Direct Reprogramming of Mouse and Human Fibroblasts into Multipotent Neural Stem Cells with a Single Factor

• Published in: Cell stem cell Vol. 11; no. 1; pp. 100 - 109
• Main Authors: Ring, Karen L., Tong, Leslie M., Balestra, Maureen E., Javier, Robyn, Andrews-Zwilling, Yaisa, Li, Gang, Walker, David, Zhang, William R., Kreitzer, Anatol C., Huang, Yadong
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 06.07.2012; Cell Press
• Subjects: Animals; Biological and medical sciences; Cell Differentiation; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Cell Survival; Cells, Cultured; Cellular Reprogramming - genetics; Embryo, Mammalian - cytology; Fetus - cytology; Fibroblasts - cytology; Fibroblasts - metabolism; Fundamental and applied biological sciences. Psychology; Humans; Mice; Molecular and cellular biology; Multipotent Stem Cells - cytology; Multipotent Stem Cells - metabolism; Neoplasms - pathology; Neural Stem Cells - cytology; Neural Stem Cells - metabolism; Neurons - cytology; Neurons - metabolism; SOXB1 Transcription Factors - metabolism; Human; Cellular reprogramming; Vertebrata; Mammalia; Mouse; Rodentia; Multipotent cell; Neural stem cell; Fibroblast
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2012.05.018

The generation of induced pluripotent stem cells (iPSCs) and induced neuronal cells (iNCs) from somatic cells provides new avenues for basic research and potential transplantation therapies for neurological diseases. However, clinical applications must consider the risk of tumor formation by iPSCs and the inability of iNCs 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 factor, Sox2. iNSCs express NSC markers and 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 multipotency. Implanted iNSCs can survive and integrate in mouse brains and, unlike iPSC-derived NSCs, do not generate tumors. Thus, self-renewable and multipotent iNSCs without tumorigenic potential can be generated directly from fibroblasts by reprogramming. [Display omitted] ► iNSCs are generated from mouse and human fibroblasts with a single factor ► iNSCs express NSC markers and are able to self-renew in culture ► iNSCs differentiate into astrocytes, oligodendrocytes, and functional neurons ► Implanted iNSCs can survive and integrate and do not form tumors in mouse brains. Under specific growth conditions, mouse fibroblasts can be reprogrammed with a single factor, Sox2, to form induced neural stem cells (iNSCs) that self-renew and differentiate into neurons, astrocytes, and oligodendrocytes and integrate after transplantation into the brain. A similar approach seems to be effective for human fibroblasts as well.