Ghrelin expression in the mouse pancreas defines a unique multipotent progenitor population

PLoS One. 2012;7(12):e52026. doi: 10.1371/journal.pone.0052026. Epub 2012 Dec 12.

Abstract

Pancreatic islet cells provide the major source of counteractive endocrine hormones required for maintaining glucose homeostasis; severe health problems result when these cell types are insufficiently active or reduced in number. Therefore, the process of islet endocrine cell lineage allocation is critical to ensure there is a correct balance of islet cell types. There are four endocrine cell types within the adult islet, including the glucagon-producing alpha cells, insulin-producing beta cells, somatostatin-producing delta cells and pancreatic polypeptide-producing PP cells. A fifth islet cell type, the ghrelin-producing epsilon cells, is primarily found during gestational development. Although hormone expression is generally assumed to mark the final entry to a determined cell state, we demonstrate in this study that ghrelin-expressing epsilon cells within the mouse pancreas do not represent a terminally differentiated endocrine population. Ghrelin cells give rise to significant numbers of alpha and PP cells and rare beta cells in the adult islet. Furthermore, pancreatic ghrelin-producing cells are maintained in pancreata lacking the essential endocrine lineage regulator Neurogenin3, and retain the ability to contribute to cells within the pancreatic ductal and exocrine lineages. These results demonstrate that the islet ghrelin-expressing epsilon cells represent a multi-potent progenitor cell population that delineates a major subgrouping of the islet endocrine cell populations. These studies also provide evidence that many of hormone-producing cells within the adult islet represent heterogeneous populations based on their ontogeny, which could have broader implications on the regulation of islet cell ratios and their ability to effectively respond to fluctuations in the metabolic environment during development.

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 / metabolism
  • Cell Differentiation / physiology
  • Ghrelin / biosynthesis*
  • Ghrelin / genetics
  • Homeobox Protein Nkx-2.2
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Islets of Langerhans / cytology*
  • Islets of Langerhans / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Multipotent Stem Cells / cytology*
  • Multipotent Stem Cells / metabolism*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Zebrafish Proteins

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Ghrelin
  • Homeobox Protein Nkx-2.2
  • Homeodomain Proteins
  • Nerve Tissue Proteins
  • Neurog3 protein, mouse
  • Transcription Factors
  • Zebrafish Proteins