Unveiling Hidden Potential of Neural Stem Cells for Spinal Cord Repair
Summary
The central nervous system (CNS) is ineffectively healed after an injury. The contribution of local brain stem cells to cell replacement is modest. The latent ability of neural stem cells to replenish significant numbers of lost oligodendrocytes in the damaged mouse spinal cord has been discovered. We discovered that neural stem cells are in a permissive chromatin state that allows the unfolding of a typically dormant gene expression program for oligodendrogenesis following injury. This resulted in integrating multimodal single-cell analyses. The abundant oligodendrogenesis produced by stem cells was revealed by the ectopic expression of the transcription factor OLIG2, which also promoted the remyelination of axons and the functional restoration of axon conduction. These processes followed the natural course of oligodendrocyte differentiation. Thus, after CNS damage, the recruitment of local stem cells may be used as an alternative to cell transplantation.
Fig.1 Graphical abstract. (Llorens-Bobadilla, 2020)
Research Criteria
They integrated single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq) to study lineage potential in adult ependymal cells of the mouse spinal cord.
Sample Type
Cells isolated from mouse spinal cord.
Result—Cell Clusters Distribution of scRNA-Seq and scATAC-Seq
They performed a scATAC-seq on the resident non-neuronal cell populations in the mouse spinal cord and then sorted ependymal cells to determine where ependymal cells might possibly travel. They were able to locate collections of vascular endothelial cells. This was made possible by combining information on marker gene expression from scRNA-seq with information on promoter and gene body accessibility from scATAC-seq.
Fig.2 Cell clusters distribution plot of scRNA-seq and scATAC-seq. (Llorens-Bobadilla, 2020)
Result—Latent Accessibility of the Regulatory Program for Oligodendrogenesis in Spinal Cord Ependymal Cells
Motif enrichment analyses on cluster-specific regulatory regions showed a high enrichment of predicted transcription factors, such as regulatory factor X (RFX) factors for ependymal cells. They found that the motifs for the canonical oligodendrocyte lineage transcription factors OLIG2 and SOX10 were easily accessible in both oligodendrocyte progenitor cells (OPCs) and ependymal cell clusters. They noticed that a SOX10 enhancer that was accessible in OPCs (28 kb upstream) was also accessible in ependymal cells, but not as much as in other clusters. Several other oligodendrocyte lineage genes showed the same pattern. The SOX10 enhancer had an OLIG2 binding site, which made us wonder if this was a more general property of OLIG2 binding sites. Even though OLIG2 wasn't being made, there were a lot of OLIG2 binding sites that could be reached by oligodendrocyte progenitors in the accessible landscape of clusters of ependymal cells. Even though the key regulators of oligodendrogenesis are not expressed in ependymal cells, the genetic program for oligodendrogenesis is still allowed to happen.
Fig.3 Latent accessibility of the regulatory program for oligodendrogenesis in spinal cord ependymal cells. (Llorens-Bobadilla, 2020)
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Reference
- Llorens-Bobadilla, E.; et al. A latent lineage potential in resident neural stem cells enables spinal cord repair. Science. 2020, 370(6512): eabb8795.
