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Abstract
Backgroundβ-cells undergo an epithelial to mesenchymal transition (EMT) when expanded in monolayer culture and give rise to highly proliferative mesenchymal cells that retain the potential to re-differentiate into insulin-producing cells.ObjectiveTo investigate whether EMT takes place in the endocrine non-β cells of human islets.MethodologyHuman islets isolated from 12 multiorgan donors were dissociated into single cells, purified by magnetic cell sorting, and cultured in monolayer.ResultsCo-expression of insulin and the mesenchymal marker vimentin was identified within the first passage (p1) and increased subsequently (insulin+vimentin+ 7.2±6% at p1; 43±15% at p4). The endocrine non-β-cells did also co-express vimentin (glucagon+vimentin+ 59±1.5% and 93±6%, somatostatin+vimentin+ 16±9.4% and 90±10% at p1 and p4 respectively; PP+vimentin+ 74±14% at p1; 88±12% at p2). The percentage of cells expressing only endocrine markers was progressively reduced (0.6±0.2% insulin+, 0.2±0.1% glucagon+, and 0.3±0.2% somatostatin+ cells at p4, and 0.7±0.3% PP+ cells at p2. Changes in gene expression were also indicated of EMT, with reduced expression of endocrine markers and the epithelial marker CDH-1 (p<0.01), and increased expression of mesenchymal markers (CDH-2, SNAI2, ZEB1, ZEB2, VIM, NT5E and ACTA2; p<0.05). Treatment with the EMT inhibitor A83-01 significantly reduced the percentage of co-expressing cells and preserved the expression of endocrine markers.ConclusionsIn adult human islets, all four endocrine islet cell types undergo EMT when islet cells are expanded in monolayer conditions. The presence of EMT in all islet endocrine cells could be relevant to design of strategies aiming to re-differentiate the expanded islet cells towards a β-cell phenotype.
Highlights
Cell therapy of diabetes is limited by the shortage of β-cells available for transplantation
Co-expression of insulin and the mesenchymal marker vimentin was identified within the first passage (p1) and increased subsequently
All four endocrine islet cell types undergo epithelial to mesenchymal transition (EMT) when islet cells are expanded in monolayer conditions
Summary
Cell therapy of diabetes is limited by the shortage of β-cells available for transplantation. Adult β-cells have a low replicative capacity, but when cultured in monolayer they undergo a phenotypic shift through an epithelial to mesenchymal transition (EMT) process and give rise to highly proliferative mesenchymal cells that can be massively expanded [1,2]. These expanded cells retain the potential to re-differentiate into insulin-producing cells [3]. We aimed to determine whether EMT takes place in the endocrine non-β-cells of human pancreatic islets expanded in vitro. Editor: Rajeev Samant, University of Alabama at Birmingham, UNITED STATES β-cells undergo an epithelial to mesenchymal transition (EMT) when expanded in monolayer culture and give rise to highly proliferative mesenchymal cells that retain the potential to redifferentiate into insulin-producing cells
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