Direct lineage conversion is a promising approach to generate therapeutically important cell types for disease modeling and tissue repair. However, the survival and function of lineage-reprogrammed cells in vivo over the long term has not been examined. Here, using an improved method for in vivo conversion of adult mouse pancreatic acinar cells toward beta cells, we show that induced beta cells persist for up to 13 months (the length of the experiment), form pancreatic islet–like structures and support normoglycemia in diabetic mice. Detailed molecular analyses of induced beta cells over 7 months reveal that global DNA methylation changes occur within 10 d, whereas the transcriptional network evolves over 2 months to resemble that of endogenous beta cells and remains stable thereafter. Progressive gain of beta-cell function occurs over 7 months, as measured by glucose-regulated insulin release and suppression of hyperglycemia. These studies demonstrate that lineage-reprogrammed cells persist for >1 year and undergo epigenetic, transcriptional, anatomical and functional development toward a beta-cell phenotype.
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We thank M. Shear, J. Brown, J. Hollister-Lock, and R. Zhao for technical assistance; H.-H. Chen for assistance with gene profiling; D. Yu and T. Fabbro for statistical analysis; Boston Children's Hospital core facility for an Illumina array; Joslin Specialized Assay Core for insulin measurement; members of the Zhou laboratory for advice and feedback; and D. Melton and D. Breault for discussion and reading of the manuscript. Q.Z. was supported by awards from the US National Institutes of Health. W.L. is supported by a postdoctoral fellowship from the Juvenile Diabetes Research Foundation. C.C.-W. is supported by postdoctoral fellowships from the Swiss Science Foundation and the Swiss Foundation for Grants in Biology and Medicine.
The authors declare no competing financial interests.
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Li, W., Cavelti-Weder, C., Zhang, Y. et al. Long-term persistence and development of induced pancreatic beta cells generated by lineage conversion of acinar cells. Nat Biotechnol 32, 1223–1230 (2014). https://doi.org/10.1038/nbt.3082
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