By Nana O 
A groundbreaking new study suggests that a novel approach to spinal cord repair could be unlocked by manipulating the behavior of pericytes, the small, flexible cells that reside within the body’s tiniest blood vessels. In experiments conducted on mice, researchers have demonstrated that a specific recombinant protein can transform these pericytes into architects of regeneration, fostering axon regrowth and leading to significant functional recovery in the animals. This discovery holds immense promise not only for spinal cord injuries but also for a broader spectrum of neurological conditions, including brain injuries, stroke, and neurodegenerative diseases.
Pericytes: Unlocking Their Regenerative Potential
The central tenet of this research, published on April 18th in the prestigious journal Molecular Therapy, revolves around the remarkable plasticity of pericytes. Traditionally, these cells have been viewed with a degree of suspicion in the context of spinal cord injury, with some prior research suggesting they might impede recovery. However, this new work, led by scientists at The Ohio State University, flips that narrative by demonstrating how to leverage their inherent properties for therapeutic benefit.
The breakthrough hinges on the application of a recombinant protein known as platelet-derived growth factor BB (PDGF-BB). This protein, previously known for its role in tumor blood vessel formation and thus targeted for inhibition in cancer research, is now revealed to have a profound and constructive impact on pericytes at injury sites.
"There’s a lot more that can be learned and a lot that can be expanded, but the more we worked on this, the more stunned we really were by the potency of this single treatment and how effective it was," stated senior study author Andrea Tedeschi, an associate professor of neuroscience at The Ohio State University College of Medicine. "This finding goes beyond spinal cord injury — it has implications in brain injury and stroke, and neurodegenerative diseases as well."
A Cellular Bridge to Axon Regeneration
The researchers observed that when PDGF-BB was introduced to the site of a spinal cord injury, pericytes, which naturally migrate to these damaged areas, underwent a significant transformation. Instead of hindering repair, these cells altered their shape, modulated the production of certain molecules, and secreted others. This orchestrated cellular response resulted in the formation of what the scientists describe as "cellular bridges." These bridges are crucial because they provide a scaffold or pathway that supports the regeneration of axons – the vital nerve fibers responsible for transmitting messages throughout the nervous system.
In the mouse experiments, a single injection of the PDGF-BB growth-factor protein at the injury site was sufficient to stimulate axon regrowth. Remarkably, the treated animals also showed a notable recovery of movement in their hind limbs, a critical indicator of functional improvement after spinal cord trauma. Further validation came from experiments involving human pericytes, suggesting that the observed regenerative effects are not exclusive to mice, thereby bolstering the potential for human therapeutic applications.
Understanding the Mechanics of Repair
The study delved into the intricate mechanisms underlying this regenerative process. Researchers meticulously documented how pericytes, when exposed to PDGF-BB, rearrange fibronectin, a critical glycoprotein involved in tissue repair, cell adhesion, and motility. Simultaneously, the pericytes themselves adopt a more elongated, fiber-like structure.
"We know these cells are going to infiltrate and deposit at the lesion epicenter. These elongated fiber structures that they become are far more permissive in promoting axons to regenerate from one end to the other and bypass the injury," Tedeschi explained. This structural transformation by pericytes effectively creates a permissive environment for the damaged axons to navigate and reconnect across the injury site.
The Critical Role of Vasculature in Neurological Recovery
This research also powerfully underscores the interconnectedness of vascular health and neurological function, particularly in the aftermath of a spinal cord injury. Spinal cord injuries are devastating not only because they disrupt neural communication but also because they severely compromise the integrity and function of the blood vessel network.
"Spinal cord injuries are severe not only because they prevent transmission of information across the site of the injury, but because all of the vasculature structure and function is also compromised," highlighted first study author Wenjing Sun, an assistant professor of neuroscience at Ohio State. "Even if you are able to reestablish neuronal connectivity from one end to the other, the overall effect will still not be maximized unless you take care of everything else that falls apart."
The study’s findings indicate that by promoting the formation of stable and functional blood vessels through pericyte modulation, the researchers are simultaneously addressing a critical component of the injured microenvironment, thereby creating a more conducive atmosphere for neuronal repair.
A Timeline of Discovery and a Glimpse into the Past
The genesis of this research can be traced back to an intriguing observation derived from cancer research. It had been noted that pericytes’ characteristics could be altered by PDGF-BB, a protein that tumors utilize to foster their own blood supply. This insight, coupled with earlier neuroscience findings that highlighted the high "plasticity" of pericytes – their responsiveness to their microenvironment – sparked the curiosity of Tedeschi and his colleagues. They began to explore whether this cell-protein relationship could be harnessed for constructive purposes in spinal cord injury.
