Total or near-total loss of insulin-producing β-cells is a situation found in diabetes (Type 1, T1D) 1,2. Restoration of insulin production in T1D 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 absence of autoimmunity 3. 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 proliferation 3. Here we studied the influence of age on β-cell reconstitution from heterologous islet cells after near-total β-cell loss. We found that senescence does not alter α-cell plasticity: α-cells can reprogram to produce insulin from puberty through adulthood, and also in aged individuals, even a long-time after β-cell loss. In contrast, prior to puberty there is no detectable α-cell conversion, although β-cell reconstitution after injury is more efficient, always leading to diabetes recovery; it occurs through a newly discovered mechanism: the spontaneous en masse reprogramming of somatostatin-producing δ-cells. The younglings display “somatostatin-to-insulin” δ-cell conversion, involving de-differentiation, proliferation and re-expression of islet developmental regulators. This juvenile adaptability relies, at least in part, upon 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, thus offering new perspectives.

Attaining proper organ size during development and regeneration hinges on the activity of mitogenic factors. Here, we performed a large-scale chemical screen in embryonic zebrafish to identify cardiomyocyte mitogens. Although commonly considered antiproliferative, vitamin D analogs like alfacalcidol had rapid, potent mitogenic effects on embryonic and adult cardiomyocytes in vivo. Moreover, pharmacologic or genetic manipulation of vitamin D signaling controlled proliferation in multiple adult cell types and dictated growth rates in embryonic and juvenile zebrafish. Tissue-specific modulation of vitamin D receptor (VDR) signaling had organ-restricted effects, with cardiac VDR activation causing cardiomegaly. Alfacalcidol enhanced the regenerative response of injured zebrafish hearts, whereas VDR blockade inhibited regeneration. Alfacalcidol activated cardiac expression of genes associated with ErbB2 signaling, while ErbB2 inhibition blunted its effects on cell proliferation. Our findings identify vitamin D as mitogenic for cardiomyocytes and other cell types in zebrafish and indicate a mechanism to regulate organ size and regeneration.

The mechanisms restricting regeneration and maintaining cell identity following injury are poorly characterized in higher vertebrates. Upon β-cell loss, 1–2% of the glucagon-producing α-cells spontaneously engage in insulin production in mice. Here we explore the mechanisms inhibiting α-cell plasticity. We show that the adaptive α-cell identity changes are constrained by intra-islet Insulin- and Smoothened-mediated signaling, among others. The combination of β-cell loss, or insulin signaling inhibition, with Smoothened inactivation in α- or δ-cells, stimulates insulin production in more α-cells. These findings suggest that removing constitutive “brake signals” is crucial for neutralizing the refractoriness to adaptive cell-fate changes. It appears that cell identity maintenance is an active process mediated by repressive signals, released by neighbor cells, curbing an intrinsic trend of differentiated cells to change.