UBC-led team claims discovery could lead to new regenerative therapies for spinal repair.
Researchers have identified radial glial (RG) progenitor cells in the spinal cords of adult mice. In the developing embryo, RG cells generate the majority of neurons and glia throughout the developing central nervous system, but the retention of this progenitor population in adult spinal cord tissue has not previously been demonstrated.
Using embryonic RG cell transcripts as a cell type-specific signature, researchers at the University of British Columbia (UBC), the Montreal Neurological Institute at McGill University, and the Allen Institute for Brain Science in Seattle mined the interactive Allen Spinal Cord Atlas (ASCA) genetic database to see if the same signature could be found in adult spinal cord.
They identified a population of spinal cord RG (SCRG) cells in a nonventricular niche at the spinal cord pial boundary—essentially alongside the outer edge of the spinal cord—rather than in deeper SC tissue where most work has focused on identifying where spinal stem cells has been concentrated.
It has previously been assumed that pial boundary cells, with their characteristic long projections, are astrocytes derived from RG cells in the embryo. However, gene-expression studies by the UBC-led team suggests that the cells represent a population of adult RG cells. The researchers, led by UBC’s A. Jane Roskams, Ph.D., report their findings in PLoS One, in a paper titled “Adult spinal cord radial glia display a unique progenitor phenotype.”
Although many embryonic SCRG clearly do become astrocytes postnatally, genes expressed by RG and neural stem cells persist in SCRG subpopulations in the adult SC white matter but not in astrocytes, they claim.
The scientists identified a differential set of 122 genes expressed by the neonatal and/or adult SCRGs. Most of the 122 genes were found to be expressed by both neonatal and adult SCRG, a number of which are involved in neural stem cell regulation and many of which have established roles in proliferation, differentiation, and adhesion or migration, the authors note.
There were differences in gene expression between the adult and neonatal cell types, however. The more mature, adult SCRGs demonstrate a distinct shift in the expression of genes that regulate progenitor interaction with extracellular matrix and cell-cell communication.
Importantly, many of the SCRG genes are also shared with what the researchers term “classic” NSCs of the subventricular zone (SVZ) and SC central canal (CC) and in particular a core set of genes associated with human disease, the researchers note. However, collective gene expression and phenotypic analysis showed that the CC and SCRG cells represent two distinct populations with different potentials and modes of regulation.
Cross-comparison of genes suggested showed that SCRGs share 62 genes (i.e., 51% of the SCRG gene set) with CC and 39 genes with SVG progenitors. Seven percent of the cell type-specific genes evaluated were expressed by progenitors in all three niches, some of which have distinct expression patterns and roles in early embryonic tissue development.
Having established that SCRGs demonstrate progenitor gene expression, the researchers tested if and how the cells would respond in vivo, as a result of either mechanical trauma to the SC or to experimental allergic encephalomyelitis. They found that both SCRG and CC progenitors located near to the injury responded to damage by dividing.
They demonstrated altered process morphology and number and the upregulation of developmental gene expression. Distinct SCRG and CC progenitor responses were also mounted during the peak phase of EAE autoimmune demyelination, again, both in terms of process morphology and gene expression.
The response of adult SCRGs to lesions indicates that they may have the capacity to serve as a peripherally accessible progenitor pool for use in cell therapies as long as the triggers needed to activate them efficiently can be identified, the authors conclude.
“These data not only illuminate the uniquess and heterogeneity of SCRG within their nice, but they also highlight how SCRG differ from other CNS progenitors, and identify a set of human disease genes that can now be localized within different CNS progenitor compartments,” the researchers remark. “This SCRG gene-expression signature may not only significantly enhance our understanding of NSC regulation but also serves as an expression map to search for the alternative progenitor-subpopulations in nonventricular molecular environments throughout the CNS.”