By Nana O 
New research spearheaded by scientists at The Ohio State University has unveiled a potentially transformative strategy for spinal cord repair, focusing on the remarkable plasticity of pericytes – tiny cells that reside within the body’s smallest blood vessels. In a groundbreaking study conducted on mice, researchers demonstrated that by introducing a specific recombinant protein, they could induce these pericytes to facilitate significant axon regeneration and restore motor function after spinal cord injury. This finding not only offers a beacon of hope for individuals living with spinal cord injuries but also hints at broader applications for neurological damage across various conditions.
The Pericyte Puzzle: From Obstacle to Ally
Historically, pericytes have been viewed with a degree of skepticism in the context of spinal cord injury recovery. Some prior research suggested that these cells might actually impede the healing process. This perception was partly influenced by observations in cancer research, where pericytes play a role in tumor growth and blood vessel formation. In that context, the protein platelet-derived growth factor BB (PDGF-BB) was identified as a key signaling molecule that pericytes respond to, often in ways that support pathological vascularization. Scientists in that field sought to block PDGF-BB signaling to starve tumors.
However, the Ohio State University team, led by senior study author Andrea Tedeschi, an associate professor of neuroscience, recognized that the very responsiveness of pericytes – their inherent "plasticity" – could be harnessed for therapeutic benefit. Pericytes are highly adaptable cells, meaning they readily change their behavior and function in response to signals in their microenvironment. This characteristic, combined with insights from cancer research indicating pericytes’ involvement with PDGF-BB, sparked the investigation into whether this cell-protein interaction could be manipulated to promote healing rather than hinder it.
"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 Professor Tedeschi. "This finding goes beyond spinal cord injury – it has implications in brain injury and stroke, and neurodegenerative diseases as well."
The PDGF-BB Breakthrough: Engineering Cellular Bridges
The core of the new research lies in the specific application of PDGF-BB to the site of a spinal cord injury. Following a spinal cord severance in mice, the researchers observed that pericytes, which are normally distributed along blood vessels, migrated to the lesion zone. However, without external intervention, these cells did not effectively support the growth of functional blood vessels crucial for repairing damaged nerve tissue.
The pivotal moment came when the research team introduced PDGF-BB to these pericyte-rich injury sites. The results were dramatic. Upon exposure to PDGF-BB, the pericytes underwent a remarkable transformation. They altered their shape, becoming more elongated and fiber-like. Simultaneously, their molecular activity shifted: they began to inhibit the production of certain inhibitory molecules and secrete others that are conducive to nerve regeneration.
Crucially, these activated pericytes formed what the researchers described as "cellular bridges" across the injured area. These bridges, constructed from the reorganized pericyte structures and associated extracellular matrix proteins like fibronectin, provided a supportive scaffold. This scaffold then served as a pathway for axons – the long, slender projections of nerve cells that transmit electrical and chemical signals – to regrow and extend across the injury site.
From Lab Bench to Animal Models: Demonstrating Efficacy
The research team conducted a series of experiments to validate their findings. Initial in vitro studies involved creating a "carpet" of pericytes in cell culture. When PDGF-BB was added and adult mouse sensory neurons were placed on top, the axons exhibited significant growth within 24 hours, reaching lengths comparable to those of healthy axons under normal conditions. This demonstrated that PDGF-BB, in conjunction with pericytes, could create a highly permissive environment for axon extension.
Further analysis revealed that the pericytes, under the influence of PDGF-BB, didn’t just passively form bridges. They actively rearranged fibronectin, a key protein involved in tissue repair, cell adhesion, and motility. This reorganization, coupled with the pericytes’ shape change, created a robust and growth-promoting substrate.
"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," explained Professor Tedeschi.
To ascertain the clinical relevance of their findings, the researchers conducted experiments using human pericytes. When cultured with PDGF-BB, these human cells also demonstrated a growth-promoting effect on mouse neurons, suggesting that the observed phenomenon is not species-specific and holds potential for human therapies.
Animal Trials Show Significant Functional Recovery
The most compelling evidence emerged from experiments with mice that had sustained spinal cord injuries. The researchers waited seven days after the injury – a period roughly equivalent to nine months in human adults, allowing the initial inflammatory response to subside and pericytes to migrate to the injury site. At this point, a single injection of PDGF-BB was administered.
Four weeks post-treatment, tissue analysis revealed substantial axon regenerative growth in the treated mice, far exceeding that observed in untreated control groups. The study’s first author, Wenjing Sun, an assistant professor of neuroscience at Ohio State, detailed the findings: "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 treated animals exhibited notable functional improvements. Electrophysiological assessments confirmed sensory activity beyond the lesion site, indicating the re-establishment of nerve signal transmission. Critically, these mice regained better control of their hind limbs compared to their untreated counterparts. Furthermore, the treated animals displayed reduced sensitivity to non-painful stimuli, suggesting a decrease in neuropathic pain, a debilitating condition often associated with spinal cord injuries.
Beyond Regeneration: Anti-inflammatory Effects and Cellular Stability
The research also uncovered a surprising anti-inflammatory benefit associated with PDGF-BB administration. Analysis of inflammatory proteins during the repair process indicated that the treatment not only fostered axon regeneration but also appeared to dampen the inflammatory cascade. This is significant because chronic inflammation can further exacerbate damage and impede recovery after spinal cord injury.
RNA sequencing provided further insights into the behavior of pericytes. The study found that while spinal cord injury did lead to a decrease in some gene expression in pericytes, these cells largely retained their fundamental identity. They did not convert into entirely different cell types that could potentially be detrimental to the healing environment. Instead, they exhibited enhanced functions related to rebuilding cellular bridges and supporting vascular repair.
"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," explained Sun. "From the overall gene signature in our data, they’re still classified as a pericyte." This stability is crucial, as it ensures the therapeutic intervention leverages the pericytes’ inherent capabilities without inducing unwanted cellular transformations.
A Multimodal Approach to Spinal Cord Repair
The implications of this research are profound, suggesting a paradigm shift in how spinal cord injuries are approached therapeutically. The study underscores the critical role of vascular restoration in neurological recovery. As Professor Sun emphasized, "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. 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 researchers are now contemplating the potential for multimodal therapeutic strategies. Building on previous work by Professor Tedeschi and colleagues demonstrating the efficacy of gabapentin in promoting neural circuit regeneration after spinal cord injury, they envision combining different approaches.
"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," Professor Sun suggested. Such a combined approach could potentially address both the neuronal damage and the compromised supportive environment simultaneously, leading to more comprehensive and effective recovery.
Future Directions and Broader Impact
While the results are highly promising, further research is needed to optimize the therapeutic application of PDGF-BB. Key areas of investigation include determining the precise timing for PDGF-BB administration, considering the migration time of pericytes to the injury site. The ideal concentration of the growth factor and the development of a potential time-released delivery system are also critical considerations for translating these findings into clinical practice.
The study, published on April 18 in the journal Molecular Therapy, was supported by significant funding from the National Institute of Neurological Disorders and Stroke and Ohio State’s Chronic Brain Injury Program. The collaborative effort involved a team of researchers from The Ohio State University and Case Western Reserve University, highlighting the power of interdisciplinary scientific pursuit.
The broader implications of this research extend beyond spinal cord injury. The findings suggest that manipulating pericyte behavior could offer new therapeutic avenues for other forms of brain injury, stroke, and even neurodegenerative diseases, where vascular integrity and cellular support play crucial roles in disease progression and recovery. By understanding and harnessing the plasticity of these fundamental cellular components of our vascular system, scientists are paving the way for novel treatments that could significantly improve the lives of millions affected by neurological damage.