By Nana O 
New research emerging from The Ohio State University is illuminating a groundbreaking approach to spinal cord injury repair, focusing on the remarkable plasticity of pericytes, tiny cells that reside within the body’s smallest blood vessels. These often-overlooked cells, when strategically stimulated, have demonstrated an unprecedented ability to foster axon regeneration and restore motor function in animal models, offering a beacon of hope for individuals living with paralysis. The findings, published on April 18th in the prestigious journal Molecular Therapy, suggest a paradigm shift in how scientists approach the complex challenge of neurological recovery.
The Pericyte Powerhouse: A New Frontier in Regeneration
For years, the prevailing understanding of spinal cord injuries has centered on the damage to neurons and the subsequent interruption of signal transmission. However, this latest research underscores a critical, interconnected element: the compromised state of the spinal cord’s vasculature. The delicate network of blood vessels, essential for supplying nutrients and removing waste, is severely disrupted following an injury. This damage not only impedes neuronal survival but also creates a hostile environment for any potential repair.
The study’s lead author, Wenjing Sun, assistant professor of neuroscience at Ohio State, emphasized this interconnectedness: "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 stated. "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 is where pericytes come into play. These cells, which ensheath capillaries and venules, were previously thought by some to hinder recovery, leading to strategies aimed at their removal. However, insights gleaned from cancer research, which investigated how tumors manipulate pericytes to generate their own blood supply, provided a crucial clue. Specifically, research indicated that pericytes’ behavior changes dramatically when exposed to platelet-derived growth factor BB (PDGF-BB). This protein, a key player in tumor angiogenesis, also demonstrated a profound influence on pericytes in the context of spinal cord injury.
A Molecular Trigger for Cellular Transformation
The research team, led by senior study author Andrea Tedeschi, associate professor of neuroscience at Ohio State, hypothesized that they could harness this pericyte-PDGF-BB interaction to promote spinal cord repair. Their approach involved introducing PDGF-BB to the site of a spinal cord injury in mice. The results were nothing short of astonishing.
Upon exposure to PDGF-BB, pericytes underwent a remarkable transformation. They changed shape, becoming elongated and forming what the researchers described as "cellular bridges." Crucially, these cellular structures inhibited the production of certain inhibitory molecules while simultaneously secreting others that are conducive to nerve regeneration. This shift in pericyte function created a more supportive microenvironment for axons, the long extensions of nerve cells that transmit signals.
"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," Tedeschi remarked, highlighting the unexpected efficacy of the intervention.
From Cell Culture to Animal Models: A Robust Discovery
The journey to this breakthrough began with meticulous laboratory work. Initially, the researchers observed that following a spinal cord severing, pericytes migrate to the injury site. However, in their natural state, they did not facilitate the growth of the functional blood vessels vital for axon regeneration.
To test their hypothesis, the team conducted cell-culture experiments. 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 compelling: axons from these neurons exhibited significant growth, extending nearly as much as they would under normal, healthy conditions. This growth was not achieved with PDGF-BB alone; it was the synergistic interaction between the pericytes and the growth factor that proved pivotal.
Further analysis revealed that the combination of pericytes and PDGF-BB led to the rearrangement of fibronectin, a critical glycoprotein involved in tissue repair, cell attachment, and motility. The pericytes themselves adopted a more elongated, fiber-like structure. "We know these cells are going to infiltrate and deposit at the lesion epicenter," Tedeschi explained. "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."
Human Cells Confirm Broad Applicability
A critical step in validating the potential clinical relevance of these findings was to assess whether the same effects could be observed with human cells. The researchers cultured mouse neurons on a layer of human pericytes that had been exposed to PDGF-BB. The positive results from this experiment strongly suggest that the observed growth-promoting effects are not limited to mice, indicating a potentially generalized phenomenon across species. This finding significantly bolsters the prospects for translating this research into human therapies.
Animal Trials: Restoring Movement and Reducing Pain
Emboldened by the cell culture results, the team moved to experiments involving mice with actual spinal cord injuries. They waited seven days post-injury – an interval roughly equivalent to nine months in a human adult – before administering a single dose of PDGF-BB directly to the injury site.
The impact of this single injection was profound. Four weeks after treatment, tissue analysis revealed robust axon regenerative growth in the treated mice, far exceeding that observed in control groups with untreated injuries. Wenjing Sun elaborated on these critical observations: "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."
Beyond structural regeneration, the functional recovery was equally impressive. Electrophysiological assessments confirmed sensory activity beyond the lesion site. Furthermore, the treated mice demonstrated a significant regain of control in their hind limbs compared to their untreated counterparts. Notably, these animals also exhibited reduced sensitivity to non-painful stimuli, suggesting a decrease in neuropathic pain, a debilitating side effect that frequently accompanies spinal cord injuries.
Beyond Regeneration: Anti-Inflammatory Effects and Cellular Stability
The research also uncovered an additional benefit of PDGF-BB treatment: a reduction in inflammation. Analysis of inflammatory proteins during the repair process indicated that the growth factor not only stimulated axon regeneration but also modulated the inflammatory response, a crucial aspect of healing and recovery.
RNA sequencing provided further insights into the behavior of pericytes post-injury. The study revealed that while spinal cord injury led to decreased gene expression in pericytes, they retained their fundamental identity and did not transform into detrimental cell types. Instead, they gained functions related to rebuilding cellular bridges and functional 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 explained. "From the overall gene signature in our data, they’re still classified as a pericyte." This stability is vital, as uncontrolled cellular differentiation can sometimes exacerbate injury environments.
A Multimodal Future for Spinal Cord Therapy
The potential of this research extends beyond a single therapeutic agent. The Ohio State team has previously demonstrated that gabapentin can promote neural circuit regeneration after spinal cord injury. This prior work suggests the possibility of a multimodal therapeutic approach, combining strategies that target both the neuronal and the non-neuronal environments.
"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, outlining a vision for synergistic treatments.
Next Steps and Broader Implications
While the results are highly promising, the researchers acknowledge that further investigation is necessary. Future work will focus on optimizing the timing of PDGF-BB administration, considering the time it takes for pericytes to migrate to the injury site. Determining the ideal concentration of the treatment and exploring potential time-released delivery systems are also key priorities.
The implications of this research extend beyond spinal cord injuries. Tedeschi noted, "This finding goes beyond spinal cord injury — it has implications in brain injury and stroke, and neurodegenerative diseases as well." The fundamental role of pericytes and vascular health in neurological function suggests that similar therapeutic strategies could be beneficial in a wide range of neurological conditions characterized by cellular damage and impaired blood vessel integrity.
This groundbreaking work was generously supported by the National Institute of Neurological Disorders and Stroke and Ohio State’s Chronic Brain Injury Program. The research team included 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, who all contributed significantly to this transformative study.
