By Nana O 
A groundbreaking new study is illuminating a potentially revolutionary strategy for repairing spinal cord injuries by capitalizing on the inherent flexibility of pericytes, specialized cells found within the body’s smallest blood vessels. This research, conducted by scientists at The Ohio State University, suggests that by manipulating these pericytes at the site of injury, significant regeneration of nerve fibers and subsequent recovery of motor function can be achieved.
Unlocking Pericyte Potential for Neural Regeneration
The core of this innovative approach lies in understanding and redirecting the behavior of pericytes. These cells, typically encasing capillaries and venules, play a crucial role in maintaining vascular stability. However, in the aftermath of a spinal cord injury, they migrate in large numbers to the lesion zone. While previously thought by some to be an impediment to recovery, this new research posits that pericytes can be coaxed into becoming active participants in the repair process.
In meticulously designed experiments involving mice, researchers introduced a specific recombinant protein, platelet-derived growth factor BB (PDGF-BB), to the injured spinal cord regions where pericytes had congregated. The results were striking: upon exposure to PDGF-BB, these pericytes underwent a remarkable transformation. They altered their morphology, ceasing the production of certain inhibitory molecules and commencing the secretion of others. This orchestrated cellular activity led to the formation of what the researchers describe as "cellular bridges"—structures that effectively scaffold and support the regeneration of axons, the vital long, slender extensions of nerve cells responsible for transmitting signals.
Evidence of Functional Recovery in Animal Models
The efficacy of this single-injection treatment was vividly demonstrated in the mouse experiments. Animals that received the growth-factor protein exhibited significant axon regrowth across the injury site. Crucially, this biological repair translated into tangible functional improvements, with the mice regaining movement in their hind limbs. This recovery was not a fleeting phenomenon; the study detailed a sustained improvement in motor control.
To assess the broader applicability of their findings, the research team also conducted experiments using human pericytes in cell cultures. The results from these experiments suggested that the observed growth-promoting effects were not exclusive to rodent biology, hinting at a conserved mechanism with potential for human therapeutic translation.
A Paradigm Shift in Spinal Cord Injury Treatment
Dr. Andrea Tedeschi, Associate Professor of Neuroscience at The Ohio State University College of Medicine and senior study author, expressed profound optimism about the discovery. "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," Dr. Tedeschi stated. She further elaborated on the far-reaching implications of this research, suggesting that its impact could extend beyond spinal cord injuries. "This finding goes beyond spinal cord injury — it has implications in brain injury and stroke, and neurodegenerative diseases as well."
The study underscores a fundamental principle often overlooked in spinal cord injury research: the indispensable role of vascular restoration in achieving neurological recovery. Spinal cord injuries present a dual challenge: they disrupt the transmission of neural information and simultaneously compromise the intricate network of blood vessels that nourish and support nervous tissue.
"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," explained Dr. Wenjing Sun, Assistant Professor of Neuroscience at Ohio State and first study author. "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 Scientific Journey: From Observation to Intervention
The genesis of this research can be traced back to earlier scientific observations that painted a complex picture of pericyte behavior following spinal cord injury. Some prior research had suggested that pericytes might hinder recovery, leading to strategies aimed at their clearance from the injury site. However, insights gleaned from cancer research offered a different perspective. Studies on tumor angiogenesis, the process by which tumors generate their own blood supply, revealed that pericytes’ functional properties are significantly altered when exposed to PDGF-BB. In the context of cancer, the objective is often to block PDGF-BB signaling to starve tumors.
This provided a crucial pivot point for Dr. Tedeschi and his colleagues. They recognized that the inherent "plasticity" of pericytes—their remarkable responsiveness to environmental cues—could be harnessed rather than suppressed. Neuroscience research had already established that pericytes are highly adaptable to microenvironmental changes, including the presence of growth factors like PDGF-BB. The Ohio State team hypothesized that by strategically introducing PDGF-BB, they could leverage this plasticity to stabilize the compromised vasculature surrounding a spinal cord injury and, in doing so, create a conducive environment for axonal regeneration.
