Neurogenin3 is sufficient for transdetermination of hepatic progenitor cells into neo-islets in vivo but not transdifferentiation of hepatocytes

Dev Cell. 2009 Mar;16(3):358-73. doi: 10.1016/j.devcel.2009.01.012.

Abstract

The transcription factor Neurogenin3 (Ngn3) is required for islet-cell type specification. Here, we show that hepatic gene transfer of Ngn3 transiently induces insulin in terminally differentiated hepatocytes but fails to transdifferentiate them, i.e., switch their lineage into islet cells. However, Ngn3 leads to long-term diabetes reversal in mice due to the emergence of periportal islet-like cell clusters. These neo-islets display glycemia-regulated insulin, beta-cell-specific transcripts, and an islet-specific transcription cascade, and they produce all four major islet hormones. They appear to arise from hepatic progenitor cells, most likely endoderm-derived oval cells. Thus, transfer of a single lineage-defining transcription factor, Ngn3, is sufficient to induce cell-lineage switching from a hepatic to an islet lineage in these progenitor cells, a process consistent with transdetermination, i.e, lineage switching in lineage-determined, but not terminally differentiated, cells. This paradigm of induced transdetermination of receptive progenitor cells in vivo may be generally applicable to therapeutic organogenesis for multiple diseases, including diabetes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / physiology*
  • Betacellulin
  • Cell Differentiation / physiology
  • Cell Transdifferentiation / physiology
  • Diabetes Mellitus, Experimental / genetics
  • Diabetes Mellitus, Experimental / pathology
  • Diabetes Mellitus, Experimental / physiopathology
  • Diabetes Mellitus, Experimental / therapy
  • Gene Transfer Techniques
  • Hepatocytes / cytology*
  • Hepatocytes / physiology
  • Insulin / biosynthesis
  • Insulin / genetics
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / physiology
  • Islets of Langerhans / cytology*
  • Islets of Langerhans / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Models, Biological
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / physiology*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Stem Cells / cytology*
  • Stem Cells / physiology
  • Transcription, Genetic

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Betacellulin
  • Btc protein, mouse
  • Insulin
  • Intercellular Signaling Peptides and Proteins
  • Nerve Tissue Proteins
  • Neurog3 protein, mouse
  • RNA, Messenger