By Nana O 
Capitalizing on the inherent flexibility of tiny cells residing within the body’s smallest blood vessels may represent a significant breakthrough in spinal cord repair, according to groundbreaking new research. Scientists have demonstrated in preclinical models that a targeted intervention can transform these cells, known as pericytes, into crucial facilitators of neural regeneration, offering a novel therapeutic avenue for devastating spinal cord injuries.
Pericytes: From Cellular Obstacles to Regenerative Allies
For years, the role of pericytes in spinal cord injury (SCI) recovery has been a subject of debate. These cells, which wrap around the capillaries and venules throughout the body, were often viewed as contributing to the glial scar that forms after an injury, potentially hindering the regrowth of damaged nerve fibers. However, this latest research, published on April 18th in the journal Molecular Therapy, flips that perception, revealing a remarkable capacity for pericytes to actively support axon regeneration when appropriately stimulated.
The study, conducted by a team at The Ohio State University College of Medicine, focused on a specific type of recombinant protein: platelet-derived growth factor BB (PDGF-BB). This protein is well-known in cancer research for its role in promoting blood vessel formation in tumors, a process often targeted for therapeutic blockade. However, the researchers hypothesized that this same mechanism could be harnessed for beneficial purposes in tissue 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," stated senior study author Andrea Tedeschi, an associate professor of neuroscience at Ohio State. "This finding goes beyond spinal cord injury — it has implications in brain injury and stroke, and neurodegenerative diseases as well."
The Mechanism of Action: Cellular Bridges and Axon Guidance
The research team’s experiments involved introducing PDGF-BB to the site of spinal cord injuries in mice. They observed that in the presence of this growth factor, pericytes, which naturally infiltrate the lesion zone following an injury, undergo a dramatic transformation. Instead of forming scar tissue, these pericytes change their shape, becoming more elongated and organized. Crucially, this morphological shift leads to a dual action: the inhibition of certain inhibitory molecules and the secretion of others that are conducive to nerve fiber repair.
This orchestrated cellular response results in the formation of what the researchers term "cellular bridges." These bridges, composed of reoriented pericytes and associated extracellular matrix proteins like fibronectin, create a physical scaffold and a permissive environment that guides the regrowth of axons – the long, slender extensions of nerve cells that transmit signals.
Wenjing Sun, assistant professor of neuroscience at Ohio State and the study’s first author, elaborated on the significance of this finding. "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 explained. "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."
Preclinical Success: Restored Movement and Reduced Pain
The impact of this pericyte-modulating therapy was evident in the animal models. Mice that received a single injection of PDGF-BB at the injury site demonstrated significant axon regrowth. This anatomical repair translated directly into functional recovery, with the animals regaining movement in their hind limbs. Beyond motor function, the treated animals also showed a reduced sensitivity to non-painful stimuli, suggesting a potential mitigation of neuropathic pain, a debilitating common consequence of SCI.
The study’s authors also conducted experiments using human pericytes. By culturing human cells with PDGF-BB and then exposing them to mouse neurons, they observed a similar growth-promoting effect. This finding is critical, indicating that the therapeutic potential of this approach may not be limited to rodents and could hold relevance for human therapies.
Background and Context: Rethinking the Glial Scar
The prevailing understanding of SCI pathophysiology has long emphasized the detrimental role of the glial scar. This dense network of cells and molecules, primarily astrocytes and extracellular matrix components, forms rapidly after injury to wall off the damaged area. While intended to prevent further damage, it also presents a significant physical and biochemical barrier to axonal regeneration.
Previous research had sometimes implicated pericytes in the formation of this inhibitory scar tissue. However, the growing understanding of cellular plasticity – the ability of cells to adapt and change their function in response to their environment – began to suggest alternative roles. The observation in cancer research that pericytes’ behavior is dramatically altered by PDGF-BB provided a crucial clue. Scientists realized that instead of trying to eliminate pericytes, perhaps they could be reprogrammed to promote repair.
