Influence of microgravity on the self-organization of neural stem cells into complex human brain (µ-brain)

Kurzfassung

The human brain is the most complex organs of the body and even small disruptions in the development of the brain can dramatically affect its functionality. Since it was suggested that gravity, as an omnipresent mechanical stimulus, codetermines the self-organization of the single neural stem cells, an extreme decrease in the gravitational field, such as present in space, might lead to alterations in the neuronal development. Indeed, several adaptive processes could be observed ameliorating the self-renewal capacities of neural progenitor cells (NPCs) and thus probably also brain formation can be studied closer. Therefore, human induced pluripotent stem cells-derived NPCs (hiPS-NPCs) were exposed for three days to simulated microgravity achieved by fast clinorotation and the key characteristics of them were investigated. In this thesis, it was shown that NPCs exposed to simulated microgravity exhibited an enhanced proliferation, probably caused by a premature cilia disassembly. This premature cilium disassembly results in a faster cell cycle re-entry and thereby in the enhanced proliferation seen under altered gravity conditions. The expression pattern of differentiation and stem cell markers indicated also a partly increased stem cell characteristic of the NPCs exposed to simulated microgravity. Taken together with the altered morphological seen under simulated microgravity, it seem that the symmetric division is promoted, such as seen during the formation of the ventricular zone by ameliorating cell-substrate contacts, and the differentiation inhibited by the disruption of the cytoskeleton. Additionally, the re-adaption of neural tissues following space flight effects was simulated by exposing the NPCs for three days to simulated microgravity and then culturing them again for one day under normal gravity conditions. The approach revealed durable increase in stem cell characteristics of the NPCs. However, a largely re-accommodated level of ciliated cells indicates a rapid re-adaptation towards a normal cilia assembly to cilia disassembly ratio. Thus, the cilia were suggested to be acute gravity sensitive structures.