Integration and function of new neurons generated from fibroblasts and adult neural stem cells in the pathological brain

Sammanfattning: In Papers One through Six we have investigated the function and integration of “new” neurons – new neurons born from neural stem cells in the adult brain, and new neurons in the sense that they were generated from fibroblasts. Papers One and Two focused on the new neurons generated from neural stem cells in the SVZ and SGZ after pathological insults. We investigated how the newly generated neurons migrate and integrate in the brain. These two phenomena, migration and integration are intimately linked. Without the proper migratory cues new cells exhibit ectopic placement and aberrant integration, as observed in the hippocampus after severe epileptic insults. Papers Three to Six focused on generating (and characterizing) neurons from fibroblasts. First it was crucial to investigate the functional characteristics of the newly generated neurons to demonstrate that they indeed had the properties of mature neurons. The functional properties of the new cells will determine how and importantly if they will integrate in the brain. This is of key importance if we envision using iN or iPS cells for transplantation in the future. In Paper 6 we demonstrate for the first time that transplanted iPS cells survive, migrate beyond the transplantation core, and exhibit the functional properties of mature neurons. Taken together, this thesis demonstrates that the environment encountered by new neurons will influence their migration and integration. We also demonstrate that human fibroblasts can be reprogrammed to neurons and show that fibroblast-derived neurons can integrate in the mammalian brain. Thus, fibroblasts may be a valuable source of neurons for transplantation but the environment encountered will influence their integration and function which will determine their therapeutic effect.