Pushing The Case For Regeneration

Posted by Sam Maddox in Research News on July 20, 2015 # Health, Research

Is there a realistic case to be made for regeneration? You hear folks say they don't want a bridge or a segmental patch job on their spinal cord injuries. They don't want an on-off switch either. They want the real biological cure, and the way this can only go is by regeneration of axons that start in the brain. These are the long nerve wires that run the full length of the spinal cord – three feet or more – and hook up to the body's motor system. FYI, here's a primer on the basics of regeneration.

Can it be done? Can the spinal cord be regenerated? Well, in theory, yes, but in reality, no. Not yet anyway.

There are a couple of main ways scientists approach long-axon regrowth. One is to provide long nerve fibers (axons) that originate in neurons in the brain with a roadway free of inhibitors and scars. This works to a degree, the axons respond, but this isn't enough to get them to cross the injury site and move on down the cord.

Photo: Courtesy of The Journal of NeuroScience of a sagittal section showing the regeneration of mouse corticospinal tract axons (red) 7 months after Pten deletion was initiated in motor cortex. Pten deletion was initiated 1 year after spinal cord injury in this mouse. Green labels glial fibrillary acidic protein.

The other approach is to repower intrinsic axon growth by changing the genetic properties of the nerve cell in the brain, thus turning on the mechanisms of regeneration. We're going to address progress in this area, building on what we've been calling the PTEN story for five or six years now, and as recently as this past April.

The Latest

A Chinese scientist named Kai Liu and his team from Hong Kong University of Science and Technology (HKUST) published a research paper in The Journal of Neuroscience a couple of weeks ago that makes perhaps the best case yet for the promise of regeneration in the injured spinal cord. They were able to regenerate corticospinal tract axons (CST), the long ones needed for lower extremity movement. According to a press release from HKUST, this "may spell the dawn of a new beginning on chronic SCI treatments."

OK, so before we look more closely at the new Liu paper, let's review what we already know about this line of work. The nerve cell genetic manipulation story took off in 2010. A team from the Harvard lab of Zhigang He, led by Kai Liu, showed with dramatic microscopic imagery that repowered corticospinal nerve axons could grow very long distances – unprecedentedly long. Their paper, which made the cover of top-tier Nature Neuroscience, was titled "PTEN Deletion Enhances the Regenerative Ability of Adult Corticospinal Neurons." The basic idea is that by using genetic tools it is possible to turn off PTEN molecules; this then powers up mTOR, which then fuels axon growth. It's quite complicated. The experiments in that paper, however, deleted PTEN after animals had been injured, which is not going to mean much for people dealing with paralysis.

The new paper, titled "PTEN Deletion Promotes Regrowth of Corticospinal Tract Axons 1 Year after Spinal Cord Injury," shows how Liu et al knocked down PTEN in three models: right after injury, four months later, and 12 months post injury. From the paper:

Chronic spinal cord injury (SCI) is a formidable hurdle that prevents a large number of injured axons from crossing the lesion, particularly the corticospinal tract (CST). This study shows that PTEN deletion in the adult mouse cortex enhances compensatory sprouting of uninjured CST axons. Furthermore, forced upregulation of mammalian target of rapamycin (mTOR) initiated either 1 month or 1 year after injury promoted regeneration of CST axons. Our results indicate that both developmental and injury-induced mTOR down regulation in corticospinal motorneurons can be reversed in adults. Modulating neuronal mTOR activity is a potential strategy for axon regeneration after chronic SCI.

...our results indicate that PTEN deletion in postinjured adult corticospinal neurons enables a regenerative response that, to the best of our knowledge, has not been observed previously in the mammalian spinal cord.

From the press release:

The team recorded a regenerative response of CST axons in all three samples -- showing that PTEN deletion stimulates CST sprouting and regeneration, even though the injury was sustained a long time ago. "As one of the long descending tracts controlling voluntary movement, the corticospinal tract (CST) plays an important role for functional recovery after spinal cord injury," says Professor Liu. "The regeneration of CST has been a major challenge in the field, especially after chronic injuries. Here we developed a strategy to modulate PTEN/mTOR signaling in adult corticospinal motor neurons in the post-injury paradigm."

"It not only promoted the sprouting of uninjured CST axons, but also enabled the regeneration of injured axons past the lesion in a mouse model of spinal cord injury, even when treatment was delayed up to 1 year after the original injury. The results considerably extend the window of opportunity for regenerating CST axons severed in spinal cord injuries."

Growth is limited (the scar matrix at the lesion site remains a formidable issue) but impressive. What about connection? The regenerating CST axons acquire the molecular wherewithal to make synapses, or connections to motor units. Liu calls these "tentative" synapses, functionality unknown. Did the regenerating axons hook up with new targets and make any recovery possible? That, as they say, remains to be tested.