditions lead to the production of molecules that recruit glial cells to infiltrate the site in an effort to affect repair; unfortunately however, poor design of the system leads to reactive gliosis, which basically means the glial cells are looking to "plug the hole" instead of forming a nice, stable tube to guide the damaged axon back to its target. This glial scarring is an enormous barrier to regeneration of the spinal cord and recovery of function.

Stem cells represent a viable treatment option following spinal cord injury. Undifferentiated stem cells excrete a variety of neurotrophic factors that encourage axon growth, promote the replacement of damaged non-neural structures such as blood vessels, promote the breakdown of the glial scar, and temper inflammatory responses. Embryonic stem cells in particular have a penchant for adopting the glial phenotype, that is they will readily transform into the support cells required by neurons (e.g. astrocytes, oligodendrocytes) once they are transfused into the site of injury. They may also be used to overcome glial repulsion of axons; myelinating cells produce inhibitory factors that can prevent an axon from regenerating.

With that in mind, there are a couple exciting papers coming out. The first I point to uses embryonic stem cells in the rat. These cells, when added to the site of damage along with a PDE-4 inhibitor to block the axon-repulsive effects of glia, were experimentally differentiated into a neural phenotype to form bridge connections between the degenerating axons and the muscle. The interesting manipulation in this paper was the infusion of cells that produce the trophic factor GDNF into the target muscle; GDNF provides a signal that attracts growth of axons from the embryonic stem cells. Here's a crappy MS Paint schematic I made to show what's going on.

Here is an example of a confocal microscopy image of neuromuscular junction formation. The green axons express GFP for labeling purposes, and the red is muscle as labeled by alpha-bungarotoxin. Note the tight association between muscle and axon. Functional recovery was assessed via hind-limb grip strength and mobility, and electrophysiological measures. Significant recovery is shown at 120 days.

A second paper that I won't go into in detail (primarily because it is only available as a PDF and I can't easily dissect out the pretty pictures to show you) expands upon the promise of animal stem cell models of spinal cord injury by using human neural stem cells in a rodent model. They demonstrate differentiation of the human cells into neuronal and glial tissue, axon remyelination, synapse formation, and locomotor recovery. It seems, then, that stem cell therapies hold promise for treatment of traumatic spinal cord injury. While much work remains to develop a stable, consistent model in animals we are definitely making progress, and a variety of very creative approaches are being used. Some of these approaches point directly to potential of human stem cells. A truly pro-life culture would embrace the exploration and use of these technologies for the benefit of all its citizens.

References

• Garbossa D, Fontanella M, Fronda C, Benevello C, Muraca G, Ducati A, Vercelli A. Neurol Res. 2006 Jul;28(5):500-4.
• Deshpande DM, Kim YS, Martinez T, Carmen J, Dike S, Shats I, Rubin LL, Drummond J, Krishnan C, Hoke A, Maragakis N, Shefner J, Rothstein JD, Kerr DA. Ann Neurol. 2006 Jun 26;60(1):32-44 [Epub ahead of print]
• Cummings BJ, Uchida N, Tamaki SJ, Anderson AJ. Neurol Res. 2006 Jul;28(5):474-81.