Neural stem cells in the spinal cord : identity, function and potential

Abstract

A large body of work has been dedicated to understanding and remedying the pathological processes that take place after spinal cord injury. Despite these efforts, treatment options are limited and patients with spinal cord injury are left with life-long disability. The work described in this thesis is part of an ongoing effort to learn about endogenous neural stem cells as potential targets for therapies aiming to repair the injured spinal cord.

In paper I, we studied the effects of ablating the ependymal neural stem cell response to spinal cord injury, in order to understand their functional role in the injury response. We found that the ependymal cell contribution to the injury response keeps the injury from growing deeper and severing additional axonal tracts, as well as limits neuronal loss. These findings identify ependymal cells as an interesting target for intervention. In paper II, we discovered a latently accessible program for oligodendrogenesis in ependymal cells by analyzing their gene expression and chromatin accessibility patterns. We activated the oligodendrogenesis program using a combination of forced Olig2 expression and spinal cord injury. The activation of the oligodendrogenesis program leads to an increased production of ependymal-derived oligodendrocytes, enhances remyelination and supports conduction of nerve impulses in the corticospinal tract after spinal cord injury. In paper III, we identified a subset of ependymal cells – EpA cells – that harbors the in vitro stem cell capacity of the spinal cord and responds to spinal cord injury by both self- duplicating and generating migrating progeny that differentiates into scar-forming astrocytes and oligodendrocytes. By performing single cell RNA sequencing we found that shortly after injury, the highly differentiated EpA cells dedifferentiate to acquire a stem cell-like state.

The work presented in this thesis supports an important role of ependymal cells in the response to spinal cord injury, and explores their plasticity as well as the manipulation of their lineage fate choices. Lastly, it describes the activation of a subgroup of ependymal neural stem cells with the ability to respond to spinal cord injury. Through these studies, we have identified and characterized a population of resident neural stem cells that represents a promising therapeutic target to treat spinal cord injury.