Inflammatory events and their effect on neural stem cell differentiation

Inflammation plays a dual role in the central nervous system (CNS), serving as a defence mechanism to protect and restore neural tissue following injuries or infections, but also driving degeneration and aggravating damage. This study examines the intricate relationship between inflammation and neural stem cells (NSCs) within the CNS. NSCs are highly versatile cells capable of self-renewal and differentiation into various brain cell types, such as neurons, oligodendrocytes, and astrocytes, which are crucial for maintaining brain homeostasis. In Paper I we investigated the impact of NSC transplantation into an inflammatory environment following a spinal cord injury (SCI). The transplanted NSCs differentiated into oligodendrocytes and modulated the inflammatory environment, resulting in accelerated functional recovery after SCI. In Paper II we focused on the effect of irradiation on NSCs in young mice and their subsequent response to brain injuries. Irradiation poses an inflammatory challenge to the irradiated areas initiating for example microglial activation. Irradiated mice demonstrated a reduction in new neuron production post-stroke and a decrease in microglia cell numbers, indicating the influence of radiation on NSC behaviour during inflammation. In Paper III we delved into the role of secreted factors during an inflammatory reaction. We created a region-specific model by generating brain-stem specific astrocytes from embryonic stem cells (ESC) which, when exposed to inflammatory cues, exert neurotoxic effects on motor neurons. These findings present possibilities to recapitulate inflammatory scenarios using ESC. Finally, the Manuscript examines the impact of hydrogen peroxide (H2O2), a free radical released during inflammation, on the proliferation and differentiation of NSCs in vitro and in vivo. The results show that H2O2 increased NSC division and prompted a higher proportion of these cells to differentiate into oligodendrocytes. Moreover, this NSC behaviour was accompanied by transcriptional changes as seen in bulk RNA sequencing.

Collectively, this doctoral thesis provided new cell-molecular insights into NSC biology in disease models of inflammatory responses involved in stroke, spinal cord injury or to inflammatory mediators. This is essential knowledge when developing therapeutic strategies aimed at mitigating harmful outcomes and promoting neurological health. Such insights may pave the way for future advancements in treating neurological disorders and injuries by leveraging the interaction between inflammation and NSC.

List of scientific papers

I. Sankavaram S R, Hakim R, Covacu R, Frostell A, Neumann S, Svensson M, Brundin L,. Adult Neural Progenitor Cells Transplanted into Spinal Cord Injury Differentiate into Oligodendrocytes, Enhance Myelination, and Contribute to Recovery. Stem Cell Reports. 2019, 12(5):950-966.
https://doi.org/10.1016/j.stemcr.2019.03.013

II. Neumann S, Porritt M J, Osman A M, Kuhn H G,. Cranial irradiation at early postnatal age impairs stroke-induced neural stem/progenitor cell response in the adult brain. Scientific Reports. 2020, 10:12369.
https://doi.org/10.1038/s41598-020-69266-7

III. Lindblad C, Neumann S, Kolbeinsdóttir S, Zachariadis V, Thelin EP, Enge M, Thams S, Brundin L, Svensson M. Stem cell-derived brainstem mouse astrocytes obtain a neurotoxic phenotype in vitro upon neuroinflammation. Journal of Inflammation. 2023, 20:22.
https://doi.org/10.1186/s12950-023-00349-8

IV. Neumann S, Ewing E, Fonseca L, Covacu R, Brundin L,. H2O2 exposure increases Neural Stem and Progenitor Cell proliferation and Oligodendrocyte lineage expansion. [Manuscript]