A Step-by-Step Unveiling of the Mechanism
The research journey began with detailed imaging studies that confirmed the migration of pericytes into the spinal cord lesion zone over time following injury. However, these naturally migrating pericytes did not spontaneously promote the formation of functional blood vessels necessary for supporting axon regeneration.
To precisely investigate the pericyte-PDGF-BB interaction, the researchers moved to controlled cell-culture experiments. They created a "carpet" of pericytes in a laboratory setting, introduced PDGF-BB, and then placed a layer of adult mouse sensory neurons on top. Over a 24-hour period, they meticulously evaluated axon growth. The results were compelling: axons cultured on the PDGF-BB-treated pericytes exhibited growth rates nearly comparable to those observed in healthy, uninjured axons.
Further analysis revealed that PDGF-BB alone was not the sole driver of this enhanced growth. Instead, the synergy between pericytes and PDGF-BB was key. Experiments demonstrated that this combination facilitated the rearrangement of fibronectin, a critical protein involved in tissue repair, cell adhesion, and motility. Simultaneously, the pericytes themselves underwent a significant morphological change, elongating into more streamlined, fiber-like structures.
"We know these cells are going to infiltrate and deposit at the lesion epicenter," Dr. 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."
Bridging the Gap: From Lab Bench to Clinical Relevance
The transition from in vitro observations to in vivo application involved rigorous animal testing. After inducing spinal cord injuries in mice, researchers waited for seven days—a timeframe considered roughly equivalent to nine months in human adults, allowing sufficient time for pericyte migration to the injury site. A single dose of PDGF-BB was then injected directly into the lesion.
Four weeks post-injection, tissue analysis revealed a dramatic difference. The PDGF-BB treated mice showed robust axon regenerative growth compared to their untreated counterparts. The cellular bridges, formed by the activated pericytes, were clearly visible and acting as conduits.
"When we looked at formation of these pericyte structures that crossed the injury site, we saw the treatment promoted the growth of these bridges," Dr. Sun elaborated. "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."
Measuring Success: Functional Recovery and Reduced Pathology
The impact of this treatment extended beyond microscopic regeneration. Electrophysiological assessments confirmed the restoration of sensory activity beyond the lesion site in the treated animals. Furthermore, behavioral tests demonstrated a significant improvement in hind limb control in the mice that received PDGF-BB. An important observation was the reduced sensitivity to non-painful stimuli in treated animals, suggesting a decrease in neuropathic pain, a debilitating consequence of spinal cord injury.
Analysis of inflammatory markers during the repair process provided another layer of insight. The study indicated that PDGF-BB administration not only stimulated axon regeneration but also played a role in mitigating inflammation, a common factor that can impede healing after injury. RNA sequencing revealed that while spinal cord injury did lead to a decrease in certain gene expressions by pericytes, these cells maintained their fundamental identity and did not transform into detrimental cell types.
"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 noted. "From the overall gene signature in our data, they’re still classified as a pericyte." This suggests that the treatment enhances, rather than alters, their core function in a beneficial way.
Future Directions and Combination Therapies
The potential for a multi-pronged therapeutic approach is also being explored. Building on previous work by Dr. Tedeschi and colleagues, which demonstrated the efficacy of gabapentin in promoting neural circuit regeneration after spinal cord injury, researchers are considering combining therapies.
"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," Dr. Sun suggested. This integrated strategy could potentially offer synergistic benefits, addressing both the neuronal and the supportive cellular microenvironment.
Significant work remains to optimize this promising therapy. Future research will focus on determining the precise timing for PDGF-BB administration, considering the time required for pericytes to migrate to the injury site. Investigations into the ideal concentration of the treatment and the development of potential time-released delivery systems are also high on the agenda.
This pioneering research was generously supported by funding from the National Institute of Neurological Disorders and Stroke and Ohio State’s Chronic Brain Injury Program. The study’s publication in the esteemed journal Molecular Therapy on April 18 marks a significant milestone in the quest for effective spinal cord injury treatments. The collaborative efforts of a dedicated team, 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, have brought this innovative strategy to the forefront of regenerative medicine.
