A study published in October in the journal "Science" raises hope: by switching on a single factor in the body's own stem cells of the epenzyme, it was possible to generate considerable new oligodendrocyte formation after injury.
The regenerative capacity of a tissue after injury depends on the potential of the resident cells to replace the damaged or lost cells. The skin or intestine can do this very well thanks to the activation of tissue-specific stem cells - injuries to the central nervous system (CNS), on the other hand, often leave permanent functional deficits, as neurons, axonal projections and oligodendrocytes are destroyed and none of these structures are efficiently replaced.
In the brain and spinal cord, or more precisely in the ependyma, there are dormant neural stem cells that are activated when damaged, but their contribution to cell renewal or replacement is insufficient. They produce mainly scar-forming astrocytes, no nerve cells and very few oligodendrocytes.
One of the problems following spinal cord injury is the secondary death of cells around the affected area, leading to the loss, not only of neurons, but also of oligodendrocytes and the myelin sheaths they produce, which normally isolate and protect the axons. The axons spared from the actual trauma are thus exposed, deprived of their trophic and mechanical support, and degenerate (or at least function deficiently).
Neural stem cell transplants have been shown to be beneficial for healing after spinal cord injury, as they provide increased oligodendrocytes that remyelinate the demyelinated axons.
The authors of a recent study by the Karolinska Institutet (Stockholm, Sweden) wanted to know whether it would not be possible without transplantation - using the body's own stem cells, which are located in the lining layer of the central channel, the ependym - because these cells have the same precursors as spinal oligodendrocytes.1,2
Using a mouse model, they discovered that there is a latent potential for increased oligodendrocyte formation in these cells. Latent in this context means that the genetic programme for the development of oligodendrocytes is accessible, the oligodendrocyte genes are only not expressed in adults.
Using multimodal single-cell analysis, the team was able to show that the neural stem cells are in a permissive chromatin state, which would allow the normally latent gene expression programme to unfold for oligodendrogenesis after injury. The chromatin regions with the binding sites for the transcription factors OLIG2 and SOX10 were accessible, although the transcription factors and their target genes are not normally expressed in adult ependymal cells. OLIG2 is a transcription factor that initiates oligodendrogenesis.
To investigate whether this latent potential of neural stem cells is associated with a greater capacity to form oligodendrocytes, the scientists genetically modified mice so that their ependymal cells expressed OLIG2. After injury, this led to increased accessibility of the latent program and consequently to the expression of genes for the determination of oligodendrocytic cell identity. This targeted activation resulted in the formation of myelinating oligodendrocytes in numbers comparable to those obtained by transplantation.
Switching on the latent program triggered efficient oligodendrocyte production from the ependymal cells. By means of complex analyses (single cell RNA sequencing), the researchers were able to show that the development program of oligodendrocyte maturation then takes place in the new cells, whereby self-proliferating oligodendrocyte precursor cells are also produced. Later, these cells matured into resident myelin-forming oligodendrocytes and migrated to sites of demyelination. There, they re-myelinated axons and optogenetic tests showed that the conductivity of the axons returned to normal after injury.
Two more things are remarkable: The ependymal oligodendrocyte production occurred in parallel and not at the expense of astrocyte scarring (which is also important for structure preservation). Furthermore, neither promoter accessibility nor oligodendrocyte production increased in the absence of trauma. This suggests that factors other than OLIG2 expression are needed to realize the latent potential. Injuries induce proliferation of ependymal cells, which alters DNA accessibility.
References:
1. Llorens-Bobadilla, E. et al A latent linear potential in resident neural stem cells enables spinal cord repair. Science 370, (2020).
2. Becker, C. G. & Becker, T. Coaxing stem cells to repair the spinal cord. Science 370, 36-37 (2020).