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Diabetes

β-cell heterogeneity — key to unlocking islet regeneration

New research has identified a subpopulation of immature adult β cells that is proliferative and can also be differentiated into mature insulin-producing β cells. The findings published in Nature by researchers from the Helmholtz Centre, Munich, Germany, represent a step towards replacing dysfunctional or lost β cells in patients with diabetes mellitus.

Credit: Helmholtz Zentrum München/Heiko Lickert/Erik Bader

“Although different subpopulations of β cells have been known to exist for over 50 years, the mechanisms underlying this heterogeneity have remained unknown due to a lack of molecular markers capable of distinguishing between the different subpopulations,” explains lead investigator Heiko Lickert. “We, therefore, screened for markers that could subdivide insulin-producing β-cell populations and identified Fltp (encoding the protein Flattop), a Wnt/planar cell polarity (PCP) effector and reporter gene involved in the acquisition of tissue polarity and 3D architecture.”

“...Fltp expression correlates with β-cell proliferative capacity and subdivides β cells into either proliferative or mature cells”

To distinguish between β cells expressing Fltp from those not expressing the gene, the investigators generated a knockin/knockout mouse (FltpZV), in which the open-reading frame of Fltp was replaced by a cassette encoding a fluorescent reporter protein designated FVR, such that cells normally expressing Fltp (FVR+) fluoresced. In heterozygous FltpZV mice, two β-cell populations were identified — FVR+ and FVR. The percentage of FVR+ cells in islets increased from 50% at postnatal day (P) 1 to 80% at 12 weeks (adult mice). The biological significance of the two β-cell populations was demonstrated by measuring their rates of proliferation at gestational day 15.5, P1, P11 and 12 weeks. At all time points, proliferation was markedly increased in FVR cells compared with FVR+ cells, which suggests that Fltp expression correlates with β-cell proliferative capacity and subdivides β cells into either proliferative or mature cells.

To test this hypothesis, the team purified the two β-cell populations and performed genome-wide mRNA profiling, identifying 997 genes differentially expressed by >1.5-fold between FVR and FVR+ cells. Noticeably, the FVR population was enriched in genes associated with G-protein-coupled receptor, Wnt and MAPK signalling pathways (which mediate responses to environmental cues), whereas the FVR+ population was enriched in genes involved in mature β-cell function (including Wnt/PCP genes), further supporting the notion that FVR+ (Fltp expressing) cells are mature β cells and linking planar polarity with β-cell maturation. As the gene expression analysis suggested the two populations of β cells react differently to environmental changes, the investigators performed in vitro single-cell tracking to follow the fate of cells over time. Remarkably, Fltp-lineage negative cells became Fltp-lineage positive cells, which indicates that FVR cells differentiate into FVR+ mature β cells. Finally, by treating reaggregated β cells and pseudo-islets of Min6 insulinoma cells with the Wnt/PCP ligand Wnt5a, the team showed that 3D architecture and Wnt/PCP ligands are sufficient to initiate β-cell maturation.

“Activating the receptors and pathways that associate with the two β-cell populations might enable us to target β-cell proliferation and maturation for islet-regeneration therapy,” speculates Lickert. “Moreover, as stem-cell-derived β-like cells can be differentiated in vitro but are not functionally mature, our finding of a novel marker of the transition and the pathway involved provides a way to improve differentiation protocols for cell-replacement therapy.”

References

  1. 1

    Bader, E. et al. Identification of proliferative and mature β-cells in the islets of Langerhans. Nature http://dx.doi.org/10.1038/nature18624 (2016)

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Wang, P. et al. Diabetes mellitus — advances and challenges in human β-cell proliferation. Nat. Rev. Endocrinol. 11, 201–212 (2015)

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Holmes, D. β-cell heterogeneity — key to unlocking islet regeneration. Nat Rev Endocrinol 12, 495 (2016). https://doi.org/10.1038/nrendo.2016.122

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