By Nana O 
In a significant breakthrough that could redefine the landscape of spinal cord injury treatment, researchers have uncovered a novel strategy that capitalizes on the inherent flexibility of pericytes, a type of cell found in the body’s smallest blood vessels. New findings suggest that by strategically manipulating these pericytes at the site of injury, it’s possible to foster remarkable regeneration of nerve fibers and restore lost motor function. This pioneering approach, demonstrated initially in mouse models, holds profound implications not only for spinal cord injuries but also for a spectrum of neurological conditions, including brain injuries, strokes, and neurodegenerative diseases.
The Pericyte Power: A Cellular Bridge to Regeneration
The crux of this groundbreaking research, published on April 18th in the esteemed journal Molecular Therapy, lies in the remarkable plasticity of pericytes. These cells, often overlooked in the context of neurological repair, have now been revealed as key players capable of orchestrating a cascade of events essential for nerve regrowth. In essence, the scientific team has discovered a way to transform these cells from potentially inhibitory to actively supportive elements within the injured spinal cord environment.
The process begins with the infiltration of pericytes into the lesion zone following a spinal cord injury. Historically, the presence of these cells has been viewed with caution, with some prior research even suggesting they might impede recovery. However, this new study, spearheaded by scientists at The Ohio State University, challenges that perspective by demonstrating how to harness their unique capabilities.
"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 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."
A Targeted Intervention: The Role of PDGF-BB
The key to unlocking the regenerative potential of pericytes lies in their interaction with a specific recombinant protein: platelet-derived growth factor BB (PDGF-BB). This growth factor, known for its role in tumor angiogenesis (the formation of new blood vessels in tumors), has been repurposed in this research to promote a beneficial cellular response.
In experiments involving mice with spinal cord injuries, scientists introduced PDGF-BB to the damaged area. The results were striking: upon exposure to this protein, the pericytes underwent a significant transformation. They changed their shape, modulated the production of certain molecules, and secreted others. This orchestrated cellular response effectively created "cellular bridges" – structures that provided a crucial scaffold for the regeneration of axons. Axons are the long, slender extensions of nerve cells that transmit vital messages throughout the nervous system.
The impact was tangible. Mice that received a single injection of the PDGF-BB growth-factor protein demonstrated observable axon regrowth across the injury site. More importantly, these animals regained significant movement in their hind limbs, a critical indicator of functional recovery. This suggests that the intervention not only promoted structural repair but also led to a restoration of neural communication.
From Bench to Potential Bedside: Early Indications of Broader Applicability
The researchers took an important step in assessing the broader applicability of their findings by conducting experiments with human pericytes. These studies indicated that the observed regenerative effects were not confined to the mouse model, hinting at the potential for this strategy to be translated to human therapies.
"To extend the clinical relevance of our findings, we cultured mouse neurons on top of human pericytes that were exposed to PDGF-BB, and that was sufficient to trigger a growth-promoting effect, suggesting that this might really be a generalized phenomenon that is not restricted to mice," explained first study author Wenjing Sun, an assistant professor of neuroscience at Ohio State.
This preliminary success with human cells is a critical step towards potential clinical trials and underscores the fundamental biological mechanisms at play.
The Importance of Vascular Restoration in Neurological Recovery
The study further emphasizes the intricate connection between vascular health and neurological function. Spinal cord injuries are notoriously debilitating not only because they sever the pathways of neural information transmission but also because they severely compromise the integrity and function of the blood vessel network within the spinal cord.
"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 elaborated. "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 research highlights that a holistic approach to spinal cord repair must address both the neuronal damage and the damage to the supporting vascular system. By stabilizing and promoting the function of blood vessels through pericyte manipulation, the therapy creates an environment conducive to axonal regeneration.
A Paradigm Shift: From Clearance to Activation
The findings represent a significant departure from some previous lines of research. In the past, the understanding of pericytes’ role in spinal cord injury recovery was less clear, leading some researchers to explore strategies for their removal from the lesion site. However, insights gleaned from cancer research began to shed light on the dynamic nature of pericytes.
It was observed that pericytes’ characteristics could be altered when exposed to PDGF-BB, a mechanism that tumors exploit to generate their own blood supply. In the context of cancer, the goal is to block this PDGF-BB signaling. This research, however, ingeniously reverses that objective, aiming to leverage the very same signaling pathway to promote healing.
