Damaged nerve cells in conditions such as multiple sclerosis (MS) communicate with stem cells using the same synaptic language they use to talk to other neurons, effectively calling for help, according to new research from the University of Cambridge.
The study, published in Nature Communications, offers fresh insight into how the brain and central nervous system attempt to repair myelin, the insulating layer that surrounds nerve fibres. These findings could inform development of therapies that enhance remyelination in disorders where myelin is lost or damaged.
Efficient brain and nervous system function depends on rapid electrical signalling along axons. That high-speed conduction is possible because axons are wrapped in myelin, a fatty insulating sheath produced by specialised cells. When myelin is lost or degraded, as in MS, nerve conduction slows and clinical symptoms such as weakness, sensory problems and cognitive difficulties can arise.
Oligodendrocyte progenitor cells (OPCs) — a type of stem cell resident in the central nervous system — can act as a biological repair kit. OPCs can differentiate into oligodendrocytes that rebuild myelin sheaths and restore function. Yet remyelination often fails in many patients, and understanding why this repair process stalls is essential to designing treatments that promote recovery.
Researchers at the Wellcome Trust–Medical Research Council Stem Cell Institute investigated the cellular mechanisms that guide remyelination. Using in vivo remyelination models and electrophysiological recordings, the team led by Dr Ragnhildur T. Káradóttir (Thora Karadottir in the news text) found that demyelinated axons remain electrically active, though they conduct signals more slowly than healthy fibres. Crucially, these demyelinated axons form new synaptic-like contacts with OPCs.
These newly formed connections are functionally similar to neuronal synapses. Damaged axons release glutamate at these contact points, and OPCs sense this neurotransmitter through AMPA/kainate-type receptors. That glutamatergic signalling serves as an instruction to OPCs, promoting their differentiation into myelinating oligodendrocytes and enabling remyelination of the affected axons. When the researchers blocked axonal activity, inhibited vesicular neurotransmitter release from axons, or prevented OPCs from sensing glutamate through AMPA receptors, remyelination was reduced.
In the absence of neuronal activity within lesions, the researchers observed an approximately sixfold increase in OPC number but a reduced proportion of these cells differentiating into mature oligodendrocytes, indicating that neuronal signalling is a key cue directing OPC maturation and successful remyelination. Co-localisation of OPCs with the presynaptic marker VGluT2 in MS tissue suggests this communication mechanism is relevant in human disease and may provide therapeutic targets.
“This is the first time we have shown that damaged axons communicate with stem cells via synaptic connections — the same type of connections they use to communicate with other neurons,” said Dr Ragnhildur T. Káradóttir. “With this new understanding, we can begin to explore strategies that enhance this communication to promote myelin repair in disease.”
Dr Hélène O. B. Gautier of the Department of Physiology, Development and Neuroscience added: “Most current therapies primarily slow damage. Our findings open the possibility of boosting the brain’s own repair mechanisms, which could lead to treatments that restore function in severe forms of MS and other demyelinating conditions.”
Source: University of Cambridge
Image credit: Holly Fischer (illustration used for explanatory purposes; licensed CC BY 3.0)
Original research: Gautier H. O. B., Evans K. A., Volbracht K., James R., Sitnikov S., Lundgaard I., James F., Lao-Peregrin C., Reynolds R., Franklin R. J. M., Káradóttir R. T., “Neuronal activity regulates remyelination via glutamate signalling to oligodendrocyte progenitors,” Nature Communications. Published online October 6, 2015. DOI: 10.1038/ncomms9518
Abstract
Neuronal activity regulates remyelination via glutamate signalling to oligodendrocyte progenitors
Spontaneous myelin regeneration can occur in demyelinating diseases such as multiple sclerosis, but its mechanisms and reasons for frequent failure are not fully understood. Using an in vivo remyelination model, the authors show that demyelinated axons remain electrically active and form de novo synapses with recruited oligodendrocyte progenitor cells (OPCs). Early after lesion induction, OPCs detect neuronal activity by expressing AMPA/kainate receptors. Blocking neuronal activity, axonal vesicular release or AMPA receptors in demyelinated lesions reduces remyelination. Without neuronal activity, OPC numbers in lesions increase by roughly sixfold while fewer OPCs differentiate into oligodendrocytes. These results indicate that neuronal activity and glutamate release instruct OPC differentiation into new myelinating oligodendrocytes that restore lost function. Co-localisation of OPCs with the presynaptic protein VGluT2 in MS lesions suggests that this signalling pathway could yield therapeutic targets to enhance remyelination.