Identification of proliferative and mature beta-cells in the islets of Langerhans
2016 (English)In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 535, no 7612, 430-+ p.Article in journal (Refereed) Published
Insulin-dependent diabetes is a complex multifactorial disorder characterized by loss or dysfunction of beta-cells. Pancreatic beta-cells differ in size, glucose responsiveness, insulin secretion and precursor cell potential(1-5); 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 beta-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(7-9). We show that 3D architecture and Wnt/PCP ligands are sufficient to trigger beta-cell maturation. By contrast, the Wnt/PCP effector Fltp is not necessary for beta-cell development, proliferation or maturation. We conclude that 3D architecture and Wnt/PCP signalling underlie functional beta-cell heterogeneity and induce beta-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 beta-cell mass in diabetic patients.
Place, publisher, year, edition, pages
2016. Vol. 535, no 7612, 430-+ p.
Cell and Molecular Biology
IdentifiersURN: urn:nbn:se:uu:diva-308258DOI: 10.1038/nature18624ISI: 000380344200042PubMedID: 27398620OAI: oai:DiVA.org:uu-308258DiVA: diva2:1049453
FunderSwedish Research Council, 2009-1039EU, European Research Council, 602587German Research Foundation (DFG), 127