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Generation of oligodendroglial cells by direct lineage conversion

Abstract

Transplantation of oligodendrocyte precursor cells (OPCs) is a promising potential therapeutic strategy for diseases affecting myelin. However, the derivation of engraftable OPCs from human pluripotent stem cells has proven difficult and primary OPCs are not readily available. Here we report the generation of induced OPCs (iOPCs) by direct lineage conversion. Forced expression of the three transcription factors Sox10, Olig2 and Zfp536 was sufficient to reprogram mouse and rat fibroblasts into iOPCs with morphologies and gene expression signatures resembling primary OPCs. More importantly, iOPCs gave rise to mature oligodendrocytes that could ensheath multiple host axons when co-cultured with primary dorsal root ganglion cells and formed myelin after transplantation into shiverer mice. We propose direct lineage reprogramming as a viable alternative approach for the generation of OPCs for use in disease modeling and regenerative medicine.

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Figure 1: Identification of candidate factors for the generation of iOPCs.
Figure 2: Induction of OPC-like cells from rat fibroblasts.
Figure 3: Global transcriptional reprogramming of iOPCs.
Figure 4: Differentiation potential of fibroblasts-derived iOPCs in vitro.
Figure 5: Fibroblast-derived iOPC cells are myelinogenic in vivo.

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Acknowledgements

We thank W. Macklin for sharing the Plp-EGFP mouse line and B. Stallcup for providing the rabbit NG2 antibody. We are extremely grateful to N. Uchida for crucial advice and would also like to thank A. Olson for help with the confocal analysis and the Neuroscience Institute Imaging facility and the Stanford genomics core for microarray hybridization. This work was supported by the Ellison Medical Foundation (M.W.), the Stinehart-Reed Foundation (M.W.), the National Institutes of Health grants R01MH092931 (M.W.), the New York Stem Cell Foundation (M.W.) and R01EY10257 (B.A.B). N.Y. is the recipient of a Walter V. and Idun Berry Fellowship. J.B.Z. is a Howard Hughes Medical Institute Fellow of the Life Sciences Research Foundation. H.A. is supported by a postdoctoral fellowship from the Swedish Research Council and the Swedish Society for Medical Research. M.W. is a New York Stem Cell Foundation–Robertson Investigator.

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N.Y., J.B.Z., H.A. and M.W. designed research; N.Y., J.B.Z., H.A., S.M., Y.H.N., T.V., J.S.H. and R.G. performed research; N.Y., J.B.Z., H.A., S.M., B.A.B. and M.W. analyzed data; and N.Y., J.B.Z., H.A. and M.W. wrote the paper.

Corresponding author

Correspondence to Marius Wernig.

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Yang, N., Zuchero, J., Ahlenius, H. et al. Generation of oligodendroglial cells by direct lineage conversion. Nat Biotechnol 31, 434–439 (2013). https://doi.org/10.1038/nbt.2564

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