Direct Conversion of Mouse Fibroblasts into Neural Stem Cells by Chemical Cocktail Requires Stepwise Activation of Growth Factors and Nup210.

Neural stem cells (NSCs) are valuable for both basic research and clinical application. We previously reported a chemical cocktail that could reprogram somatic cells into neural progenitor cells. However, the reprogramming process is complex, and the underlying mechanism remains largely elusive. Here, we identified a culture condition that greatly promotes the efficiency of NSC generation directly from mouse fibroblasts based on our reported chemical cocktail. Transcriptome and epigenome analyses demonstrated that growth factors including IL-6, FGF5, and LIF were dynamically activated and contributed to the cell fate changes. Treatment of these growth factors together can enable fibroblast to neural progenitor-like cell conversion. Moreover, the reprogramming capacity of both chemical cocktail and growth factors requires nucleoporin Nup210 to activate SoxB1 transcription factors to initiate NSC fate. Altogether, our findings reveal important roles of both extracellular signals and internal factors in direct cellular reprogramming.