Abstract
β-cell dedifferentiation has been recently suggested as an additional mechanism contributing to type-1 and to type-2 diabetes pathogenesis. Moreover, several studies demonstrated that in vitro culture of native human pancreatic islets derived from non-diabetic donors resulted in the generation of an undifferentiated cell population. Additional evidence from in vitro human β-cell lineage tracing experiments, demonstrated that dedifferentiated cells derive from β-cells, thus representing a potential in vitro model of β-cell dedifferentiation. Here, we report the microRNA expression profiles analysis of in vitro dedifferentiated islet cells in comparison to mature human native pancreatic islets. We identified 13 microRNAs upregulated and 110 downregulated in islet cells upon in vitro dedifferentiation. Interestingly, among upregulated microRNAs, we observed the activation of microRNA miR-302s cluster, previously defined as pluripotency-associated. Bioinformatic analysis indicated that miR-302s are predicted to target several genes involved in the control of β-cell/epithelial phenotype maintenance; accordingly, such genes were downregulated upon human islet in vitro dedifferentiation. Moreover, we uncovered that cell–cell contacts are needed to maintain low/null expression levels of miR-302. In conclusion, we showed that miR-302 microRNA cluster genes are involved in in vitro dedifferentiation of human pancreatic islet cells and inhibits the expression of multiple genes involved in the maintenance of β-cell mature phenotype.
Highlights
It has been previously demonstrated that in vitro culture of native adult human pancreatic islets derived from non-diabetic donors resulted into the generation/expansion of an undifferentiated cell population [1]
We and others have previously demonstrated that prolonged human pancreatic islets culture results in delamination, adhesion, and migration of endocrine cells from islet native architecture; such morphological changes are associated to the loss of pancreatic-endocrine phenotype, in a process resembling epithelial–mesenchymal transition (EMT) [1,5]
We dedifferentiated in vitro human pancreatic islets cells derived from n = 3 non-diabetic organ donors (Age 63.3 ± 23.3 year; BMI 24.8 ± 1.3 Kg/m2) and compared them to fully differentiated human native islet cells (n = 3) (Age 54.6 ± 21.3 year; BMI 25.4 ± 1.8 Kg/m2)
Summary
It has been previously demonstrated that in vitro culture of native adult human pancreatic islets derived from non-diabetic donors resulted into the generation/expansion of an undifferentiated cell population [1]. Several studies demonstrated that the resulting cell population derives from an epithelial to mesenchymal transition (EMT) program which induces specialized islet cells to lose endocrine pancreatic markers (dedifferentiation) while acquiring a mesenchymal/multipotent phenotype [2,3,4]. Even though dedifferentiated cells have been detected using multiple histological approaches, their molecular architecture has not yet been fully elucidated. Several efforts pursuing this goal have been made by analyzing a number of pathways underlying the phenotype loss in in vitro dedifferentiated β-cells
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