"Earlier neuroscience research also indicated that pericytes are highly ‘plastic,’ meaning they are very responsive to changes in the microenvironment — including the presence of PDGF-BB," the study authors noted. This inherent responsiveness provided the foundational concept for Tedeschi and colleagues to explore how to harness this cell-protein relationship for therapeutic benefit.
Chronology of Discovery: From Imaging to Animal Models
The research journey involved a systematic progression of experiments, beginning with foundational imaging studies. These initial observations confirmed that while pericytes do migrate to the injury site after a spinal cord severance, they do not, on their own, promote the growth of the functional blood vessels necessary to support axon regeneration.
Timeline of Key Research Stages:
- Initial Imaging Studies: Confirmed pericyte migration to the injury site but highlighted their inability to independently support vascular growth for regeneration.
- Cell-Culture Experiments:
- Researchers established a "carpet" of pericytes.
- PDGF-BB was introduced to the pericyte layer.
- Adult mouse sensory neurons were then placed on top.
- Evaluation of axon growth over 24 hours showed significant regeneration, nearly comparable to healthy axon extension under normal conditions.
- Mechanism Elucidation: Experiments revealed that the combination of pericytes and PDGF-BB led to the rearrangement of fibronectin, a crucial glycoprotein for tissue repair and cell adhesion. The pericytes themselves also adopted a more elongated, fiber-like morphology.
- Human Cell Validation: Culturing mouse neurons on human pericytes treated with PDGF-BB demonstrated a similar growth-promoting effect, suggesting cross-species applicability.
- Animal Model Trials:
- Mice with spinal cord injuries were treated seven days post-injury (an equivalent of approximately nine months in human adults).
- A single dose of PDGF-BB was injected at the injury site.
- Tissue analysis four weeks post-injury revealed robust axon regeneration compared to control groups.
- Electrophysiological and movement assessments confirmed sensory activity beyond the lesion and improved hind limb control.
- Neuropathic pain indicators were also reduced.
- Inflammatory and Genetic Analysis: Further investigations explored the impact on inflammation and gene expression within pericytes.
Unveiling the Molecular Mechanisms: Fibronectin and Cellular Restructuring
Delving deeper into the molecular underpinnings of the observed regeneration, the researchers discovered that PDGF-BB, in conjunction with pericytes, actively rearranges fibronectin. Fibronectin is a multifunctional adhesive glycoprotein that plays a critical role in tissue repair, cell attachment, and motility. This restructuring of the extracellular matrix, facilitated by the activated pericytes, creates a more conducive environment for axonal growth.
Furthermore, the pericytes themselves undergo a dramatic morphological change, becoming more elongated. "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."
Beyond Regeneration: Anti-inflammatory Effects and Preserved Identity
Intriguingly, the study also found that PDGF-BB administration not only promoted axon regeneration but also appeared to reduce inflammation at the injury site. This dual benefit is crucial, as chronic inflammation can often exacerbate damage and hinder recovery following spinal cord injury.
Analysis of gene expression patterns provided further clarity on the behavior of the activated pericytes. While there was a decrease in some classical pericyte markers, the cells did not transform into entirely different cell types that could be detrimental to the healing environment. Instead, they seemed to enhance their existing functions and adopt new roles 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 stated. "From the overall gene signature in our data, they’re still classified as a pericyte." This finding reassures that the therapeutic intervention works by modulating the pericytes’ capabilities rather than inducing a complete and potentially risky cellular transformation.
Future Directions: Towards a Multi-pronged Therapeutic Strategy
While the current findings are exceptionally promising, the researchers acknowledge that further work is necessary to optimize the therapeutic strategy. Key areas of future investigation include determining the precise timing for PDGF-BB administration, considering the time it takes for pericytes to migrate to the injury site. Additionally, researchers will focus on identifying the ideal concentration of the treatment and exploring the development of potential time-released delivery systems to ensure sustained therapeutic effects.
The potential for combining this pericyte-modulating therapy with other regenerative approaches is also being considered. Dr. Sun noted the team’s previous work demonstrating the efficacy of gabapentin in promoting neural circuit regeneration after spinal cord injury. This opens the door for a multi-pronged therapeutic strategy.
"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. Such a combined approach could offer synergistic benefits, maximizing the chances of functional recovery.
This groundbreaking research was generously supported by grants from the National Institute of Neurological Disorders and Stroke and Ohio State’s Chronic Brain Injury Program, underscoring the significant national interest in advancing neurological repair therapies. 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, and Jerry Silver from Case Western Reserve University. Their collective expertise has laid the foundation for a new era of hope in the quest to restore function after devastating neurological injuries.
