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.

Steady-state and transiently perturbed nitrogen-limited chemostats show that nitrogen abundance is a primary signal controlling nitrogen-responsive gene expression. When cells experience an increase in nitrogen, some transcripts are rapidly degraded, suggesting that accelerated mRNA degradation contributes to remodeling of gene expression.

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In the version of this article initially published, Yingying Zhang's name was spelled Yinying Zhang. The error has been corrected in the HTML and PDF versions of the article.