The Ohio State team built upon earlier neuroscience findings that highlighted the remarkable responsiveness of pericytes to environmental cues. Their innovative approach involved not only stimulating the pericytes but also observing how this stimulation influenced the broader microenvironment at the injury site. This led to the discovery that the activated pericytes not only facilitated axon growth but also contributed to the restoration of essential blood vessel structure and function, which is paramount for long-term tissue health and recovery.
A Chronology of Discovery and Development
The journey leading to this significant finding can be traced through several key stages of research:
- Initial Observations: Researchers first confirmed that after a spinal cord severing, pericytes migrate to the injury site. However, they observed that these cells, in their natural post-injury state, did not promote the formation of functional blood vessels necessary for axon regeneration.
- In Vitro Proof of Concept: Through meticulous cell-culture experiments, the team established a “carpet” of pericytes. When PDGF-BB was introduced, and adult mouse sensory neurons were placed on top, the axons exhibited remarkable growth, approaching levels seen in healthy, uninjured neural tissue.
- Understanding the Molecular Basis: Further investigation revealed that PDGF-BB did not directly stimulate axon growth. Instead, it induced pericytes to rearrange fibronectin, a vital protein for tissue repair and cell adhesion, and to adopt a more elongated, supportive morphology.
- Animal Model Validation: Translating these findings to live animals, the researchers administered a single dose of PDGF-BB seven days post-injury – a timeframe considered equivalent to about nine months in human SCI. Tissue analysis four weeks later showed significant axon regeneration.
- Functional and Pain Assessment: Electrophysiological recordings and behavioral assessments in the injured mice demonstrated restored sensory activity beyond the lesion site and improved hind limb control. Notably, a reduction in hypersensitivity to stimuli suggested a decrease in neuropathic pain.
- Human Cell Confirmation: The crucial step of culturing human pericytes with PDGF-BB and observing a growth-promoting effect provided strong evidence for the broad applicability of this therapeutic strategy.
Broader Implications: A Multifaceted Approach to Neurological Repair
The implications of this research extend far beyond spinal cord injury. Dr. Tedeschi highlighted the potential impact on other neurological conditions characterized by neuronal damage and loss of function. "This finding goes beyond spinal cord injury — it has implications in brain injury and stroke, and neurodegenerative diseases as well," she asserted. Conditions such as traumatic brain injury (TBI) and stroke, which also involve significant neuronal damage and vascular disruption, could potentially benefit from similar pericyte-modulating therapies. Furthermore, neurodegenerative diseases, where neuronal function declines over time, might also see novel treatment avenues opened by this research.
The study also sheds light on the complex interplay of cellular and molecular factors involved in neuroinflammation. Analysis of inflammatory proteins revealed that PDGF-BB administration not only promoted regeneration but also appeared to reduce inflammation at the injury site. RNA sequencing data indicated that while gene expression in pericytes shifted post-injury, they retained their fundamental identity, rather than transforming into potentially detrimental cell types. This suggests a finely tuned therapeutic response that promotes repair without triggering adverse cellular transformations.
Future Directions and Potential for Combination Therapies
While the results are highly promising, the research team acknowledges that further investigation is necessary before clinical translation. Key areas for future research include determining the optimal timing for PDGF-BB administration, considering the time required for pericytes to migrate to the injury site. The ideal concentration of the growth factor and the development of a potential time-released delivery system are also crucial considerations for maximizing therapeutic efficacy and minimizing potential side effects.
The potential for combining this pericyte-focused therapy with existing or emerging treatments is also a significant area of interest. Dr. Sun noted previous work by her lab 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 multimodal approach could offer a synergistic effect, addressing multiple aspects of the complex SCI pathology.
Support and Collaboration
This pioneering research was generously supported by grants from the National Institute of Neurological Disorders and Stroke and Ohio State’s Chronic Brain Injury Program. The study was a collaborative effort, with additional contributions from researchers 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, and Jerry Silver from Case Western Reserve University, underscoring the multidisciplinary nature of scientific advancement in this critical field. The findings represent a significant step forward in understanding and potentially treating a wide range of neurological injuries and diseases.