It’s time to cut out the middleman—why go from fibroblasts, to induced pluripotent stem cells, to neurons, if one can skip straight to the payload? Researchers from the Stanford University School of Medicine in Palo Alto, California, reported January 27 in Nature a way to turn fibroblasts directly into induced neuronal, or iN, cells. Led by first author Thomas Vierbuchen and principal investigator Marius Wernig, the scientists screened 19 candidate transcription factors to find a cocktail of three that push cells toward a neuronal fate. The iN cells make neuron-specific proteins, support action potentials, and form synapses, the researchers report.

The investigators started with mice that carry the green fluorescent protein (GFP) gene under control of a neuronal promoter, so they could easily see when cells switched on the neuron signal. They isolated embryonic fibroblasts from these mice to test out the iN protocol.

Vierbuchen and colleagues selected 19 candidate genes specific to neural tissues, or involved in neural development or epigenetic reprogramming. They constructed lentiviral vectors for each gene, and then pooled the lot. Next, they used this pool to transform the mouse fibroblasts, reasoning that some subset of the transformed cells would hit upon the right combination to turn neural. A month later, some of the cells had neuronal morphology and GFP fluorescence.

From there, the researchers narrowed down the necessary genes to a set of five: Ascl1, Myt1l, Zic1, Olig2, and Brn2 (also called Pou3f2). Five-factor iN cells expressed neuronal markers including MAP2, GABA, GLUT1, NeuN, and synapsin. Patch-clamp experiments confirmed they were capable of producing action potentials. They were able to form signal-carrying synapses with other neurons as well as with each other.

Finally, Wernig and colleagues further reduced the number of transcription factors necessary to make iN cells by trying all possible three-gene combinations. They settled on a set of Ascl1, Myt1l, and Brn2. These three were able to induce iN formation at up to 19.5 percent efficiency, the authors report. “Generation of iN cells from non-neuronal lineages could have important implications for studies of neural development, neurological disease modeling, and regenerative medicine,” they wrote.—Amber Dance


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Further Reading


  1. . Murine embryonic stem cell-derived pyramidal neurons integrate into the cerebral cortex and appropriately project axons to subcortical targets. J Neurosci. 2010 Jan 20;30(3):894-904. PubMed.
  2. . Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease. Proc Natl Acad Sci U S A. 2009 Aug 11;106(32):13594-9. PubMed.
  3. . Human embryonic stem cell-derived motor neurons are sensitive to the toxic effect of glial cells carrying an ALS-causing mutation. Cell Stem Cell. 2008 Dec 4;3(6):637-48. PubMed.
  4. . Neural stem cell transplantation can ameliorate the phenotype of a mouse model of spinal muscular atrophy. J Clin Invest. 2008 Oct;118(10):3316-30. PubMed.
  5. . Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson's disease. Proc Natl Acad Sci U S A. 2008 Apr 15;105(15):5856-61. PubMed.
  6. . Neural precursors derived from human embryonic stem cells maintain long-term proliferation without losing the potential to differentiate into all three neural lineages, including dopaminergic neurons. J Neurochem. 2008 Jan;104(2):316-24. PubMed.

Primary Papers

  1. . Direct conversion of fibroblasts to functional neurons by defined factors. Nature. 2010 Feb 25;463(7284):1035-41. PubMed.