Stage specific reprogramming of mouse embryo liver cells to a beta cell-like phenotype

Yang Y., AKINCI E., Dutton J. R., Banga A., Slack J. M. W.

MECHANISMS OF DEVELOPMENT, vol.130, no.11-12, pp.602-612, 2013 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 130 Issue: 11-12
  • Publication Date: 2013
  • Doi Number: 10.1016/j.mod.2013.08.002
  • Journal Name: MECHANISMS OF DEVELOPMENT
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.602-612
  • Keywords: Hepatoblast, Beta cell, Pdx1, Ngn3, MafA, Sox9, PANCREATIC EXOCRINE CELLS, IN-VIVO, ENDOCRINE-CELLS, BILE-DUCTS, INSULIN, TRANSDIFFERENTIATION, DIFFERENTIATION, TRANSCRIPTION, FIBROBLASTS, CONVERSION
  • Akdeniz University Affiliated: Yes

Abstract

We show that cultures of mouse embryo liver generate insulin-positive cells when transduced with an adenoviral vector encoding the three genes: Pdx1, Ngn3 and MafA (Ad-PNM). Only a proportion of transduced cells become insulin-positive and the highest yield occurs in the period E14-16, declining at later stages. Insulin-positive cells do not divide further although they can persist for several weeks. RT-PCR analysis of their gene expression shows the upregulation of a whole battery of genes characteristic of beta cells including upregulation of the endogenous counterparts of the input genes. Other features, including a relatively low insulin content, the expression of genes for other pancreatic hormones, and the fact that insulin secretion is not glucose-sensitive, indicate that the insulin-positive cells remain immature. The origin of the insulin-positive cells is established both by co-immunostaining for alpha-fetoprotein and albumin, and by lineage tracing for Sox9, which is expressed in the ductal plate cells giving rise to biliary epithelium. This shows that the majority of insulin-positive cells arise from hepatoblasts with a minority from the ductal plate cells. (C) 2013 Elsevier Ireland Ltd. All rights reserved.