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Conversion of adult pancreatic α-cells to β-cells after extreme β-cell loss

Abstract

Pancreatic insulin-producing β-cells have a long lifespan, such that in healthy conditions they replicate little during a lifetime. Nevertheless, they show increased self-duplication after increased metabolic demand or after injury (that is, β-cell loss). It is not known whether adult mammals can differentiate (regenerate) new β-cells after extreme, total β-cell loss, as in diabetes. This would indicate differentiation from precursors or another heterologous (non-β-cell) source. Here we show β-cell regeneration in a transgenic model of diphtheria-toxin-induced acute selective near-total β-cell ablation. If given insulin, the mice survived and showed β-cell mass augmentation with time. Lineage-tracing to label the glucagon-producing α-cells before β-cell ablation tracked large fractions of regenerated β-cells as deriving from α-cells, revealing a previously disregarded degree of pancreatic cell plasticity. Such inter-endocrine spontaneous adult cell conversion could be harnessed towards methods of producing β-cells for diabetes therapies, either in differentiation settings in vitro or in induced regeneration.

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Figure 1: β-cell ablation and regeneration.
Figure 2: Conditional β-cell lineage tracing.
Figure 3: α-to-β reprogramming.
Figure 4: β-cell marker expression.

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Acknowledgements

We are grateful to P. Vassalli and C. V. E. Wright for their comments and support. We also thank R. Stein, S. Kim and A. Ruiz i Altaba for discussions, and G. Flores, C. Gysler, O. Fazio, G. Philippin and C. Vesin for their technical help. We thank D. Melton for the RIP-CreER transgenic strain, and B. Thorens and C. V. E. Wright for anti-Glut2 and anti-Pdx1 antibodies, respectively. Work was funded with grants from the NIH/NIDDK (‘Beta Cell Biology Consortium’), JDRF (Juvenile Diabetes Research Foundation), Swiss National Science Foundation (and the NCCR ‘Frontiers in Genetics’), and 6FP EU Integrated Project ‘Beta Cell Therapy for Diabetes’ to P.L.H.

Author Contributions F.T., V.N. and I.A. contributed equally to this work. F.T. and V.N. prepared constructs for generating the transgenics, wrote the manuscript and together with I.A. performed most experiments and analyses. K.K. provided one plasmid. R.D. and S.C. conducted gene expression analyses, and S.C. performed immunofluorescence microscopy. P.L.H. conceived the experiments and wrote the manuscript with contributions from F.T., V.N., I.A. and S.C.

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Correspondence to Pedro L. Herrera.

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Thorel, F., Népote, V., Avril, I. et al. Conversion of adult pancreatic α-cells to β-cells after extreme β-cell loss. Nature 464, 1149–1154 (2010). https://doi.org/10.1038/nature08894

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