Journal Article

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

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

2016

Overview

Mature pancreatic β-cells can be distinguished from proliferating ones by expression of the Fltp reporter gene, which is triggered by Wnt signalling and β-cell polarization and islet compaction. A marker for pancreatic β-cell maturity Pancreatic β-cells are functionally heterogeneous, and differences in their characteristics may be important in the context of insulin-dependent diabetes. Heiko Lickert and colleagues have found a marker, the Fltp reporter gene, that is expressed in mature β-cell populations but not in proliferative β-cells. Fltp expression is triggered by Wnt signalling and polarization of β-cells as they organize into three-dimensional islets and the authors show that this change in architecture is sufficient to induce mouse and human β-cell maturation. 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 1 , 2 , 3 , 4 , 5 ; 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 6 , 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 7 , 8 , 9 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 14 / 38 / 59 / 631/532/489 / 631/80/304 / 64 / 64/60 / 82 / 96 / Animals / Biomarkers - analysis / Cell Differentiation / Cell Lineage - genetics / Cell Polarity / Cell Proliferation / Cells / Humanities and Social Sciences / Humans / Identification and classification / Insulin Resistance / Islands of Langerhans / Islets of Langerhans - cytology / Islets of Langerhans - metabolism / letter / Ligands / Mice / Mice, Inbred C57BL / Microtubule-Associated Proteins - genetics / Microtubule-Associated Proteins - metabolism / multidisciplinary / Physiological aspects / Science / Wnt Signaling Pathway