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Identification of miRNAs Involved in Reprogramming Acinar Cells into Insulin Producing Cells

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Listed:
  • Joan Teichenne
  • Meritxell Morró
  • Alba Casellas
  • Veronica Jimenez
  • Noelia Tellez
  • Adrien Leger
  • Fatima Bosch
  • Eduard Ayuso

Abstract

Reprogramming acinar cells into insulin producing cells using adenoviral (Ad)-mediated delivery of Pdx1, Ngn3 and MafA (PNM) is an innovative approach for the treatment of diabetes. Here, we aimed to investigate the molecular mechanisms involved in this process and in particular, the role of microRNAs. To this end, we performed a comparative study of acinar-to-β cell reprogramming efficiency in the rat acinar cell line AR42J and its subclone B13 after transduction with Ad-PNM. B13 cells were more efficiently reprogrammed than AR42J cells, which was demonstrated by a strong activation of β cell markers (Ins1, Ins2, IAPP, NeuroD1 and Pax4). miRNome panels were used to analyze differentially expressed miRNAs in acinar cells under four experimental conditions (i) non-transduced AR42J cells, (ii) non-transduced B13 cells, (iii) B13 cells transduced with Ad-GFP vectors and (iv) B13 cells transduced with Ad-PNM vectors. A total of 59 miRNAs were found to be differentially expressed between non-transduced AR42J and B13 cells. Specifically, the miR-200 family was completely repressed in B13 cells, suggesting that these cells exist in a less differentiated state than AR42J cells and as a consequence they present a greater plasticity. Adenoviral transduction per se induced dedifferentiation of acinar cells and 11 miRNAs were putatively involved in this process, whereas 8 miRNAs were found to be associated with PNM expression. Of note, Ad-PNM reprogrammed B13 cells presented the same levels of miR-137-3p, miR-135a-5p, miR-204-5p and miR-210-3p of those detected in islets, highlighting their role in the process. In conclusion, this study led to the identification of miRNAs that might be of compelling importance to improve acinar-to-β cell conversion for the future treatment of diabetes.

Suggested Citation

  • Joan Teichenne & Meritxell Morró & Alba Casellas & Veronica Jimenez & Noelia Tellez & Adrien Leger & Fatima Bosch & Eduard Ayuso, 2015. "Identification of miRNAs Involved in Reprogramming Acinar Cells into Insulin Producing Cells," PLOS ONE, Public Library of Science, vol. 10(12), pages 1-20, December.
    • Handle: RePEc:plo:pone00:0145116
    DOI: 10.1371/journal.pone.0145116
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    References listed on IDEAS

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    1. Yvonne Tay & Jinqiu Zhang & Andrew M. Thomson & Bing Lim & Isidore Rigoutsos, 2008. "MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation," Nature, Nature, vol. 455(7216), pages 1124-1128, October.
    2. Qiao Zhou & Juliana Brown & Andrew Kanarek & Jayaraj Rajagopal & Douglas A. Melton, 2008. "In vivo reprogramming of adult pancreatic exocrine cells to β-cells," Nature, Nature, vol. 455(7213), pages 627-632, October.
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