New findings from the University of Arizona, published in Cell Death and Disease, provide new insights into the biology of nerve injury healing and suggest potential ways to help treat such injuries by repurposing erythropoietin, a drug used to treat anemia.

There is no effective treatment for peripheral nerve crush injuries, which are commonly associated with physical trauma from car accidents, falls, sport-related injuries or blunt force trauma. These findings could lead to new therapies for people with nerve injuries.

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“Crush injuries are important to understand because most nerve injuries are crush injuries, not severed or cut injuries,” said senior author Dr. John Elfar, professor, surgeon and chair of the Department of Orthopaedic Surgery in the U of A College of Medicine – Tucson. “Nerve injuries are the most common reason why a limb that physically survives following an accident or trauma might have to be amputated.”

A crushed nerve is like a train wreck. Shattered pieces of the nerve’s covering, or myelin sheath, lay scattered everywhere at the injury site, including dead and dying Schwann cells that form the sheath. The piles of cellular debris delay healing.

Scientists discovered that erythropoietin, or EPO, increases the production of repair Schwann cells and macrophages, which are immune cells that clear cellular debris at the injury site. EPO also helps rebuild the myelin sheath, enabling the nerve to recover its function. 

Additionally, the researchers found that EPO stopped Schwann cells from dying after an injury and spurred some of them to morph into repair Schwann cells that aid in cleanup. During the healing process, repair Schwann cells later can become myelin-forming Schwann cells. 

During the study, mice given the EPO before or right after an injury that crushes a nerve – and even several days 

later – healed faster than mice without the drug. The findings build on earlier preclinical experiments that found evidence suggesting EPO impacted the nerve injury site, not the nerve itself.

“We found that EPO could cut the crush injury healing time in half,” Elfar said. “We also discovered that it wasn’t cells in the nerve that were affected, but rather, cells that came into the nerve after a traumatic injury.” 

To find out how EPO was working,  a team led by Dr. Prem Kumar Govindappa, veterinarian and assistant professor in the department, examined how the drug affected the nerve biology and functional activities of Schwann cells and macrophages at the injury site. 

They discovered that the EPO altered several biological pathways and associated genes, particularly those involved in cell death and cell repair. EPO also affected genes that had roles in cell breakdown and in rebuilding myelin.

“The changes in gene activity matched up with the changes we usually see after trauma,” said Elfar, who is a BIO5 Institute member. “These changes corresponded with functional improvement in the injured mice that received EPO immediately after injury. EPO clearly changes what crush injury sites look like.”

Nerve regeneration is a well-orchestrated process. Genes that instruct Schwann cells to form myelin are turned off, while genes that promote repair cells are turned on.

“We think EPO is accelerating debris clearance and the proliferation and differentiation of Schwann cells to make the myelin recovery process faster,” he said. “We found that EPO drove this faster in the period the animal is getting better.”

One potential next step is to examine the use of EPO in people with nerve injuries, Elfar said. 

“This could be about helping nerve injuries that wouldn’t recover have a chance to recover.”

Additional College of Medicine – Tucson co-authors include Govindaraj Ellur, postdoctoral research associate in the Department of Orthopaedic Surgery; Rahul V. G, postdoctoral research associate in the Department of Orthopaedics and Sports Medicine; and researcher/scientist Akash Gupta.

This study was funded in part by by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, a division of the National Institutes of Health, under award number K08AR060164‐01 and the Department of Defense under award number W81XWH‐16‐1‐0725.