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The difference between centre and periphery

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Peripheral nerves, like those in the extremities, are able to regenerate after injuries.  This ability is considerably greater than in the central nervous system (which includes the spinal cord) where cells fail to regenerate.

But why is that so?

As in many other biomedical questions, there is more than one answer. Firstly the environment in the spinal cord is different from that in the extremities. Secondly the tissues differ in their genetic reaction. For this article we’re going to focus on the environment. To understand the aftermath of different environments, you need to know what they are composed of.

The devil is in the details

Together the spinal cord and the brain form the central nervous system (CNS). It is connected to the peripheral nervous system (PNS) which includes the nerves in our extremities. But, there are big differences between the two. Firstly the nervous cells (neurons) in CNS and PNS differ in ways such as their potential to regenerate.

And, there are more cell types in the nervous system than just neurons. For a long time, those glial cells were regarded as mainly supporting cells (‘glia’ is ancient Greek name for glue).  It’s now accepted that glial cells are active partners of the neurons, not only in signal transduction, but also in development. Without glia, growing neuronal processes rarely find their target. And, if they do, they will fail to form a functioning contact (synapse).

The glue is the true

The differences in healing abilities of CNS and PNS injuries become clearer when we focus on the regional differences, which, to a large extent, depend on glial cells.

In the CNS there are three main types of glial cells: astrocytes are universal helper cells, microglia are responsible for the immune response and oligodendrocytes ensure  the isolation of the neurons, essential for proper function – just like the plastic insulation around electric wire.

But in the PNS, there are neither astrocytes nor microglia and so-called Schwann cells do the isolation. What does that mean for an injured neuron?

The basic problem

An injury to nervous tissue always leads to the same basic problem. A given signal originating from the cell body can't reach its destination any more: the synapse. If the process of a neuron is severed, the part without the cell body will degrade. The other part, with contact to the cell body, will lose its isolation sheet at the site of injury and start building new processes to find back its ‘old’ contact sites.

And, when we look at the axon’s function (axon, from the Greek axis also known as a nerve fibre) there is another problem. If the process of a neuron is not severed but loses its insolation (because oligodendrocytes in the CNS or Schwann cells in the PNS are damaged and die) then the signal will stop and attempts to regenerate the isolation sheet will start.

The situation in the PNS

Sending out new processes and re-establishing the right contacts works relatively well in the PNS, for example after a deep cut into or through a finger.

This is because regenerating neurons receive considerable support. Scavenger cells from the immune system hurry to remove the debris of the old isolation material, while they excrete molecules, which encourage Schwann cells to participate. The latter rejuvenate to a state without isolation abilities, but are capable of secreting so-called growth factors. These have the same effect on a newly built neuronal processes as fertilizer to a plant.

Now the regenerating neuron is building new processes, extending along the old path towards their old contact sites and able to re-establish these contacts. After that, the scavenger cells change back into the resting state, stopping further growth. The Schwann cells will build a new isolation sheet on the processes that were not cut, but that lost their isolation sheet, but will also do so on the newly formed processes. This mechanism, called remyelination is, in the PNS, efficient and quick. And in the end sensitivity as well as motor functions will be re-established.


The situation in the CNS

In the CNS, when the spinal cord is injured, unfortunately things are different. In the CNS immune and glial cells will react, but their signals are not supportive. In fact, it’s the opposite, they actually make the damage worse. Plus, the debris of the isolation material needs a much longer time to be cleared, inhibiting repair mechanisms.

Oligodendrocytes do not rejuvenate, nor do they secrete growth factors. In fact, they secrete substances actively suppressing the formation of new processes. They receive support from astrocytes which also secrete inhibitory substances. Worse still, the normally universally helpful astrocytes build an obstacle at the site of injury: a dense scar, which is nearly impossible to penetrate for young neuronal processes.

Even worse, there is confusion inside these young neuronal processes. Normally a skeleton of parallel-arranged microscopic tubes, promoting growth and actively pushing the tip of the cell forward, stabilizes the outgrowing tips. These tubes are actually disordered after an injury of the CNS, which inhibits outgrowth of neuronal processes.

On processes that are undamaged but that lost their isolation sheet, oligodendrocytes fail to regenerate, unlike in the PNS, meaning sensitivity as well as motor functions are not correctly re-established.

The environment makes the difference

The differences in the healing abilities after CNS and PNS injuries lie in the cellular environment. While in the PNS neurons are surrounded by friendly supporters (scavenger and Schwann cells), the CNS is in an unfriendly, destructive environment (astrocytes, oligodendrocytes).

The explanation

Taking a closer look this seemingly disadvantageous situation makes sense. The CNS is designed to do its job structurally unchanged after completion of the embryonic development. Changes necessary to, for example, learn new motor skills, occur at the synapses inside the brain. Neuronal processes, up to one meter long ‘cables’ connecting extremities, remain as unchanged as those connecting the intestinal tract or expulsion system.

Stopping the development of new processes is a protective mechanism to prevent the system from losing successfully arranged connections or establishing new inappropriate connections. For the same reason in CNS neurons, the potential to regenerate is massively down regulated.

The consequences

Scientists investigating spinal cord injuries work on ways to make the environment for neurons in the spinal cord more friendly and supportive, so that signals originating in the brain may again successfully reach their targets. Hopefully, the CNS can then grow back together what belongs together.

And there’s more…

In our next article we’ll look at the genetic component and differences in the two situations.

Text: Jochen Müller