By Nana O 
A groundbreaking discovery in spinal cord injury research is illuminating a potent new therapeutic avenue by leveraging the inherent plasticity of pericytes, a type of cell found within the body’s smallest blood vessels. New findings from The Ohio State University demonstrate that a specific recombinant protein, platelet-derived growth factor BB (PDGF-BB), can profoundly alter the behavior of these pericytes at injury sites, fostering an environment conducive to significant nerve regeneration and functional recovery in animal models. This innovative approach not only offers hope for spinal cord injury patients but also hints at broader applications for treating a range of neurological conditions, including brain injuries, strokes, and neurodegenerative diseases.
The Pericyte Powerhouse: A Shift in Understanding
For years, the role of pericytes in spinal cord injury has been a subject of scientific debate. Some earlier research suggested that these cells, which ensheath capillaries, might actually impede recovery by contributing to scar tissue formation or inhibiting axon growth. This led to theories proposing their removal as a potential strategy for enhancing repair. However, a deeper understanding of pericyte biology, partly informed by advancements in cancer research, has revealed a more nuanced and potentially beneficial role.
In oncology, it’s been observed that pericytes’ characteristics can be dramatically altered when exposed to PDGF-BB. This growth factor is known to play a crucial role in tumor angiogenesis, the process by which tumors develop their own blood supply. The therapeutic implication in cancer is often to block PDGF-BB signaling to starve the tumor. Conversely, the Ohio State University research team, led by senior author Andrea Tedeschi, associate professor of neuroscience, recognized the potential to harness this very interaction for regenerative purposes.
"We knew that pericytes were highly plastic, meaning they were very responsive to their environment, including growth factors like PDGF-BB," explained Dr. Tedeschi. "The idea was to see if we could manipulate that interaction to create a more supportive environment for nerve regeneration after a spinal cord injury."
The Experimental Journey: From Cell Culture to Animal Models
The research, published on April 18 in the prestigious journal Molecular Therapy, began with meticulous laboratory experiments. Scientists first established that following a spinal cord sever, pericytes migrate to the injury site. However, in their natural state post-injury, these cells did not appear to facilitate the growth of the functional blood vessels essential for supporting the regrowth of axons, the critical nerve fibers that transmit signals throughout the nervous system.
To test their hypothesis, researchers created a "carpet" of pericytes in cell cultures. This pericyte layer was then treated with PDGF-BB. Subsequently, adult mouse sensory neurons were introduced on top of this treated layer. The results were striking: axons from these neurons exhibited significant growth, reaching lengths comparable to those observed in healthy, uninjured neurons. This demonstrated that the combination of pericytes and PDGF-BB created a significantly more permissive substrate for axon extension than pericytes alone.
Further analysis revealed the underlying mechanism. It wasn’t just the presence of PDGF-BB that spurred growth. Instead, the growth factor induced pericytes to rearrange fibronectin, a vital protein involved in tissue repair, cell adhesion, and motility. Crucially, the pericytes themselves underwent a dramatic morphological change, elongating into fiber-like structures.
"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," Dr. Tedeschi elaborated. He emphasized that these transformed pericytes effectively formed "cellular bridges" across the damaged area, providing a physical pathway for regenerating axons.
Bridging the Gap: Human Cell Validation and Animal Success
The potential clinical relevance of these findings was further underscored by experiments involving human cells. When human pericytes, exposed to PDGF-BB, were used in the cell-culture model, they also demonstrated a growth-promoting effect on mouse neurons. This suggests that the observed phenomenon is not species-specific and holds promise for translation to human therapies.
Transitioning to animal models, the research team implemented a more clinically relevant timeline. They waited seven days after inducing spinal cord injuries in mice – a period equivalent to approximately nine months in a human adult – before administering a single injection of PDGF-BB directly at the injury site. This timing was chosen to allow pericytes sufficient time to migrate to the lesion.
