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.

Role of endogenous neural stem cells in spinal cord injury and repair.

Spinal cord injury is followed by glial scar formation, which has positive and negative effects on recovery from the lesion. More than half of the astrocytes in the glial scar are generated by ependymal cells, the neural stem cells in the spinal cord. We recently demonstrated that the neural stem cell-derived scar component has several beneficial functions, including restricting tissue damage and neural loss after spinal cord injury. This finding identifies endogenous neural stem cells as a potential therapeutic target for treatment of spinal cord injury.

Neural stem cells in the adult spinal cord.

Spinal cord injury results in cell loss, disruption of neural circuitry and chronic functional impairment. Several different cell types generate progeny in response to injury, which participate in scar formation and remyelination. Work over the last few years has identified neural stem cells and delineated the stem cell potential of different cell populations in the adult spinal cord under homeostasis and in response to injury. Neural stem cell properties are contained within the ependymal cell population, and these cells generate the majority of new astrocytes forming the glial scar. Oligodendrocyte progenitors give rise to myelinating oligodendrocytes in the intact spinal cord. They also generate the majority of remyelinating oligodendrocytes after spinal cord injury, with a minor contribution by ependymal cells. The fibrotic component of the scar tissue is generated by a subtype of pericytes. A better understanding of the regulation and precise function of different cells in the response to injury may aid in the development of regenerative strategies.

Resident neural stem cells restrict tissue damage and neuronal loss after spinal cord injury in mice.

Central nervous system injuries are accompanied by scar formation. It has been difficult to delineate the precise role of the scar, as it is made by several different cell types, which may limit the damage but also inhibit axonal regrowth. We show that scarring by neural stem cell-derived astrocytes is required to restrict secondary enlargement of the lesion and further axonal loss after spinal cord injury. Moreover, neural stem cell progeny exerts a neurotrophic effect required for survival of neurons adjacent to the lesion. One distinct component of the glial scar, deriving from resident neural stem cells, is required for maintaining the integrity of the injured spinal cord.