Direct Reprogramming of Mouse and Human Fibroblasts into Multipotent Neural Stem Cells with a Single Factor
Seminal discoveries in the field of cellular reprogramming have demonstrated that human somatic cells can be reprogrammed into induced pluripotent stem (iPS) cells and other somatic cell types such as induced neuronal (iN) cells by ectopically expressing different combinations of defined factors. The impact of these technologies is already being realized with the generation of patient- and disease-specific iPS and iN cells lines. These valuable tools provide new avenues for basic research and potential transplantation therapies for neurological diseases. However, clinical applications must consider the risk of tumor formation by iPS cells upon transplantation and the inability of iN cells to self-renew in culture. Here we report the generation of induced neural stem cells (iNSCs) from mouse and human fibroblasts by direct reprogramming with a single transcription factor, Sox2. iNSCs express neural stem cell (NSC) markers such as Nestin, Sox2, Pax6, and BLBP. They also resemble wild-type NSCs in their morphology, self-renewal, ability to form neurospheres, and gene expression profiles. Cloned iNSCs differentiate into several types of mature neurons, as well as astrocytes and oligodendrocytes, indicating that Sox2 reprogrammed iNSCs are a homogenous population of multipotent NSCs. Implanted iNSCs can survive and integrate in mouse brains and, unlike iPS cell-derived NSCs, do not generate tumors. Thus, self-renewable and multipotent iNSCs without tumorigenic potential can be generated directly from both mouse and human fibroblasts by direct reprogramming.