Neurog3 misexpression unravels mouse pancreatic ductal cell plasticity

PLoS One. 2018 Aug 9;13(8):e0201536. doi: 10.1371/journal.pone.0201536. eCollection 2018.

Abstract

In the context of type 1 diabetes research and the development of insulin-producing β-cell replacement strategies, whether pancreatic ductal cells retain their developmental capability to adopt an endocrine cell identity remains debated, most likely due to the diversity of models employed to induce pancreatic regeneration. In this work, rather than injuring the pancreas, we developed a mouse model allowing the inducible misexpression of the proendocrine gene Neurog3 in ductal cells in vivo. These animals developed a progressive islet hypertrophy attributed to a proportional increase in all endocrine cell populations. Lineage tracing experiments indicated a continuous neo-generation of endocrine cells exhibiting a ductal ontogeny. Interestingly, the resulting supplementary β-like cells were found to be functional. Based on these findings, we suggest that ductal cells could represent a renewable source of new β-like cells and that strategies aiming at controlling the expression of Neurog3, or of its molecular targets/co-factors, may pave new avenues for the improved treatments of diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cell Plasticity / physiology*
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / pathology*
  • Disease Models, Animal
  • Endocrine Cells / physiology*
  • Humans
  • Insulin-Secreting Cells / metabolism
  • Male
  • Mice
  • Mice, Transgenic
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Pancreatic Ducts / cytology
  • Pancreatic Ducts / physiology*
  • Regeneration

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Nerve Tissue Proteins
  • Neurog3 protein, mouse

Grant support

Patrick COLLOMBAT received the grants funding this work from Juvenile Diabetes Research Foundation (C1-1-SRA-2018-536-M-R, 3-SRA-2014-282-Q-R, 3-SRA-2017-415-S-B, 2-SRA-2017-416-S-B, and 17-2013-426), the Institut National de la Santé et de la Recherche Médicale AVE NIR program, the Institut National de la Santé et de la Recherche Médicale, the European Research Council (StG-2011-281265), the Fondation pour la Recherche Médicale (DRC20091217179), the Agence Nationale de la Recherche (2009 GENO 105 01/01KU0906, ANR-17-ERC2-0004-01, ANR-16-CE18-0005-02, and Betaplasticity), the “Investments for the Future” LAB EX SIG NAL IFE (ANR-11-LABX-0028-01), Mr. and Mrs. Dorato, Mr. and Mrs. Peter de Marffy-Mantuano, the Dujean family, the Fondation Générale de Santé, and the Foundation Schlumberger pour l’Education et la Recherche. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.