By Nana O 
A groundbreaking new study has unveiled a promising strategy for spinal cord repair, leveraging the inherent plasticity of pericytes, specialized cells found within the body’s smallest blood vessels. Researchers at The Ohio State University have demonstrated in preclinical models that by manipulating these pericytes with a specific growth factor, significant axon regeneration and functional recovery can be achieved following spinal cord injury. This discovery moves beyond simply addressing neuronal damage, highlighting the critical role of vascular restoration in neurological healing and opening potential avenues for treating a range of brain injuries and neurodegenerative diseases.
Pericytes: Unlocking a Hidden Regenerative Potential
Spinal cord injuries are devastating due to their dual impact: they sever vital neural communication pathways and simultaneously compromise the intricate network of blood vessels that nourish and support the central nervous system. Traditionally, research has focused on directly stimulating neuronal regeneration. However, this new research, published in the journal Molecular Therapy on April 18, shifts the paradigm by focusing on the often-overlooked pericytes.
Pericytes, which wrap around capillaries, are highly responsive to their microenvironment. Previous research had even suggested that in the context of spinal cord injury, these cells might impede recovery. This perspective stemmed partly from observations in cancer research, where pericytes play a role in tumor blood vessel formation. However, insights from cancer studies also revealed that a protein called platelet-derived growth factor BB (PDGF-BB) can significantly alter pericyte behavior. This observation sparked the curiosity of the Ohio State team, who hypothesized that this interaction could be harnessed for therapeutic benefit in spinal cord repair.
"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," said senior study author Andrea Tedeschi, 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."
The PDGF-BB Intervention: A Cellular Transformation
The core of the research involved understanding how PDGF-BB influences pericytes at the site of a spinal cord lesion. In their experiments, scientists first observed that following a spinal cord severing, pericytes do indeed migrate to the injury zone. However, in their natural state, they did not appear to foster the growth of functional blood vessels necessary for axon regeneration.
The critical breakthrough came when pericytes were exposed to PDGF-BB. This exposure triggered a remarkable transformation. The pericytes changed their shape, becoming more elongated and fibrous. Crucially, this morphological change was accompanied by a shift in their molecular activity: they began to inhibit the production of certain molecules while actively secreting others. This complex cellular reprogramming led to the formation of what the researchers termed "cellular bridges."
These bridges, formed by the altered pericytes, served a dual purpose. Firstly, they helped to stabilize and rebuild the compromised vasculature around the injury site. Secondly, and perhaps most significantly, they provided a supportive scaffold for the regeneration of axons – the long, slender extensions of nerve cells that transmit signals.
To validate these findings, the team conducted cell-culture experiments. They created a "carpet" of pericytes, exposed them to PDGF-BB, and then introduced adult mouse sensory neurons. The results were striking: axons from the neurons grew nearly as extensively as they do under normal, healthy conditions. Further investigation revealed that it wasn’t PDGF-BB alone, but rather the synergistic interaction between the growth factor and the pericytes that facilitated this growth. This interaction involved the rearrangement of fibronectin, a critical protein for tissue repair, cell attachment, and motility.
"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."
Promising Results in Animal Models
The true potential of this approach was then tested in mice with induced spinal cord injuries. The researchers waited for seven days post-injury – a timeframe considered equivalent to about nine months in a human adult, allowing for the natural inflammatory and cellular responses to establish – before administering a single injection of PDGF-BB directly to the injury site.
The outcomes observed four weeks after this single treatment were highly encouraging. Mice that received the PDGF-BB injection exhibited robust axon regenerative growth, a stark contrast to the limited regeneration seen in control groups. More importantly, these regenerated axons were observed to be "riding" the pericyte-formed cellular bridges, effectively bypassing the injury site.
"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, 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 anatomical regeneration, functional recovery was also a key indicator of success. Electrophysiological assessments confirmed sensory activity beyond the lesion site in the treated mice. Furthermore, these animals demonstrated a notable regained control of their hind limbs compared to their untreated counterparts. A significant observation was also a reduced sensitivity to non-painful stimuli, suggesting a decrease in neuropathic pain, a debilitating symptom that frequently accompanies spinal cord injuries.
Broader Implications and Future Directions
The implications of this research extend far beyond spinal cord injury. The study’s authors posit that this pericyte-based regenerative strategy could hold promise for treating other neurological conditions characterized by neuronal damage and vascular compromise, including traumatic brain injury, stroke, and various neurodegenerative diseases.
"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," Dr. Sun emphasized. "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 study also provided insights into the inflammatory response. Analysis of inflammatory proteins indicated that PDGF-BB administration not only stimulated axon regeneration but also appeared to reduce inflammation at the injury site. RNA sequencing revealed that while spinal cord injury led to some changes in gene expression within pericytes, they retained their core identity and did not transform into destructive cell types. Instead, they exhibited enhanced functions related to rebuilding and forming supportive structures.
"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 research builds upon previous work by Dr. Tedeschi and his colleagues, who have previously demonstrated that the drug gabapentin can promote neural circuit regeneration after spinal cord injury in mice. This prior success suggests the potential for a multipronged therapeutic approach, combining the modulation of intrinsic neuronal properties with the enhancement of the non-neuronal environment.
"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.
The research team is now focused on refining this therapeutic strategy. Future work will aim to determine the optimal timing for PDGF-BB administration, considering the time it takes for pericytes to migrate to the injury site. Investigations into the ideal concentration of the growth factor and the development of potential time-released delivery systems are also underway. The goal is to translate these promising preclinical findings into a viable clinical treatment.
A Timeline of Discovery
The journey leading to this significant discovery involved several key stages:
- Initial Observation: Researchers noted that pericytes accumulate at spinal cord injury sites but do not spontaneously promote functional blood vessel growth for regeneration.
- Leveraging Cancer Research Insights: Knowledge from cancer studies about PDGF-BB’s influence on pericyte behavior in tumor vascularization provided a critical clue.
- Cell Culture Experiments: Laboratory experiments demonstrated that exposing pericytes to PDGF-BB induced shape changes and created a scaffold conducive to axon growth.
- Animal Model Testing: Mice with spinal cord injuries received a single PDGF-BB injection, leading to significant axon regeneration and functional recovery.
- Human Cell Validation: Experiments with human pericytes confirmed that the observed growth-promoting effect is likely a generalized phenomenon.
- Publication: The comprehensive findings were published in the journal Molecular Therapy on April 18, making this advanced research accessible to the broader scientific community.
This research was generously supported by the National Institute of Neurological Disorders and Stroke and Ohio State’s Chronic Brain Injury Program, underscoring the national importance placed on advancing neurological repair strategies. 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, alongside Jerry Silver from Case Western Reserve University.
