Identification of Transiently Formed Immune-Endogenous Neural Stem Cell Niches in Spinal Cord Injury

Despite endogenous neural stem cells (eNSCs) being present in the adult mammalian central nervous system (CNS), their neuronal potential upon injury is rarely achieved in the brain and never in the spinal cord (SC) environment. This makes widespread SC injuries (SCIs) especially challenging to treat.

Even though SC eNSCs give rise to astrocytes, oligodendrocytes, and neurons in vitro, they almost exclusively generate glial scar-forming astrocytes, seldom myelinating oligodendrocytes, and never neurons in mammalian models.

We still do not know the exact SC niche cues preventing eNSCs from efficiently assuming oligodendrocyte and neuronal fates, averting a functional SC healing.

Notably, SCI induces a vast immune response and I hypothesise that immune cells that are responsive to the SCI, contribute to eNSC niche formation, where they can exert an effect on eNSC regulation.

I will investigate this by unravelling (O1) temporal, heterogenous immune responses to the SCI and (O2) their spatial interplay with the eNSCs using advanced methodologies, such as spectral flow cytometry and spatial transcriptomics.

This will enable me to identify which of these immune cells affect eNSC gene regulatory networks leading to instigation of astrocyte but not oligodendrocyte or neuronal fates.

Finally, (O3) I will identify SCI-specific enhancer elements of the immune cells of interest by comparing chromatin signatures of these immune cell types located across different tissues.

This knowledge will present a ‘divide and conquer’ opportunity – to compartmentalise and disconnect immune system across different tissues enabling a targeted immune cell manipulation specifically within the SCI environment.

The long-term outcome of this project will help the design of enhancer-based immuno-modulatory therapies to dictate eNSC fates and generate oligodendrocytes and neurons in vivo leading to a functional SCI recovery.