The development and potential of spinal cord stem and progenitor cells

Spinal cord injury (SCI) is an incurable condition, which is mainly due to the highly limited regenerative potential of the adult spinal cord. The discovery of ependymal cells as the source of spinal cord stem cells raises hopes for the development of new therapies, while cell transplantations for SCI also provide promising means for potential treatments. However, curing SCI has been proven difficult as the potential of these progenitors and ependymal stem cells is still understudied. Moreover, the development of the spinal cord is a key factor influencing the regenerative potential of neural stem/progenitor stem cells, but the link between the development of spinal cord progenitors and adult spinal cord regeneration has been largely overlooked. By using different transgenic mouse lines and biomedical techniques, we studied the neural progenitors and stem cells during spinal cord development, after SCI and after cell transplantation in this thesis.

FoxJ1 is traditionally regarded as a transcription factor involved in ciliogenesis and a specific marker for ependymal cells. In Paper I, however, we discovered that FoxJ1 is transiently expressed in neuronal and glial progenitors, which will further give rise to subsets of interneurons, two subsets of astrocytes and all ependymal cells. FoxJ1 is required for the maintenance of stemness of the progenitors during development and the stem cell potential during adulthood. After SCI, FoxJ1 is required for the normal stem cell potential, proliferation and migration of ependymal cells to promote regeneration.

After the early developmental stage, in Paper II, we observed that the stem cell potential is fully confined to ependymal cells from P10 in mice, and the potential of self-renewal and oligodendrocytic differentiation decreases over time. Juvenile ependymal cells have higher stem cell potential after SCI than adult ones, but their contribution to the glial scar formation in vivo is lesion size- and age-dependent. We found that the resident astrocytes and stromal derived pericytes show higher regenerative potential at the juvenile stage, and ependymal cells serve as a backup regeneration candidate after SCI.

Clinically in the adult spinal cord, the transplantation of bulbar olfactory ensheathing cell (bOEC) has shown significant functional recovery in SCI patients, but the mechanisms are not elucidated. In Paper III, we found that after SCI, bOEC transplantation increases the proliferation and self-renewal potential of ependymal cells. The transplantation of bOECs promotes higher astrocytic differentiation of ependymal cells but reduces the axonal growth inhibitors after SCI. The microenvironment of the injured spinal cord is enriched after bOEC transplantation in terms of less axonal growth inhibitor, a higher level of neurotrophic factors and better neuronal survival. Unexpectedly, we found newborn neurons after SCI with bOEC transplantation, challenging the current central stream theory that there is no neurogenesis after SCI.

Altogether, this thesis provides new insights into the potential of ependymal cells and progenitors during development, regeneration after SCI and after transplantation for SCI treatment, and hopefully can contribute to new therapeutic approaches.

List of scientific papers

I. Li, X., Floriddia, E. M., Toskas, K., Chalfouh, C., Honore, A., Aumont, A., Vallières, N., Lacroix, S., Fernandes, K.J.L., Guérout, N., & Barnabé-Heider, F. (2018). FoxJ1 regulates spinal cord development and is required for the maintenance of spinal cord stem cell potential. Experimental cell research. 368(1), 84-100.
https://doi.org/10.1016/j.yexcr.2018.04.017

II. Li, X., Floriddia, E. M., Toskas, K., Fernandes, K. J., Guérout, N., & Barnabé-Heider, F. (2016). Regenerative potential of ependymal cells for spinal cord injuries over time. EBioMedicine. 13, 55-65.
https://doi.org/10.1016/j.ebiom.2016.10.035

III. Li, X., Honore, A., Habib N., Chalfouh, C., Delarue, Q., Giovanni M.D., Vaudry, D., Marie, J.P., Barnabé-Heider F., Regev, A., Guérout, N. (2018). The transplantation of olfactory ensheathing cells promotes endogenous stem and progenitor cell reactivity and induces neurogenesis after spinal cord injury. [Manuscript]