By Nana O 
A groundbreaking new study suggests that harnessing the inherent flexibility of pericytes, the minuscule cells found within the body’s smallest blood vessels, could represent a potent new strategy for repairing spinal cord injuries. Researchers at The Ohio State University have demonstrated in mouse models that a specific recombinant protein can transform these pericytes into cellular architects, building bridges that support the regrowth of damaged nerve fibers and leading to significant functional recovery. This discovery not only offers a promising avenue for spinal cord injury treatment but also carries potential implications for a range of neurological conditions, including brain injury, stroke, and neurodegenerative diseases.
The Pericyte Pathway: A New Approach to Spinal Cord Regeneration
For years, the scientific community has grappled with the complex challenges of spinal cord injury (SCI). The severity of these injuries stems not only from the disruption of nerve signal transmission but also from the cascading damage to the intricate network of blood vessels that supply the spinal cord. This compromised vasculature further impedes the body’s natural healing processes, creating a formidable barrier to functional recovery.
Previous research had, in some instances, pointed towards pericytes as potential impediments to spinal cord repair. These cells, which wrap around capillaries and venules, play a crucial role in maintaining blood vessel integrity. However, their behavior in the context of injury had been a subject of ongoing investigation. The new research, published on April 18 in the esteemed journal Molecular Therapy, flips this narrative by revealing a remarkable capacity within pericytes to facilitate regeneration when appropriately stimulated.
The Ohio State University team, led by senior study author Andrea Tedeschi, an associate professor of neuroscience, and first author Wenjing Sun, an assistant professor of neuroscience, focused on the interaction between pericytes and a specific protein: platelet-derived growth factor BB (PDGF-BB). This growth factor is already known in cancer research for its role in promoting tumor vascularization, where the goal is typically to block its signaling. However, the researchers hypothesized that in the context of spinal cord injury, PDGF-BB might have a restorative effect.
From Cell Culture to Functional Recovery: A Chronology of Discovery
The journey of this discovery began with meticulous laboratory experiments. Initially, researchers observed that following a spinal cord severing injury in mice, pericytes did migrate to the lesion site. However, they did not spontaneously promote the growth of the robust, functional blood vessels necessary to support the regeneration of axons, the vital extensions of nerve cells that transmit signals.
To investigate further, the team conducted in vitro experiments using cell cultures. They created a "carpet" of pericytes and then introduced PDGF-BB. On top of this treated pericyte layer, they placed adult mouse sensory neurons. The results were striking: the axons of these neurons exhibited significant growth, extending nearly as much as they would under normal, healthy conditions within just 24 hours. This indicated that the combination of pericytes and PDGF-BB created a highly conducive environment for axon regeneration.
Crucially, PDGF-BB alone did not elicit this growth-promoting effect. The research revealed that when pericytes were exposed to PDGF-BB, they underwent a transformation. They rearranged fibronectin, a critical protein involved in tissue repair, cell adhesion, and motility. More dramatically, the pericytes themselves changed shape, becoming more elongated and forming what the researchers termed "cellular bridges." These structures, the study suggests, provide a physical scaffold and a permissive pathway for regenerating axons to navigate across the injury site.
"We know these cells are going to infiltrate and deposit at the lesion epicenter," explained Dr. 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."
Translating Findings to Human Relevance and Animal Models
The potential clinical relevance of these findings was further explored through experiments involving human cells. The team cultured mouse neurons on top of human pericytes that had been exposed to PDGF-BB. This experiment also triggered a growth-promoting effect, suggesting that the observed phenomenon is not exclusive to mice and could hold true for human spinal cord injuries.
Building on these promising cell-culture results, the researchers moved to animal models with actual spinal cord injuries. A critical aspect of this phase was the timing of intervention. Recognizing that pericytes need time to migrate to the injury site, the scientists waited seven days after inducing the injury in mice – a timeframe roughly equivalent to nine months in a human adult. At this point, they administered a single injection of PDGF-BB directly to the injury site.
The outcomes observed four weeks post-injury were compelling. The PDGF-BB injection led to robust axon regenerative growth when compared to the injured control mice that did not receive the treatment. Detailed analysis of the tissue revealed that the treatment significantly promoted the formation of the pericyte-derived cellular bridges spanning the injury. Importantly, a substantial proportion of these regenerating axons successfully navigated the injury site by utilizing these newly formed bridges.
"When we looked at formation of these pericyte structures that crossed the injury site, we saw the treatment promoted the growth of these bridges," stated Dr. Sun. "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 Axon Regrowth: Functional Recovery and Reduced Inflammation
The impact of the PDGF-BB treatment extended beyond mere anatomical regeneration. Electrophysiological assessments confirmed sensory activity beyond the lesion site, indicating that nerve signals were being transmitted once again. Furthermore, the treated mice demonstrated improved control over their hind limbs, a significant indicator of functional recovery. Anecdotally, these animals also exhibited reduced sensitivity to a non-painful stimulus, suggesting a potential decrease in neuropathic pain, a debilitating consequence often associated with spinal cord injuries.
The study also delved into the inflammatory response following injury and treatment. Analysis of inflammatory proteins indicated that PDGF-BB administration not only facilitated axon regeneration but also appeared to mitigate inflammation. RNA sequencing provided further insights, revealing that while spinal cord injury led to a decrease in gene expression by pericytes, these cells largely retained their fundamental identity. They did not appear to transform into destructive cell types that could exacerbate the injury environment.
"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," Dr. Sun elaborated. "From the overall gene signature in our data, they’re still classified as a pericyte." This finding is crucial, as it suggests that the treatment is not forcing a complete cellular identity change, but rather coaxing existing cells to perform a beneficial regenerative function.
A Multimodal Future for Neurological Repair
The implications of this research are far-reaching. While spinal cord injury is the primary focus, the underlying principle of modulating the non-neuronal environment to support neural regeneration holds promise for other neurological conditions.
"This finding goes beyond spinal cord injury — it has implications in brain injury and stroke, and neurodegenerative diseases as well," emphasized Dr. Tedeschi. The complexity of these conditions often involves compromised vasculature and glial scar formation, both of which could potentially be addressed by strategies similar to the one explored in this study.
The researchers are also considering the potential for multimodal therapeutic approaches. Dr. Sun noted their previous work demonstrating that gabapentin can promote neural circuit regeneration after SCI. "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 synergistic approach could offer a more comprehensive and effective treatment strategy.
Next Steps and Broader Impact
The path from laboratory discovery to clinical application is often a long one, and the Ohio State University team is actively planning the next stages of their research. Key areas for further investigation include precisely determining the optimal timing for PDGF-BB administration, considering the migration kinetics of pericytes. They also aim to identify the ideal concentration of the growth factor and explore the development of a potential time-released delivery system to ensure sustained therapeutic effects.
The study was supported by significant funding from the National Institute of Neurological Disorders and Stroke and Ohio State’s Chronic Brain Injury Program, underscoring the national importance of this research. The collaborative effort involved a dedicated team of researchers, including 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, along with Jerry Silver from Case Western Reserve University.
This pioneering work offers a beacon of hope for individuals living with spinal cord injuries and other devastating neurological conditions. By revealing the remarkable regenerative potential of pericytes, the research team has opened a new frontier in the quest for effective neurological repair, demonstrating that even the smallest components of our vascular system can play a monumental role in healing. The ability to coax these tiny cells into rebuilding critical pathways represents a significant leap forward, promising a future where recovery and improved quality of life are within closer reach.