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 potential1,2,3,4,5; 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 gene6, 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-organs7,8,9. 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.
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Gene Expression Omnibus
Microarray data have been submitted to GEO with accession number GSE68853.
We thank A. Raducanu, A. Böttcher and E. Schlüssel for comments and discussions; A. Theis, B. Vogel and K. Diemer for technical support; the Human Tissue Laboratory (HTL) of Lund University Diabetes Centre (LUDC) for high-quality RNA sequencing expression data from human pancreatic islets donors; to InSphero for human microislets; the European Consortium for Islet Transplantation (ECIT) for human islets; and R. Scharfmann for the EndoC-β H1 cell line. The human islet research was supported by a Strategic Research Grant from the Swedish Research Council (2009-1039). A.M. was funded by the Helmholtz post-doctoral fellowship program. This work was supported by an Emmy-Noether Fellowship, the European Union (ERC starting grant Ciliary Disease) and the HumEn project from the European Union's Seventh Framework Programme for Research, Technological Development and Demonstration under grant agreement No. 602587 (http://www.hum-en.eu/). This work was funded (in part) for H.L. and J.B. by the Helmholtz Alliance ICEMED – Imaging and Curing Environmental Metabolic Diseases, through the Initiative and Networking Fund of the Helmholtz Association. We thank the Helmholtz Society, Helmholtz Portfolio Theme 'Metabolic Dysfunction and Common Disease, German Research Foundation and German Center for Diabetes Research (DZD e.V.) for financial support. This work was supported with funds for S.S. from the Emmy-Noether Program, the Center for Regenerative Therapies Dresden-DFG Research Center for Regenerative Therapies Dresden, Cluster of Excellence (CRTD), the DFG-Collaborative Research Center/Transregio 127 and the German Ministry for Education and Research to the German Centre for Diabetes Research and to the Network of Competence for Diabetes.