Cell bridges promote axon growth after spinal cord injury

Utilizing the flexibility of small cells within the body’s minimal blood vessels could be a powerful spinal cord repair strategy, new research suggests.

In mouse experiments, scientists introduced certain types of recombinant proteins at sites of spinal cord injury. There, these cells, called the surroundings, flooded the lesion zone. When exposed to this protein, the results show that pericytes change shape, secrete others while inhibiting the production of some molecules, creating “cell bridges” that support axonal regeneration.

The researchers observed axonal regrowth in injured mice receiving a single treatment injection of growth factor protein, and animals also restored hindlimb movement. Experiments involving human cells suggest that results are not limited to mice.

There are many things you can learn and expand on, but the more you tackle this, the more you are surprised at the efficacy of this single treatment and how effective it is. This finding goes beyond spinal cord injury. It also affects brain damage, stroke and neurodegenerative diseases. ”

Andrea Tedeschi, Advanced research authors, Associate Professor of Neuroscience, Ohio State University School of Medicine

The study highlights how important blood vessel recovery is for restoring neurological function after spinal cord injury, the researchers said.

“Wenging Sun,” said Wenging Sun, the first research author of Ohio’s assistant professor of neuroscience. “Even if we can reestablish neuronal connectivity from one end to the other, the overall effect will not be maximized unless we take care of all the other dismembered.”

The study was published in the journal Molecular Therapy on April 18th.

Previous studies suggesting conditions that interfere with the recovery of spinal cord injuries have come to recommend removing them from the lesion site to aid in repair. However, cancer studies have shown that exposure to a protein called platelet-derived growth factor BB (PDGF-BB) changes the properties of pericytes. In cancer, the goal is to block PDGF-BB signaling.

Previous neuroscience studies have shown that pericytes are highly “plastic.” In other words, it is highly responsive to changes in the microenvironment, including the presence of PDGF-BB. Tedeschi and colleagues considered the possibility of exploiting its intercellular protein relationship to stabilize the vasculature surrounding spinal cord injury. In the process, they discovered that newly germinated blood vessels had established a pathway for regenerated axons to continue.

Starting with imaging studies, the team showed that when the spinal cord is cut, pericytes migrate to the site of injury over time, but do not promote the growth of functional vessels required to support axonal regeneration.

In cell culture experiments, researchers established a “carpet” of pericytes, added PDGF-BB, then placed a layer of adult mouse sensory neurons on top to assess the amount of axons grown in 24 hours. The treated axons grew almost as much as healthy axons stretched under normal conditions.

The PDGF-BB alone did not produce this result. Instead, the experiments showed that growth factors, a multifunctional adhesive protein that plays an important role in tissue repair, cell attachment and motility, combined with phelicites, combined with rearranged fibronectin. The cells themselves also change shape and become even longer.

“We know that these cells penetrate and deposit into the lesion epicenter. These elongated fibrous structures are much more tolerant to the axons regenerate from one end to the other, bypassing damage,” Tedesti said.

“To expand the clinical relevance of the findings, mouse neurons are cultured on human pericytes exposed to PDGF-BB and are sufficient to induce growth-promoting effects, suggesting that this may be a generalized phenomenon that is not restricted to mice.”

Turning to experiments with animals with spinal cord injuries, the researchers waited seven days after the injury (equivalent to approximately nine months in human adults) before injecting one PDGF-BB into the site of injury. Analysis of tissues 4 weeks after injury showed that PDGF-BB injection caused robust axonal regenerative growth compared to axonal responses in injured control mice.

“When I looked at the formation of these pericyte structures across the site of injury, I saw that treatment promoted the growth of these bridges, and all of these regenerative axons were able to escape the site of injury by riding these cell bridges formed in response to PDGF-BB administration,” San said.

Electrophysiological and motor assessments in injured animals treated with PDGF-BB detected sensory activity beyond the lesion site, indicating that mice restored better control of the hindlimb compared to control mice. The animals also suggest that they were not sensitive to non-stimulating stimuli and did not experience neuropathic pain often caused by spinal cord injury.

Analysis of the presence of inflammatory proteins during the repair process suggests that PDGF-BB administration not only promotes axonal regeneration but also reduces inflammation. RNA sequencing showed that spinal cord injury led to a decrease in gene expression by pericytes, but the cells retained core properties and did not convert them to other types of cells.

“Some classic pericyte markers have been reduced, but we have achieved some additional features linked to attempts to reconstruct cell bridges and functional vessels,” San said. “From the overall genetic signatures of our data, they are still classified as pericy.”

Tedeski, Sun and colleagues previously showed that in mice gabapentin promotes regeneration of neural circuits after spinal cord injury, so a multiplex approach to treatment may be considered, San said.

“We can combine both — what we do here with drugs and drugs to create cellular interactions that regulate the non-neurological environment and provide a more tolerant substrate for neurons to grow,” she said.

More work is planned to determine the exact timing for administering PDGF-BB. The estimated that pericytes take a little time to migrate to the injury, and the ideal concentration and potential time-release delivery system for treatment.

This study was supported by the National Institute of Neurological Disorders and Stroke and the Ohio Chronic Brain Injury Program.

Additional co-authors were Elliot Dion, Fabio Laredo, Allison Oconak, Jesse Sepedadada, Esla Heicar, Min Zhou, Haisem El Hodiri, Andy Fisher, Juan Penn, Andrew Sass, Ohio, and Jerry Silver of Case Western Reserve University.