Identification of proliferative and mature β-cells in the islets of Langerhans
E. Bader, A. Migliorini, M. Gegg, N. Moruzzi, J. Gerdes, S. S. Roscioni, M. Bakhti, E. Brandl, M. Irmler, J. Beckers, M. Aichler, A. Feuchtinger, C. Leitzinger, H. Zischka, R. Wang-Sattler, M. Jastroch, M. Tschöp, F. Machicao, H. Staiger, H.-U. Häring, H. Chmelova, J. A. Chouinard, N. Oskolkov, O. Korsgren, S. Speier & H. Lickert , nature , DOI:10.1038/nature18624
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 evelopment, 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.