Direct conversion of normal and patient human fibroblasts into neuronal cells

Neuronal conversion from human fibroblasts can be induced by lineage-specific transcription factors, holding great promise for human neurological disease modeling and regenerative medicine. However, the introduction of ectopic genes limits their therapeutic applications. Here, we report that neuronal cells could be directly induced from human fibroblasts by a chemical cocktail of seven small molecules bypassing neural progenitor stage. These chemical-induced neuronal cells (hciN cells) resembled hES-derived neurons regarding morphology, gene expression profiles, and electrophysiological properties. Our further experiments show that hciN cells were able to develop into mature neurons in vivo in embryonic mouse brain. Moreover, this approach was further applied to induce hciN cells from fibroblasts of familial Alzheimer’s disease patients and the hciN cells showed abnormal Aβ production. Together, we established a transgene-free chemical approach to directly induce neuronal cells from human fibroblasts, thus providing alternative strategies for modeling of related neurological diseases and regenerative medicine. We used microarray to comparethe global gene expression patterns of hES-derived neurons (control neurons), HAFs, pre-hciN cells (VCRFSGY-treated HAFs at day 3 and 7) and hciN cells (induced with VCRFSGY for 14 days) hciNs RNA samples were selected at different time points, i.e. pre-hciN cells (VCRFSGY-treated HAFs at day 3 and 7) and hciN cells (induced with VCRFSGY for 14 days), to study molecular mechanism and marker gene expression happened at the early stage of chemical induction by compared with hES-neurons (positve control) and HAFs (negtive control).