Identification of proliferative and mature β-cells in the islets of Langerhans - PubMed (original) (raw)

. 2016 Jul 21;535(7612):430-4.

doi: 10.1038/nature18624. Epub 2016 Jul 11.

Adriana Migliorini, Moritz Gegg, Noah Moruzzi, Jantje Gerdes, Sara S Roscioni, Mostafa Bakhti, Elisabeth Brandl, Martin Irmler, Johannes Beckers, Michaela Aichler, Annette Feuchtinger, Christin Leitzinger, Hans Zischka, Rui Wang-Sattler, Martin Jastroch, Matthias Tschöp, Fausto Machicao, Harald Staiger, Hans-Ulrich Häring, Helena Chmelova, Julie A Chouinard, Nikolay Oskolkov, Olle Korsgren, Stephan Speier, Heiko Lickert

Identification of proliferative and mature β-cells in the islets of Langerhans

Erik Bader et al. Nature. 2016.

Abstract

Insulin-dependent diabetes is a complex multifactorial disorder characterized by loss or dysfunction of β-cells. Pancreatic β-cells differ in size, glucose responsiveness, insulin secretion and precursor cell potential; understanding the mechanisms that underlie this functional heterogeneity might make it possible to develop new regenerative approaches. Here we show that Fltp (also known as Flattop and Cfap126), a Wnt/planar cell polarity (PCP) effector and reporter gene acts as a marker gene that subdivides endocrine cells into two subpopulations and distinguishes proliferation-competent from mature β-cells with distinct molecular, physiological and ultrastructural features. Genetic lineage tracing revealed that endocrine subpopulations from Fltp-negative and -positive lineages react differently to physiological and pathological changes. The expression of Fltp increases when endocrine cells cluster together to form polarized and mature 3D islet mini-organs. We show that 3D architecture and Wnt/PCP ligands are sufficient to trigger β-cell maturation. By contrast, the Wnt/PCP effector Fltp is not necessary for β-cell development, proliferation or maturation. We conclude that 3D architecture and Wnt/PCP signalling underlie functional β-cell heterogeneity and induce β-cell maturation. The identification of Fltp as a marker for endocrine subpopulations sheds light on the molecular underpinnings of islet cell heterogeneity and plasticity and might enable targeting of endocrine subpopulations for the regeneration of functional β-cell mass in diabetic patients.

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