In vivo reprogramming of pancreatic acinar cells to three islet endocrine subtypes

Elife. 2014 Jan 1;3:e01846. doi: 10.7554/eLife.01846.

Abstract

Direct lineage conversion of adult cells is a promising approach for regenerative medicine. A major challenge of lineage conversion is to generate specific cell subtypes. The pancreatic islets contain three major hormone-secreting endocrine subtypes: insulin(+) β-cells, glucagon(+) α-cells, and somatostatin(+) δ-cells. We previously reported that a combination of three transcription factors, Ngn3, Mafa, and Pdx1, directly reprograms pancreatic acinar cells to β-cells. We now show that acinar cells can be converted to δ-like and α-like cells by Ngn3 and Ngn3+Mafa respectively. Thus, three major islet endocrine subtypes can be derived by acinar reprogramming. Ngn3 promotes establishment of a generic endocrine state in acinar cells, and also promotes δ-specification in the absence of other factors. δ-specification is in turn suppressed by Mafa and Pdx1 during α- and β-cell induction. These studies identify a set of defined factors whose combinatorial actions reprogram acinar cells to distinct islet endocrine subtypes in vivo. DOI: http://dx.doi.org/10.7554/eLife.01846.001.

Keywords: acinar to endocrine conversion; direct lineage conversion; in vivo reprogramming; islet delta, alpha, beta cells; pancreatic endocrine cells.

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 Lineage
  • Cell Transdifferentiation
  • Cellular Reprogramming*
  • Gene Expression Regulation, Developmental
  • Genes, Reporter
  • Glucagon-Secreting Cells / metabolism
  • Glucagon-Secreting Cells / physiology*
  • HEK293 Cells
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / physiology*
  • Luminescent Proteins / biosynthesis
  • Luminescent Proteins / genetics
  • Maf Transcription Factors, Large / genetics
  • Maf Transcription Factors, Large / metabolism
  • Mice, Knockout
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Pancreas, Exocrine / cytology
  • Pancreas, Exocrine / metabolism
  • Pancreas, Exocrine / physiology*
  • Somatostatin-Secreting Cells / metabolism
  • Somatostatin-Secreting Cells / physiology*
  • Time Factors
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transfection

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Homeodomain Proteins
  • Luminescent Proteins
  • Maf Transcription Factors, Large
  • Nerve Tissue Proteins
  • Trans-Activators
  • pancreatic and duodenal homeobox 1 protein
  • red fluorescent protein
  • RAG-1 protein