Conversion of Mature Human β-Cells Into Glucagon-Producing α-Cells

  1. Eelco J.P. de Koning1,5,7
  1. 1Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands
  2. 2Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands
  3. 3Twente University, Enschede, the Netherlands
  4. 4Section of Islet Cell & Regenerative Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts
  5. the 5Hubrecht Institute, Utrecht, the Netherlands
  6. 6Department of Anatomy & Embryology, Leiden University Medical Center, Leiden, the Netherlands
  7. 7Department of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands
  1. Corresponding author: Eelco J.P. de Koning, e.dekoning{at}lumc.nl.

Abstract

Conversion of one terminally differentiated cell type into another (or transdifferentiation) usually requires the forced expression of key transcription factors. We examined the plasticity of human insulin-producing β-cells in a model of islet cell aggregate formation. Here, we show that primary human β-cells can undergo a conversion into glucagon-producing α-cells without introduction of any genetic modification. The process occurs within days as revealed by lentivirus-mediated β-cell lineage tracing. Converted cells are indistinguishable from native α-cells based on ultrastructural morphology and maintain their α-cell phenotype after transplantation in vivo. Transition of β-cells into α-cells occurs after β-cell degranulation and is characterized by the presence of β-cell–specific transcription factors Pdx1 and Nkx6.1 in glucagon+ cells. Finally, we show that lentivirus-mediated knockdown of Arx, a determinant of the α-cell lineage, inhibits the conversion. Our findings reveal an unknown plasticity of human adult endocrine cells that can be modulated. This endocrine cell plasticity could have implications for islet development, (patho)physiology, and regeneration.

Footnotes

  • Received July 25, 2012.
  • Accepted March 13, 2013.

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