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Pancreas-specific miR-216a regulates proliferation and endocrine and exocrine cell function II

ABSTRACT: Several miRNAs have tissue-specific patterns consistent with crucial functions in many biological processes and are candidate biomarkers of disease. Yet, there is limited knowledge about the role of pancreas-specific miRNAs in pancreatic pathologies. Here, we show that miR-216a is a conserved, pancreas-specific miRNA with important roles in pancreatic islet and acinar cells. By profiling miRNAs from human islets and subsequent systematic tissue analysis we found that miR-216a is highly enriched in endocrine and exocrine pancreas. Deletion of miR-216a in mice lead to a reduction in islet size, β-cell mass and insulin levels. RNA-sequencing indicated that cell cycle and proliferation were the most significantly regulated biological processes in miR-216 knockout pancreata. miR-216a was induced by TGF-β signalling and inhibition of miR-216a increased apoptosis and decreased cell proliferation in both β- and exocrine cells. Deletion of miR-216a in the pancreatic cancer prone mouse line Kras G12D ;Ptf1a CreER reduced the propensity of pancreatic cancer precursor lesions. Notably, circulating miR-216a levels were elevated in both mice and humans with pancreatic cancer. Collectively, our study gives insights into how β-cell mass and acinar cell growth are modulated by a pancreas-specific miRNA but also suggests miR-216a as a promising biomarker for diagnosis of pancreatic diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE159970 | GEO | 2021/10/22

REPOSITORIES: GEO

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Project description:deBack2012 - Lineage Specification in Pancreas Development This model of two neighbouring pancreas precursor cells, describes the exocrine versus endocrine lineage specification process. To account for the tissue scale patterns, this couplet model has been extended to hundreds of coupled cells. This model is described in the article: On the role of lateral stabilization during early patterning in the pancreas de Back W., Zhou JX, Brusch L J. R. Soc. Interface 6 February 2013 vol. 10 no. 79 20120766 Abstract: The cell fate decision of multi-potent pancreatic progenitor cells between the exocrine and endocrine lineages is regulated by Notch signalling, mediated by cell–cell interactions. However, canonical models of Notch-mediated lateral inhibition cannot explain the scattered spatial distribution of endocrine cells and the cell-type ratio in the developing pancreas. Based on evidence from acinar-to-islet cell transdifferentiation in vitro, we propose that lateral stabilization, i.e. positive feedback between adjacent progenitor cells, acts in parallel with lateral inhibition to regulate pattern formation in the pancreas. A simple mathematical model of transcriptional regulation and cell–cell interaction reveals the existence of multi-stability of spatial patterns whose simultaneous occurrence causes scattering of endocrine cells in the presence of noise. The scattering pattern allows for control of the endocrine-to-exocrine cell-type ratio by modulation of lateral stabilization strength. These theoretical results suggest a previously unrecognized role for lateral stabilization in lineage specification, spatial patterning and cell-type ratio control in organ development. This model is hosted on BioModels Database and identified by: MODEL1211010000 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Pancreas-specific miR-216a regulates proliferation and endocrine and exocrine cell function II

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