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

E Bader, A Migliorini, M Gegg, N Moruzzi, J Gerdes… - Nature, 2016 - nature.com
E Bader, A Migliorini, M Gegg, N Moruzzi, J Gerdes, SS Roscioni, M Bakhti, E Brandl…
Nature, 2016nature.com
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 …
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.
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