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Direct lineage conversions: unnatural but useful?

Abstract

Classic experiments such as somatic cell nuclear transfer into oocytes and cell fusion demonstrated that differentiated cells are not irreversibly committed to their fate. More recent work has built on these conclusions and discovered defined factors that directly induce one specific cell type from another, which may be as distantly related as cells from different germ layers. This suggests the possibility that any specific cell type may be directly converted into any other if the appropriate reprogramming factors are known. Direct lineage conversion could provide important new sources of human cells for modeling disease processes or for cellular-replacement therapies. For future applications, it will be critical to carefully determine the fidelity of reprogramming and to develop methods for robustly and efficiently generating human cell types of interest.

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Figure 1: Epigenetic models of development and reprogramming.
Figure 2: Various modes of induced cell fate changes.
Figure 3: Potential mechanism of the stepwise activation of silent genes by reprogramming factors.

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Acknowledgements

We would like to thank the many colleagues who have contributed to this work through many insightful discussions on the topic over the last year. These include T. Graf, F. Guillemot, M. Götz, J. Crabtree, A. Smith, R. Jaenisch, J. Wysocka, H. Blau, H. Chang, A. Kriegstein and I. Weissman. M.W. is a New York Stem Cell Foundation (NYSCF) Robertson Investigator, and our research is also supported by grants from the US National Institutes of Health, the Department of Defense, the California Institute of Regenerative Medicine, the BioX program at Stanford, the Baxter Foundation and the Stinehart-Reed Foundation. T.V. is supported by the Ruth and Robert Halperin Stanford Graduate Fellowship. We apologize to numerous authors whose valuable contributions we were unable to cite due to space constraints.

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Correspondence to Marius Wernig.

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Vierbuchen, T., Wernig, M. Direct lineage conversions: unnatural but useful?. Nat Biotechnol 29, 892–907 (2011). https://doi.org/10.1038/nbt.1946

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