In vivo reprogramming of adult pancreatic exocrine cells to β-cells

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Abstract

One goal of regenerative medicine is to instructively convert adult cells into other cell types for tissue repair and regeneration. Although isolated examples of adult cell reprogramming are known, there is no general understanding of how to turn one cell type into another in a controlled manner. Here, using a strategy of re-expressing key developmental regulators in vivo, we identify a specific combination of three transcription factors (Ngn3 (also known as Neurog3) Pdx1 and Mafa) that reprograms differentiated pancreatic exocrine cells in adult mice into cells that closely resemble β-cells. The induced β-cells are indistinguishable from endogenous islet β-cells in size, shape and ultrastructure. They express genes essential for β-cell function and can ameliorate hyperglycaemia by remodelling local vasculature and secreting insulin. This study provides an example of cellular reprogramming using defined factors in an adult organ and suggests a general paradigm for directing cell reprogramming without reversion to a pluripotent stem cell state.

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Figure 1: A combination of three transcription factors induces insulin+ cells in adult mouse pancreas in vivo.
Figure 2: Induced new β-cells originate from differentiated exocrine cells.
Figure 3: Endogenous and induced β-cells are indistinguishable in morphology and ultrastructure.
Figure 4: Molecular marker characterization of induced β-cells.
Figure 5: Induced new β-cells remodel vasculature and ameliorate hyperglycaemia.

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Gene Expression Omnibus

Data deposits

The microarray data were deposited in the Gene Expression Omnibus (GEO) under accession number GSE 12025.

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Acknowledgements

We are grateful to M. Ericsson for expert assistance on electron microscopy, R. Hellmiss-Peralta for advice on graphics, and B. Tilton and P. Rogers for FACS. We thank R. Martinez and G. Kenty for technical assistance; H. Edlund for the gift of Ptf1a antiserum; A. Kweudjeu for microarray analysis; members of the Melton laboratory for advice and feedback; and J. Sneddon, J. Annes and W. Anderson for critical reading of the manuscript. Q.Z. was supported by a Damon-Runyon Cancer Research Foundation Postdoctoral Fellowship and a Pathway to Independence (PI) Award from the National Institute of Health. D.A.M. is an HHMI investigator and this work was supported in part by the Harvard Stem Cell Institute and the NIH.

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Correspondence to Douglas A. Melton.

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