For first time, researchers show functional benefit in animal model of key motor control system.
Writing in the March 28, 2016 issue of Nature Medicine, researchers at University of California, San Diego School of Medicine and Veterans Affairs San Diego Healthcare System, with colleagues in Japan and Wisconsin, report that they have successfully directed stem cell-derived neurons to regenerate lost tissue in damaged corticospinal tracts of rats, resulting in functional benefit.
“The corticospinal projection is the most important motor system in humans,” said senior study author 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. “It has not been successfully regenerated before. Many have tried, many have failed — including us, in previous efforts.”
“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.”
Specifically, the researchers grafted multipotent neural progenitor cells into sites of spinal cord injury in rats. The stem cells were directed to specifically develop as a spinal cord, and they did so robustly, forming functional synapses that improved forelimb movements in the rats. The feat upends an existing belief that corticospinal neurons lacked internal mechanisms needed for regeneration.
Previous studies have reported functional recovery in rats following various therapies for spinal cord injury, but none had involved regeneration of corticospinal axons. In humans, the corticospinal tract extends from the cerebral cortex in the upper brain down into the spinal cord.
“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.”
Nonetheless, the road to testing and treatment in people remains long and uncertain.
“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.”
About this genetics research
Co-authors include Ken Kadoya, UC San Diego and Kokkaido University, Japan; Paul Lu, UC San Diego and VA San Diego Healthcare System; Kenny Nguyen, Corrine Lee-Kubli, Kumamaru Hiromi, Gunnar Poplawski, Jennifer Dulin, Yoshio Takashima, Jeremy Biane and James Conner, UC San Diego; Lin Yao, Joshua Knackert and Su-Chun Zhang, University of Wisconsin.
Funding: Funding for this research came, in part, from the Veterans Administration, the National Institutes of Health (grant NS09881), the Craig H. Neilsen Foundation, the Bernard and Anne Spitzer Charitable Trust, the D. Miriam and Sheldon Adelson Medical Research Foundation and Kitami Kobayashi Hospital.
Source: Scott LaFee – UCSD Image Credit: The image is in the public domain. Original Research:Abstract for “Spinal cord reconstitution with homologous neural grafts enables robust corticospinal regeneration” by Ken Kadoya, Paul Lu, Kenny Nguyen, Corinne Lee-Kubli, Hiromi Kumamaru, Lin Yao, Joshua Knackert, Gunnar Poplawski, Jennifer N Dulin, Hans Strobl, Yoshio Takashima, Jeremy Biane, James Conner, Su-Chun Zhang and Mark H Tuszynski in Nature Medicine. Published online March 28 2016 doi:10.1038/nm.4066
The corticospinal tract (CST) is the most important motor system in humans, yet robust regeneration of this projection after spinal cord injury (SCI) has not been accomplished. In murine models of SCI, we report robust corticospinal axon regeneration, functional synapse formation and improved skilled forelimb function after grafting multipotent neural progenitor cells into sites of SCI. Corticospinal regeneration requires grafts to be driven toward caudalized (spinal cord), rather than rostralized, fates. Fully mature caudalized neural grafts also support corticospinal regeneration. Moreover, corticospinal axons can emerge from neural grafts and regenerate beyond the lesion, a process that is potentially related to the attenuation of the glial scar. Rat corticospinal axons also regenerate into human donor grafts of caudal spinal cord identity. Collectively, these findings indicate that spinal cord ‘replacement’ with homologous neural stem cells enables robust regeneration of the corticospinal projection within and beyond spinal cord lesion sites, achieving a major unmet goal of SCI research and offering new possibilities for clinical translation.
“Spinal cord reconstitution with homologous neural grafts enables robust corticospinal regeneration” by Ken Kadoya, Paul Lu, Kenny Nguyen, Corinne Lee-Kubli, Hiromi Kumamaru, Lin Yao, Joshua Knackert, Gunnar Poplawski, Jennifer N Dulin, Hans Strobl, Yoshio Takashima, Jeremy Biane, James Conner, Su-Chun Zhang and Mark H Tuszynski in Nature Medicine. Published online March 28 2016 doi:10.1038/nm.4066