Total or near-total loss of insulin-producing β-cells occurs in type 1 diabetes1,2. Restoration of insulin production in type 1 diabetes is thus a major medical challenge. We previously observed in mice in which β-cells are completely ablated that the pancreas reconstitutes new insulin-producing cells in the absence of autoimmunity3. The process involves the contribution of islet non-β-cells; specifically, glucagon-producing α-cells begin producing insulin by a process of reprogramming (transdifferentiation) without proliferation3. Here we show the influence of age on β-cell reconstitution from heterologous islet cells after near-total β-cell loss in mice. We found that senescence does not alter α-cell plasticity: α-cells can reprogram to produce insulin from puberty through to adulthood, and also in aged individuals, even a long time after β-cell loss. In contrast, before puberty there is no detectable α-cell conversion, although β-cell reconstitution after injury is more efficient, always leading to diabetes recovery. This process occurs through a newly discovered mechanism: the spontaneous en masse reprogramming of somatostatin-producing δ-cells. The juveniles display ‘somatostatin-to-insulin’ δ-cell conversion, involving dedifferentiation, proliferation and re-expression of islet developmental regulators. This juvenile adaptability relies, at least in part, upon the combined action of FoxO1 and downstream effectors. Restoration of insulin producing-cells from non-β-cell origins is thus enabled throughout life via δ- or α-cell spontaneous reprogramming. A landscape with multiple intra-islet cell interconversion events is emerging, offering new perspectives for therapy.
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We are grateful to D. Belin, P. Vassalli, R. Stein, A. Cookson, A. Ruiz i Altaba, M. González Gaitán, B. Galliot and I. Rodríguez for comments, support and discussions, and to G. Gallardo, O. Fazio, K. Hammad and B. Polat for technical help. We thank G. Gradwohl for the Ngn3-YFP mice. F.M.G. and F.R. were funded by Wellcome Trust grants WT088357/Z/09/Z and WT084210/Z/07/Z, respectively. This work was funded with grants from the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (Beta Cell Biology Consortium), the Juvenile Diabetes Research Foundation and the Swiss National Science Foundation (NRP63) to P.L.H.
Extended data figures
This file contains Supplementary Methods and Data, Supplementary References and Supplementary Tables 1-39.