Conversion of astrocytic cells to neurons, through dedifferentiation to neural stem cells (NSC), can be an ideal approach to cure neurodegeneration and brain injuries. The signaling pathways regulating such a cell conversion are not fully elucidated, and it is quite challenging to determine in complex disease models or regular cell culture systems. In order to solve this problem, we established a serum-free, strictly controlled cellular model of pure and homogeneous "Mouse astrocytes generated from murine embryonic stem cells (mAGES)." mAGES cells proliferated by exposure to FGF and caused conversion of GFAP-expressing mAGES to nestin-expressing NSC. As a result of standard phenotyping, mAGES dedifferentiation gave rise to NSC which is similar to NSC lineage obtained directly by differentiation of ESC to neural cells. Inflammatory mediator molecules, especially interferon-gamma, affected mAGES de-differentiation and robustly debilitated the generation of NSCs from mAGES by STAT1 phophorylation independent of nitric oxide generation. Thus, in this project, signaling mechanism, which affect conversion of astrocytes without genetic manipulation, were described. The complex interaction between related signaling molecules promoting/inhibiting astrocyte dedifferentiation may disclose the reason why astrocytes ar not able to generate NSC in neurodegenerative diseases. Increased knowledge of such factors may provide innovative therapeutic opportunities to support such conversions as regeneration targets. |