title: Identification of proliferative and mature β-cells in the islets of Langerhans.
abstract: 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.
authors.forename: Erik
authors.initials: E
authors.lastname: Bader
authors.forename: Adriana
authors.initials: A
authors.lastname: Migliorini
authors.forename: Moritz
authors.initials: M
authors.lastname: Gegg
authors.forename: Noah
authors.initials: N
authors.lastname: Moruzzi
authors.forename: Jantje
authors.initials: J
authors.lastname: Gerdes
authors.forename: Sara S
authors.initials: SS
authors.lastname: Roscioni
authors.forename: Mostafa
authors.initials: M
authors.lastname: Bakhti
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Brandl
authors.forename: Martin
authors.initials: M
authors.lastname: Irmler
authors.forename: Johannes
authors.initials: J
authors.lastname: Beckers
authors.forename: Michaela
authors.initials: M
authors.lastname: Aichler
authors.forename: Annette
authors.initials: A
authors.lastname: Feuchtinger
authors.forename: Christin
authors.initials: C
authors.lastname: Leitzinger
authors.forename: Hans
authors.initials: H
authors.lastname: Zischka
authors.forename: Rui
authors.initials: R
authors.lastname: Wang-Sattler
authors.forename: Martin
authors.initials: M
authors.lastname: Jastroch
authors.forename: Matthias
authors.initials: M
authors.lastname: Tschöp
authors.forename: Fausto
authors.initials: F
authors.lastname: Machicao
authors.forename: Harald
authors.initials: H
authors.lastname: Staiger
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Häring
authors.forename: Helena
authors.initials: H
authors.lastname: Chmelova
authors.forename: Julie A
authors.initials: JA
authors.lastname: Chouinard
authors.forename: Nikolay
authors.initials: N
authors.lastname: Oskolkov
authors.forename: Olle
authors.initials: O
authors.lastname: Korsgren
authors.forename: Stephan
authors.initials: S
authors.lastname: Speier
authors.forename: Heiko
authors.initials: H
authors.lastname: Lickert
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000032:analysis; D002454:Cell Differentiation; D019070:Cell Lineage / Q000235:genetics; D016764:Cell Polarity; D049109:Cell Proliferation; D006801:Humans; D007333:Insulin Resistance; D007515:Islets of Langerhans / Q000166:cytology* / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: D015415:Biomarkers; C000598970:Flattop protein, mouse; D008024:Ligands; D008869:Microtubule-Associated Proteins