Summary: New research demonstrates that resident stem cells in the spinal cord can be stimulated to produce large numbers of oligodendrocytes, offering a promising approach to repair after spinal cord injury.
Source: Karolinska Institutet
Spinal cord injury often causes lasting functional deficits. In a recent study published in the journal Science, researchers at Karolinska Institutet in Sweden show in mice that it is possible to activate stem cells within the spinal cord so they generate abundant new oligodendrocytes—cells essential for insulating nerve fibres and enabling efficient signal transmission—and that this activation can contribute to repair after injury.
The spinal cord carries signals between the brain and the body. When it is injured, some nerve fibres are severed and others become less effective, often resulting in partial or complete paralysis. Much of that loss of function is linked to the loss of oligodendrocytes, the glial cells that produce myelin, the insulating sheath that speeds electrical conduction along axons. Without sufficient oligodendrocytes and myelin, surviving axons conduct signals poorly.
In many tissues, stem cells enable repair by replacing lost cell types. The adult spinal cord contains resident neural stem cells, but after injury these cells mostly generate scar-forming cells. While the scar limits tissue disruption and stabilizes the injury site, it does not replace lost oligodendrocytes and therefore does not restore normal conduction.
The new study used detailed single-cell and chromatin analyses to map the genetic and epigenetic state of spinal cord stem cells in mice. The researchers discovered that these resident stem cells are not irreversibly committed to making scar tissue. Instead, their chromatin exists in a permissive configuration that keeps a latent oligodendrogenic gene program available. By understanding which genes and regulatory states were involved, the team was able to manipulate gene activity to redirect stem cell fate.
Specifically, forced expression of the transcription factor OLIG2 in resident spinal cord stem cells unlocked the latent program for oligodendrogenesis. Stem cell–derived oligodendrocytes progressed through the typical differentiation sequence, contributed to remyelination of axons, and improved the electrical conduction properties of surviving nerve fibres in the damaged spinal cord.
“We found that the stem cells were not locked into forming only scar tissue, and we learned how to nudge them toward generating cells that contribute to repair,” says Enric Llorens-Bobadilla, the study’s first author and a researcher at the Department of Cell and Molecular Biology, Karolinska Institutet. The principal investigator, Jonas Frisén, professor at the same department, adds that the results reveal a conceptually new strategy for promoting recovery after nervous system injury: recruiting and reprogramming resident stem cells instead of—or in addition to—transplanting external cells.
The discoveries were made in mouse models and the authors caution that direct translation to human patients will require further research. Nonetheless, the findings identify a latent regenerative capacity in the adult spinal cord that can be harnessed to produce myelinating cells and improve functional outcomes in preclinical settings.
Funding: The work was supported by multiple fellowships and grants, including the Human Frontier Science Programme long-term fellowship, a Marie Sklodowska-Curie Action fellowship, the Swedish Research Council, the Swedish Cancer Society, the Swedish Foundation for Strategic Research, the Knut and Alice Wallenberg Foundation, the Strategic Research Area in Stem Cells and Regenerative Medicine at Karolinska Institutet (StratRegen), St. Petersburg University, Karolinska Institutet, the Torsten Söderberg Foundation, and the Wings for Life Spinal Cord Research Foundation. The authors note that four contributors, including Enric Llorens-Bobadilla and Jonas Frisén, serve as consultants to the biotechnology company 10X Genomics, and one author is employed by 10X Genomics.
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Original Research: Closed access
“A latent lineage potential in resident neural stem cells enables spinal cord repair” by Enric Llorens-Bobadilla, James M. Chell, Pierre Le Merre, Yicheng Wu, Margherita Zamboni, Joseph Bergenstråhle, Moa Stenudd, Elena Sopova, Joakim Lundeberg, Oleg Shupliakov, Marie Carlén, Jonas Frisén. Science.
Abstract
A latent lineage potential in resident neural stem cells enables spinal cord repair
Injuries to the central nervous system (CNS) are inefficiently repaired. Resident neural stem cells manifest a limited contribution to cell replacement. We have uncovered a latent potential in neural stem cells to replace large numbers of lost oligodendrocytes in the injured mouse spinal cord. Integrating multimodal single-cell analysis, we found that neural stem cells are in a permissive chromatin state that enables the unfolding of a normally latent gene expression program for oligodendrogenesis after injury. Ectopic expression of the transcription factor OLIG2 unveiled abundant stem cell–derived oligodendrogenesis, which followed the natural progression of oligodendrocyte differentiation, contributed to axon remyelination, and stimulated functional recovery of axon conduction. Recruitment of resident stem cells may thus serve as an alternative to cell transplantation after CNS injury.