The outcomes observed four weeks post-treatment were remarkable. Mice that received the PDGF-BB injection showed robust axon regenerative growth across the injury site. Detailed tissue analysis revealed that the pericyte-formed cellular bridges, induced by PDGF-BB, were instrumental in guiding these regenerating axons, allowing them to bypass the lesion.
"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," stated Wenjing Sun, assistant professor of neuroscience at Ohio State and first author of the study.
Restoring Function: Movement and Pain Reduction
The regenerative success translated into significant functional recovery. Electrophysiological assessments confirmed sensory activity beyond the lesion site in treated mice. More importantly, behavioral tests revealed that these animals regained better control of their hind limbs compared to untreated control groups.
Beyond motor function, the study also indicated a reduction in neuropathic pain, a debilitating and common consequence of spinal cord injury. Treated animals showed a decreased sensitivity to non-painful stimuli, suggesting a amelioration of this often-untreatable condition.
Unpacking the Mechanisms: Inflammation and Cellular Stability
Further investigations delved into the cellular and molecular responses. Analysis of inflammatory proteins revealed that PDGF-BB administration not only promoted axon regeneration but also appeared to reduce inflammation at the injury site. This dual action is critical, as chronic inflammation can exacerbate damage and hinder recovery.
RNA sequencing provided insights into the pericytes’ gene expression patterns. The study found that while spinal cord injury led to a decrease in some gene expression by pericytes, they retained their fundamental identity. They did not convert into entirely different cell types that could be detrimental to the healing environment. Instead, they acquired new functions related to rebuilding cellular bridges and functional blood vessels.
"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 clarified. "From the overall gene signature in our data, they’re still classified as a pericyte." This finding is crucial, as it indicates the therapy leverages the existing cellular machinery rather than introducing foreign elements or inducing potentially harmful transformations.
A Multimodal Future: Synergistic Therapies on the Horizon
The implications of this research extend beyond a single therapeutic agent. Dr. Sun highlighted the potential for combining this pericyte-modulating strategy with other promising interventions. The Ohio State team has previously demonstrated that gabapentin, a commonly prescribed medication, can promote neural circuit regeneration after spinal cord injury in mice.
"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," she suggested. This vision of a multimodal approach, integrating therapies that address both neuronal and non-neuronal components of the injured spinal cord, represents a significant leap forward in developing comprehensive treatment strategies.
Next Steps and Broader Implications
While the results are highly encouraging, researchers acknowledge that further work is necessary before this therapy can be translated to human clinical trials. Key areas for future investigation include determining the optimal timing for PDGF-BB administration, considering the time required for pericyte migration to the injury site. Establishing the ideal concentration of the growth factor and exploring potential time-released delivery systems to ensure sustained therapeutic effects are also critical next steps.
The significance of this research is amplified by the understanding that spinal cord injuries are not solely about the interruption of neural signals. As Dr. Tedeschi noted, "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." This study directly addresses the critical need for blood vessel restoration, recognizing that maximizing functional recovery requires a holistic approach that accounts for all damaged components of the nervous system.
The potential impact of harnessing pericytes through PDGF-BB therapy could be far-reaching. Beyond spinal cord injury, the principles demonstrated in this research offer a compelling rationale for exploring similar strategies in the treatment of brain injuries, which share commonalities in cellular and vascular damage. Furthermore, neurodegenerative diseases, characterized by the progressive loss of neurons and often associated with microvascular dysfunction, could also benefit from therapies that promote vascular health and create a supportive environment for neuronal survival and function.
This pioneering work, supported by the National Institute of Neurological Disorders and Stroke and Ohio State’s Chronic Brain Injury Program, represents a significant paradigm shift in spinal cord injury research. By unlocking the regenerative potential of pericytes, scientists are moving closer to developing effective treatments that could restore not only nerve function but also the intricate vascular network essential for neurological health, offering renewed hope to millions affected by devastating neurological conditions.
