The same mechanism by which damaged peripheral nerves can regenerate after an injury could be activated in cells of the central nervous system – after a spinal cord injury, for instance, new research indicates.
“An injury in the peripheral nervous system quickly triggers the activation of a fascinating repair process that allows the injured nerve to regenerate and regain its function. There is no such repair process in the central nervous system, thus injuries often lead to permanent damage such as paraplegia,"
explains Claire Jacob, Head of Cellular Neurobiology at Johannes Gutenberg University Mainz (JGU). Strategies to improve axon regeneration in the central nervous system must therefore be developed to enable healing.
“Myelin is extremely important for the function of the entire nervous system, however it also hinders the repair process in case of an injury,"
adds Claire Jacob. Myelin is produced by Schwann cells in the peripheral nervous system and by oligodendrocytes in the central nervous system; this difference has a major impact on axon regeneration, because Schwann cells and oligodendrocytes respond very differently to axonal injury.
When axons of the peripheral nervous system are injured, Schwann cells rapidly induce the disintegration of the cut-out axonal segments into small fragments, which can then be digested by Schwann cells themselves or later by macrophages. This elimination of axonal debris is one of the first and critical steps of the repair process.
“Schwann cells can do everything. We discovered that they not only digest myelin following injury, but they also induce the disintegration of the long axon segments that are separated from their cell bodies due to the injury,"
points out Claire Jacob. In order to do that, Schwann cells form small spheres made of a protein called actin; these actin spheres exert pressure on the isolated axon segments until their disintegration into small pieces.
This targeted degradation of cell debris is essential to enable the healthy part of the axon that remained attached to the neuron cell body to grow back, connect to its former target and thereby regain full functionality.
Of particular interest, the Jacob team found that severed axonal segments send a signal to Schwann cells that prompts them to start the actin sphere formation and axon disintegration process, an impressive and precisely coordinated form of interaction between the two cell types.
If this mechanism is disrupted, axonal disintegration is slowed down and axonal fragments impair the regeneration of the affected nerve.
Claire Jacob’s team went on to study the central nervous system and the behavior of oligodendrocytes.
“After an injury, oligodendrocytes either die or remain apparently unresponsive,"
says Claire Jacob.
Oligodendrocytes are not (normally) able, like Schwann cells, to form actin spheres and thus break down axon segments. One reason for this is that, unlike Schwann cells, they do not express VEGFR1, the receptor that triggers the production of actin spheres in Schwann cells.
In the next step, the research team induced the expression of VEGFR1 in oligodendrocytes. This allowed oligodendrocytes to produce actin structures and disintegrate severed axonal fragments; this is an essential step to promote the regeneration of neurons in the central nervous system.
The team is currently working at identifying the molecular processes that trigger the removal of myelin at the site of injury in the central nervous system. In addition to the disposal of axonal debris, myelin removal is a second prerequisite necessary for the complete regeneration of neurons.
“We have discovered a pathway that accelerates myelin degradation in the peripheral nervous system and are now trying to determine whether this can also trigger myelin removal in the central nervous system,"
adds Claire Jacob, describing the results of on-going research in her lab.
Adrien Vaquié, Alizée Sauvain, Mert Duman, Gianluigi Nocera, Boris Egger, Felix Meyenhofer, Laurent Falquet, Luca Bartesaghi, Roman Chrast, Christophe Maurice Lamy, Seokyoung Bang, Seung-Ryeol Lee, Noo Li Jeon, Sophie Ruff, Claire Jacob Injured Axons Instruct Schwann Cells to Build Constricting Actin Spheres to Accelerate Axonal Disintegration Cell Reports. doi:10.1016/j.celrep.2019.05.060
Image: Adrien Vaquié. Actin spheres (green) wrapped around a severed axon (red).