By Nana O 
Capitalizing on the inherent flexibility of pericytes, minuscule cells found within the body’s smallest blood vessels, may represent a powerful new strategy for repairing spinal cord injuries, according to groundbreaking research published on April 18 in the journal Molecular Therapy. This innovative approach, demonstrated in mouse models, has shown remarkable potential in promoting axon regeneration and restoring motor function, suggesting a paradigm shift in how scientists approach neurological damage.
Unlocking Pericyte Potential: A Cellular Bridge to Regeneration
The crux of this discovery lies in manipulating pericytes, cells that typically ensheath capillaries, playing a crucial role in vascular stability and blood-brain barrier integrity. Historically, research on spinal cord injuries had sometimes viewed pericytes as impediments to recovery, with some studies suggesting their clearance might aid repair. However, this new research, spearheaded by scientists at The Ohio State University, flips that notion on its head, revealing their untapped regenerative capacity.
In meticulously designed mouse experiments, researchers observed that following a spinal cord injury, pericytes migrate to the lesion zone. The pivotal breakthrough came when scientists introduced a specific recombinant protein, platelet-derived growth factor BB (PDGF-BB), to these pericyte-rich areas. The results were striking: exposure to PDGF-BB triggered a profound transformation in the pericytes. They altered their morphology, becoming more elongated and forming what the researchers describe as "cellular bridges." Concurrently, these cells modulated the production of certain molecules, inhibiting inhibitory factors and secreting others that actively support the regeneration of axons—the critical nerve fibers responsible for transmitting signals throughout the nervous system.
"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 Timeline of Discovery: From Observation to Intervention
The journey to this pivotal discovery was built upon a foundation of existing scientific knowledge and careful observation. For years, the complex cellular environment following a spinal cord injury has been a significant challenge for researchers. Injuries not only sever neuronal pathways but also severely disrupt the intricate network of blood vessels, compromising the vital supply of oxygen and nutrients to the damaged tissue.
Previous research had hinted at the plasticity of pericytes, their remarkable ability to adapt to their microenvironment. This, coupled with insights from cancer research—where PDGF-BB is known to play a role in tumor vascularization—provided a crucial link. In cancer, the goal is often to block PDGF-BB signaling to inhibit tumor growth. Tedeschi and his team hypothesized that the opposite might be true in the context of spinal cord injury: could activating PDGF-BB signaling in pericytes promote repair?
Their initial investigations began with advanced imaging studies. These confirmed that while pericytes do infiltrate the injury site, they do not, on their own, foster the growth of functional blood vessels essential for supporting axon regeneration. This observation underscored the need for an external intervention.
The team then moved to in vitro experiments, creating a "carpet" of pericytes in cell cultures. Upon adding PDGF-BB and subsequently introducing adult mouse sensory neurons, they observed unprecedented axon growth. In a 24-hour period, the treated axons extended nearly as much as healthy axons do under normal physiological conditions. This indicated that the PDGF-BB, in conjunction with the pericytes, was creating a more hospitable environment for neuronal repair.
Further analysis revealed that PDGF-BB alone was insufficient. The synergy lay in how the pericytes, activated by PDGF-BB, rearranged fibronectin, a key protein involved in tissue repair, cell adhesion, and motility. The pericytes themselves transformed into elongated, fiber-like structures. "We know these cells are going to infiltrate and deposit at the lesion epicenter," explained Tedeschi. "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."
Clinical Relevance and Translational Potential
Crucially, the researchers sought to determine if these findings extended beyond mouse models. They conducted experiments using human pericytes, culturing them with PDGF-BB and then exposing them to mouse neurons. The observed growth-promoting effect in these experiments suggests that the therapeutic potential of this approach is likely not limited 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," the researchers reported.
Animal Studies: Demonstrating Functional Recovery
The most compelling evidence for this novel therapy emerged from experiments involving mice with induced spinal cord injuries. The researchers strategically waited for seven days post-injury—a timeframe analogous to approximately nine months in a human adult—before administering a single injection of PDGF-BB directly at the injury site. This waiting period allowed for the natural migration of pericytes to the injury zone.
Four weeks after this single intervention, tissue analysis revealed a significant difference. The PDGF-BB treated mice exhibited robust axon regenerative growth, a stark contrast to the limited regeneration 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," said first study author Wenjing Sun, an assistant professor of neuroscience at Ohio State. "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."
Beyond structural regeneration, the functional outcomes were equally encouraging. Electrophysiological assessments demonstrated sensory activity beyond the lesion site in treated animals, indicating the successful transmission of nerve signals. Furthermore, behavioral tests revealed that the treated mice regained significantly better control of their hind limbs compared to their untreated counterparts. Notably, the treated animals also showed a reduced sensitivity to a non-painful stimulus, suggesting a potential decrease in neuropathic pain, a common and debilitating complication of spinal cord injuries.
Beyond Regeneration: Anti-Inflammatory Effects and Cellular Stability
The study also delved into the broader impact of PDGF-BB treatment on the injured spinal cord environment. Analysis of inflammatory markers revealed that the administration of PDGF-BB not only promoted axon regeneration but also appeared to reduce inflammation. This dual action is critical, as chronic inflammation can further exacerbate tissue damage and hinder recovery.
RNA sequencing data provided further insights into the behavior of pericytes under these conditions. While spinal cord injury led to a decrease in certain gene expressions typically associated with pericytes, the cells retained their fundamental identity and did not transform into entirely different cell types that could be detrimental to the healing process. "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 elaborated. "From the overall gene signature in our data, they’re still classified as a pericyte." This finding is crucial, as it suggests the treatment harnesses the existing pericyte population rather than relying on unpredictable cellular transdifferentiation.
The Broader Implications: A Multifaceted Approach to Neurological Repair
The implications of this research extend far beyond spinal cord injuries. The fundamental principle of leveraging the regenerative capacity of pericytes in response to specific growth factors holds promise for treating a range of neurological conditions. "This finding goes beyond spinal cord injury—it has implications in brain injury and stroke, and neurodegenerative diseases as well," Tedeschi emphasized.
The work underscores the profound importance of vascular restoration in achieving neurological recovery. "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," Sun explained. "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." This integrated approach, addressing both neuronal and vascular components of injury, is a key takeaway.
Furthermore, this research opens the door to potentially combining therapeutic strategies for enhanced outcomes. Tedeschi and colleagues have previously demonstrated the efficacy of gabapentin in promoting neural circuit regeneration after spinal cord injury. This new research suggests a synergistic approach. "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 proposed.
Future Directions and Funding
While the current findings are highly encouraging, further research is necessary to optimize this promising therapy. Future studies will focus on determining the precise timing for PDGF-BB administration, considering the time required for pericytes to migrate to the injury site. Researchers will also investigate the ideal concentration of the treatment and explore the development of potential time-released delivery systems to ensure sustained therapeutic effects.
This significant research was made possible through funding from the National Institute of Neurological Disorders and Stroke and Ohio State’s Chronic Brain Injury Program. The study’s co-authors include Elliot Dion, Fabio Laredo, Allyson Okonak, Jesse Sepeda, Esraa Haykal, Min Zhou, Heithem El-Hodiri, Andy Fischer, Juan Peng, and Andrew Sas from The Ohio State University, as well as Jerry Silver from Case Western Reserve University. Their collective efforts have paved the way for a new era of potential spinal cord repair.