The research team initiated their investigation with imaging studies to map the behavior of pericytes following a spinal cord sever. They observed that pericytes did indeed migrate to the injury site over time but, in the absence of specific intervention, did not contribute to the growth of the functional blood vessels essential for axon regeneration.
Subsequently, in controlled cell-culture experiments, the researchers created a "carpet" of pericytes, introduced PDGF-BB, and then introduced adult mouse sensory neurons. The results were striking: axons in the treated cultures grew significantly, nearly matching the extent of growth observed in healthy, uninjured axons under normal conditions. This demonstrated that the pericyte-PDGF-BB interaction was a potent driver of axon elongation.
Further experiments revealed that PDGF-BB alone was not the sole factor. The key lay in the synergistic interaction between the pericytes and the growth factor, which collectively orchestrated the rearrangement of fibronectin and led to the pericytes adopting their elongated, regenerative form.
Extending Clinical Relevance: From Mice to Humans
A crucial step in translating these findings towards human therapies involved testing the approach with human cells. The researchers successfully cultured mouse neurons on a layer of human pericytes that had been exposed to PDGF-BB. The outcome was a significant growth-promoting effect, providing compelling evidence that this regenerative phenomenon might be a generalized biological mechanism rather than being confined to rodents.
"To extend the clinical relevance of our findings, we cultured mouse neurons on top of human pericytes that were exposed to PDGF-BB, and that was sufficient to trigger a growth-promoting effect, suggesting that this might really be a generalized phenomenon that is not restricted to mice," stated Sun.
Animal Studies: Demonstrating Functional Recovery
Transitioning to animal models with induced spinal cord injuries, the researchers implemented a strategic treatment protocol. They waited seven days post-injury – a period roughly equivalent to nine months in a human adult – before administering a single dose of PDGF-BB directly to the injury site.
The results, analyzed four weeks after the initial injury, were highly encouraging. The PDGF-BB injection led to robust axon regenerative growth, significantly surpassing the regenerative capacity observed in injured control mice that did not receive the treatment.
"When we looked at formation of these pericyte structures that crossed the injury site, we saw the treatment promoted the growth of these bridges. And most if not all of these regenerating axons were able to escape the injury site by riding these cellular bridges that have formed in response to PDGF-BB administration," Sun elaborated.
Beyond structural regeneration, the treated animals exhibited tangible functional improvements. Electrophysiological assessments confirmed sensory activity beyond the lesion site, indicating restored nerve signaling. Furthermore, behavioral tests showed that the mice regained better control of their hind limbs compared to the untreated control group. An additional benefit observed was a reduced sensitivity to non-painful stimuli, suggesting a decrease in neuropathic pain, a common and debilitating consequence of spinal cord injuries.
Broader Implications and Future Directions
The research also shed light on the impact of PDGF-BB treatment on the inflammatory response following injury. Analysis of inflammatory proteins indicated that the treatment not only promoted axon regeneration but also helped to mitigate inflammation. Gene expression analysis revealed that while spinal cord injury led to a decrease in some gene expression by pericytes, these cells largely retained their fundamental identity and did not transform into destructive cell types.
"There was a decrease in some classical pericyte markers, but a gain of some additional function linked to the attempt to rebuild cellular bridges and functional vessels," Sun noted. "From the overall gene signature in our data, they’re still classified as a pericyte." This suggests a controlled and beneficial modulation rather than a complete cellular transformation.
The research team is also exploring the potential for combination therapies. Building on prior work by Tedeschi and colleagues demonstrating the efficacy of gabapentin in promoting neural circuit regeneration after spinal cord injury, there is a clear avenue for a multi-pronged therapeutic strategy.
"We could combine both — modulating intrinsic properties of adult neurons with a drug, and what we are doing here, modulating the non-neuronal environment to produce cellular interactions that provide a more permissive substrate for the neuron to grow on," Sun suggested.
The next phase of this research will focus on refining the therapeutic approach. Key areas of investigation include determining the optimal timing for PDGF-BB administration, considering the time it takes for pericytes to migrate to the injury site. Researchers will also aim to establish the ideal dosage and explore the development of a potential time-released delivery system to ensure sustained therapeutic effects.
This pioneering work was generously supported by funding from the National Institute of Neurological Disorders and Stroke and Ohio State’s Chronic Brain Injury Program. The collaborative efforts of a dedicated team, including Elliot Dion, Fabio Laredo, Allyson Okonak, Jesse Sepeda, Esraa Haykal, Min Zhou, Heithem El-Hodiri, Andy Fischer, Juan Peng, and Andrew Sas from Ohio State, alongside Jerry Silver from Case Western Reserve University, were instrumental in achieving these significant findings. The potential impact of this research on improving the lives of individuals affected by neurological damage is profound, offering a beacon of hope for future recovery and rehabilitation.
