MiR-375 promotes redifferentiation of adult human β cells expanded in vitro

PLoS One. 2015 Apr 13;10(4):e0122108. doi: 10.1371/journal.pone.0122108. eCollection 2015.

Abstract

In-vitro expansion of β cells from adult human pancreatic islets could provide abundant cells for cell replacement therapy of diabetes. However, proliferation of β-cell-derived (BCD) cells is associated with dedifferentiation. Here we analyzed changes in microRNAs (miRNAs) during BCD cell dedifferentiation and identified miR-375 as one of the miRNAs greatly downregulated. We hypothesized that restoration of miR-375 expression in expanded BCD cells may contribute to their redifferentiation. Our findings demonstrate that overexpression of miR-375 alone leads to activation of β-cell gene expression, reduced cell proliferation, and a switch from N-cadherin to E-cadherin expression, which characterizes mesenchymal-epithelial transition. These effects, which are reproducible in cells derived from multiple human donors, are likely mediated by repression of PDPK1 transcripts and indirect downregulation of GSK3 activity. These findings support an important role of miR-375 in regulation of human β-cell phenotype, and suggest that miR-375 upregulation may facilitate the generation of functional insulin-producing cells following ex-vivo expansion of human islet cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Phosphoinositide-Dependent Protein Kinases / biosynthesis
  • Adult
  • Cadherins / biosynthesis
  • Cell Differentiation / genetics*
  • Cell Proliferation / genetics
  • Cell- and Tissue-Based Therapy*
  • Diabetes Mellitus / genetics*
  • Diabetes Mellitus / therapy
  • Epithelial-Mesenchymal Transition / genetics
  • Gene Expression Regulation, Developmental
  • Humans
  • In Vitro Techniques
  • Insulin / metabolism
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / transplantation
  • Islets of Langerhans / cytology
  • Islets of Langerhans / metabolism
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism

Substances

  • Cadherins
  • Insulin
  • MIRN375 microRNA, human
  • MicroRNAs
  • 3-Phosphoinositide-Dependent Protein Kinases
  • PDPK1 protein, human

Grant support

This work was funded by a grant from the Israel Science Foundation to SE. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.