Brain repair after irradiation or ischemia : role of neural stem cells and microglia
Brain injury has devastating consequences for the affected individual, and causes a burden for society. This is largely due to the fact that the mammalian brain has a limited capacity to regenerate. Recent discoveries in neurobiology revealed that the mammalian brain, including humans, is harboring neural stem cells (NSCs) that daily generate new neurons in the hippocampus and the olfactory bulb that contribute to maintain learning and memory throughout life, a process known as adult neurogenesis. When the brain is exposed to an injury or damage, these NSCs migrate to the damaged area, raising the possibilities of spontaneous recovery. Therefore, in this thesis we aimed to study the role of NSCs in brain repair, particularly after injuries caused by irradiation and ischemia. As the brain injury is often associated with inflammation, we also wanted to study the impact of microglia, the resident immune cells in the brain, on NSC biology.
Irradiation is used as an efficient tool to treat primary brain tumors and metastases. However, it leads to long-lasting cognitive decline in the cancer survivors. As a possible mechanism, depletion of hippocampal neurogenesis by irradiation has been proposed as a cause for the cognitive decline. As a restorative intervention, transplanted brain-derived NSCs into the irradiated brain have shown to generate neurons and astrocytes, and subsequently improve cognitive performance. However, such an approach might demand a clinically relevant source of cells, preferentially taken from the same patient. We therefore proposed the enteric neural stem/progenitor cells (ENSPCs), which are present in the enteric nervous system, as a source for cells that could be utilized to treat central nervous system (CNS) pathologies. Here, we transplanted the ENSPCs into the hippocampus of young irradiated mice. Our results displayed that ENSPCs showed poor survival in the brain, remained undifferentiated, triggered neuro-inflammation, and did not restore irradiationinduced loss of hippocampal neurogenesis.
Brain ischemia is caused by insufficient blood flow that leads to inadequate oxygen and nutrient supply, eventually resulting in neuronal death. After ischemic damage, NSCs increase in numbers and migrate toward the lesioned area, however whether they replace lost neurons is still controversial, 5 especially in the cortex. Here our aim was two-fold: First, we wanted to look at the temporal and spatial response of migrating neural progenitors when the brain undergoes cortical stroke; and second to assess the cortical neurogenesis after ischemia. To promote the survival of the neural progenitors in the injury site, and subsequently cortical neurogenesis, we interrupted the caspase–mediated cell death with a pan-caspase inhibitor. We induced cortical ischemia using the photothrombotic stroke model, and found that neural progenitors migrate to the injured cortex for at least one year after the onset of the lesion. Neural progenitors were migrating along the corpus callosum fiber tract to reach the damaged cortex. We also observed that cortical neurogenesis was very rare, and caspase inhibition, contrary to our expectations, did not enhance this process. Interestingly, we found that caspase inhibition even diminished the ischemia-induced NSC response to stroke, and that appeared to be associated with a reduced pro-inflammatory profile, but not anti-inflammatory profile. Hence, caspase inhibition warrants caution when intended for neuroprotection after CNS injury.
After brain injury, microglia become activated and they are abundant in the injury site. Depending on the activation signals, microglia can become either pro-inflammatory (neurotoxic, M1 phenotype) or anti-inflammatory (neuroprotective, M2). We therefore wanted to investigate the impact of either microglial phenotype on NSC survival, proliferation, migration, and differentiation. Our results revealed that factors associated with the proinflammatory phenotype were cytotoxic and triggered astrocytogenesis, while factors released associated with the anti-inflammatory phenotype promoted NSC migration.
List of scientific papers
I. Osman A. M., Zhou K., Zhu C., Blomgren K. Transplantation of enteric neural stem/progenitor cells into the irradiated young mouse hippocampus. 2014. Cell Transplantation. 23:1657-1671.
https://doi.org/10.3727/096368913X674648
II. Osman, A.M., Porritt M.J., Nilsson M., Kuhn H.G. 2011. Long-term stimulation of neural progenitor cell migration after cortical ischemia in mice. Stroke. 42:3559-3565.
https://doi.org/10.1161/STROKEAHA.111.627802
III. Osman, A.M., Neumann S., Kuhn H.G., and Blomgren K. Caspase inhibition impaired the neural stem/progenitor cell response after cortical ischemia in mice. [Manuscript]
IV. Osman, A.M., Rodhe J., Shen X., Joseph B., Blomgren K. The antiinflammatory microglial secreteome promoted neural stem cell survival and migration, but reduced astrocytogenesis. [Manuscript]
History
Defence date
2015-09-18Department
- Department of Women's and Children's Health
Publisher/Institution
Karolinska InstitutetMain supervisor
Blomgren, KlasPublication year
2015Thesis type
- Doctoral thesis
ISBN
978-91-7676-029-1Number of supporting papers
4Language
- eng