Stem Cell-Based Spinal Cord Repair Enables Robust Corticospinal Regeneration

In the March 28th, 2016 issue of the journal Nature Medicine, Mark Tuszynski and his colleagues from the University of California, San Diego, in collaboration with colleagues from Japan and Wisconsin, report that they were able to successfully coax stem cell-derived neurons to regenerate damaged corticospinal tracts in rats. Furthermore, this regeneration produced observable, functional benefits.

What is the “corticospinal tract” you ask? The corticospinal tracts are part of the “pyramidal tracts” that include the corticospinal and corticobulbar tracts. The pyramidal tracts are the main controllers of voluntary movement and connect their nerve fibers eventually to cells that serve voluntary muscles and allow them to contract. We call such nerves “motor nerves,” and the corticospinal nerve tracts are among the most important of the motor nerve tracts.

These neural tracts are collectively called “pyramidal tracts” because they pass through a small area of the brain stem known as the pyramids, which lie on the ventral side of the medulla oblongata. Both pyramidal tracts originate in the forebrain; specifically from the so-called “motor cortex” of the forebrain. The motor cortex lies just in front of the central sulcus of the forebrain. In the motor cortex, lies thousands of “upper motor neurons” that extend their axons down to the brain stem and spinal cord.

Forebrain areas

In the brain stem, the majority of these corticospinal tracts crossover (or decussate) to the other side of the brain stem and travel down the opposite side of the spinal cord. The corticospinal axons extend all the way down the spinal cord, until they make a connection (synapse) with a “lower motor neuron” that extends its axon to the skeletal muscles that it will direct to contract. The corticobulbar tract contains nerves that conduct nerve impulses from cranial nerves and these help the muscles of the face and neck contract, and are involved in facial expressions, swallowing, chewing, and so on.

Corticospinal tracts

Damage to the upper motor neurons as a result of a stroke can rob a person of the ability to move, since the muscles that are attached to the upper motor neurons cannot receive any signals to contract. Likewise, damage to the axonal tracts (also known as nerve fibers) can paralyze a patient and rob them of their ability to move.

The director of this research project, Mark Tuszynski, MD, PhD, professor in the UC San Diego School of Medicine Department of Neurosciences and director of the UC San Diego Translational Neuroscience Institute, said: “The corticospinal projection is the most important motor system in humans. It has not been successfully regenerated before. Many have tried, many have failed – including us, in previous efforts.”

Dr. Tuszynski continued, “The new thing here was that we used neural stem cells for the first time to determine whether they, unlike any other cell type tested, would support regeneration. And to our surprise, they did.”

In this experiment, Tuszynski, and his colleagues and collaborators used rats that had suffered spinal cord injuries and had trouble moving their forelimbs. Then they implanted grafted multipotent neural progenitor cells (MNPCs) into those sites within the spinal cord that had suffered injury, where corticospinal axonal tracts had been severed or damaged. The MNPCs had been previously treated to differentiate into spinal cord-specific motor neurons. Fortunately, the MNPCs prodigiously formed lower motor neurons that made good, solid, functional synapses with interneurons and upper motor neurons that improved forelimb movements in the rats. This work put the lie to previous beliefs about corticospinal neurons; namely that they lacked any of the internal mechanisms required to regenerate severed or damaged connections.

Even though several previous studies have demonstrated functional recovery in spinal cord-injured rats through the use of stem cell-based treatments, none of these studies has convincingly demonstrated regeneration of corticospinal axons.

“We humans use corticospinal axons for voluntary movement,” said Tuszynski. “In the absence of regeneration of this system in previous studies, I was doubtful that most therapies taken to humans would improve function. Now that we can regenerate the most important motor system for humans, I think that the potential for translation is more promising.”

This is certainly exciting work, but even though it worked in rats, it may not yet work in humans. The road from pre-clinical studies in animals to clinical trials in humans is a long, tedious, frustrating, and uncertain pathway, pockmarked with the failures of past therapies that worked well in animals but failed to translate into successes in human patients.

“There is more work to do prior to moving to humans,” Tuszynski said. We must establish long-term safety and long-term functional benefit in animals. We must devise methods for transferring this technology to humans in larger animal models. And we must identify the best type of human neural stem cell to bring to the clinic.”