Though there are many reasons why nerves fail to regenerate, researchers from Ruhr-Universität Bochum (RUB) have made a breakthrough in their discovery a new mechanism which could lead to effective treatments.
Damage to nerve fibers in the central nervous system – brain, spinal cord, or optic nerve– often results in lifelong and severe disabilities, such as paraplegia or blindness. Though there are various known reasons why nerves fail to regenerate, treating them has not thus far not resulted in success.
Now, the RUB researchers have discovered that nerves release a protein at the injury site that attracts growing nerve fibres — and keeps them entrapped there. This prevents them from growing in the right direction to bridge the injury. Their findings are published in the journal Proceedings of the National Academy of Science (PNAS).
There are three known main causes for the inability of injured nerves of the central nervous system (CNS) to regenerate: insufficient activation of a regeneration program in injured nerve cells that stimulates the growth of fibres, so-called axons; scar formation at the injury site that is difficult for nerve fibres to penetrate; and an inhibitory effect of molecules in the nerve on regrowing axons. “Although experimental approaches have been found in recent decades to address these individual aspects by therapeutic means, even combinatorial approaches have shown only little success,” said Fischer. “So there must be other yet unknown causes for why nerve fibres in the CNS don’t regenerate.”
Using the optic nerve as a model, the research time has now shown another — quite surprising — cause for the regenerative failure in the CNS. The underlying mechanism is not based on inhibition of axon growth, as in the previously identified causes, but instead on a positive effect of a protein at the injury site on the nerve. This molecule is a so-called chemokine known as CXCL12. “The protein actually promotes the growth of axons and attracts regenerating fibers. It is, therefore, chemoattractive,” explained lead investigator Professor Dietmar Fischer. However, this chemoattraction turned out to be more hindrance than help after nerve injury in living animals.
Nerve fibres are trapped
The scientists showed that this protein is released at the nerve’s lesion site and, as a result, keeps the axons at the injured area through the chemoattractive effect. As a result, even some fibres that had already regenerated across the injury site reversed direction, growing backwards to the injury site. The regrowing fibers thus remained trapped due to CXCL12’s attractive effect.
The researchers figured out this effect when they knocked out the receptor for CXCL12 in the retinal nerve cells, rendering them blind to this protein. “Surprisingly, this led to greatly increased fibre growth in the injured optic nerves, and axons showed significantly less regrowth back to the injury site,” Dietmar Fischer points out.
New drug possibilities
The researchers then investigated where at the injury site the CXCL12 originated. They found out that about eight percent of the nerve cells in the retina produce this protein themselves, transport it along their fibers to the injury site in the optic nerve, and release it there from the severed axons. “It is still unknown why some of these nerve cells make CXCL12 and others make the receptor,” said Prof Fischer. “We don’t yet understand the physiological role of the protein, but we can see that it is a major inhibitor of neural repair.”
In further experiments, the researchers showed that knocking out CXCL12 in retinal nerve cells to prevent its release at the injury site equally improved axonal regeneration into the optic nerve. “These new findings open the opportunity to develop pharmacological approaches aimed at disrupting the interaction of CXCL12 and its receptor on the nerve fibres, to free them from their captivity at the site of injury,” concluded Prof Fischer.
His team is now investigating whether similar approaches can also promote the regeneration of axons in other areas of the injured brain or spinal cord.
Source: Ruhr-Universität Bochum
Journal information: Alexander M. Hilla, et al. CXCR4/CXCL12-mediated entrapment of axons at the injury site compromises optic nerve regeneration, in: PNAS, 2021, DOI: 10.1073/pnas.2016409118
