Adult neural stem cells and their differentiation choices : examples from experimental inflammation and transplantation

The aim of this thesis is to study how inflammation influences the fate of NPCs, which can impact the regenerative capacities of the CNS.

In paper I, we used a hypoglossal nerve avulsion model, to study if survival, differentiation, and integration of transplanted NPCs could be achieved. Transplanted NPCs were present after 3 months post grafting, and expressed differentiation markers specific for neurons, astrocytes, and oligodendrocytes. Motor neuronal cell survival was increased in injured animals which received the NPC graft. This results show that transplanted NPCs can modulate the microenvironment increasing motor neuronal survival. Further, in Paper II, we explored the same transplantation setting in a transection injury of the hypoglossal nerve, i.e. an injury that yields significantly less neuronal cell death in contrast to the more severe avulsion injury. Comparison of transplanted NPCs into both injury models was then investigated. In the transection injury model we found that NPC transplanted to the hypoglossal nucleus, maintained their Sox2 expression after three months transplantation. Also, no differentiated progeny derived from the graft was observed. Motor neuronal survival was not significantly different from non-transplanted animals, indicating that the cues for NPCs differentiation provided from the environment were different comparing to the avulsion model.

Reactive oxygen species (ROS), are an integral part of inflammation, so we next questioned whether H2O2 a member of the ROS family would have an effect on the differentiation outcome of NPC from the brain lateral ventricles. In paper III I found that NPCs exposed to H2O2 resulted in more neurons and oligodendrocytes. H2O2 exposure influenced proliferation and the expression of genes involved in chromatin remodeling and antioxidant defense. These results indicate that H2O2 has a specific modulatory effect on the differentiation potential of NPCs.

In paper IV the global gene expression and differentiation outcome from NPCs from the brain and the spinal cord were analyzed under normal conditions and after Experimental Allergic Encephalomyelitis (EAE), a model for multiple sclerosis (MS). We found that NPC from naïve rat brains were more neurogenic compared to spinal cord (SC) naïve NPCs. In contrast, NPCs from the SC of EAE rats became more neurogenic comparing to healthy SC NPCs. Thus, the inflammatory environment produced during EAE proves to be able to change NPC fate.

Overall the findings presented in this thesis suggest the inflammatory milieu as well as its individual components, like H2O2, act as mediators of the regenerative properties of NPCs

List of scientific papers

I. Neural stem/progenitor cells transplanted to the hypoglossal nucleus integrates with the host CNS in adult rats and promotes motor neuron survival. Michael Fagerlund, Cynthia Pérez Estrada, Nasren Jaff, Mikael Svensson and Lou Brundin Cell Transplantation 2012, 21 (4):739-747
https://doi.org/10.3727/096368911X612459

II. Integration differences of transplanted adult neural progenitors in two models of axotomy. Cynthia Pérez Estrada, Michael Fagerlund, Nasren Jaff, Lou Brundin and Mikael Svensson [Manuscript].

III. Oxidative stress increases neurogenesis and oligodendrogenesis in adult neural progenitor cells. Cynthia Pérez Estrada, Ruxandra Covacu, Mikael Svensson, Lou Brundin Stem Cell and Development 2014, (Epub ahead of print).
https://doi.org/10.1089/scd.2013.0452

IV. Change of fate commitment in adult neural progenitor cells subjected to chronic inflammation. Ruxandra Covacu, Cynthia Pérez Estrada, Lisa Arvidsson, Mikael Svensson & Lou Brundin The Journal of Neuroscience, 2014, 34 (35): 11571-11582
https://doi.org/10.1523/JNEUROSCI.0231-14.2014.