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

Nature 535, 430-434 (2016)
Publ. Version/Full Text DOI
Open Access Green as soon as Postprint is submitted to ZB.
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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Publication type Article: Journal article
Document type Scientific Article
Keywords Inducible Insulin-secretion; Pancreatic-islets; B-cells; Polarity; Mouse; Expression; Line; Dedifferentiation; Differentiation; Communication
ISSN (print) / ISBN 0028-0836
e-ISSN 1476-4687
Journal Nature
Quellenangaben Volume: 535, Issue: 7612, Pages: 430-434 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed