Conversion of immortal liver progenitor cells into pancreatic endocrine progenitor cells by persistent expression of Pdx-1

J Cell Biochem. 2008 May 1;104(1):224-36. doi: 10.1002/jcb.21617.

Abstract

The conversion of expandable liver progenitor cells into pancreatic beta cells would provide a renewable cell source for diabetes cell therapy. Previously, we reported the establishment of liver epithelial progenitor cells (LEPCs). In this work, LEPCs were modified into EGFP/Pdx-1 LEPCs, cells with stable expression of both Pdx-1 and EGFP. Unlike previous work, with persistent expression of Pdx-1, EGFP/Pdx-1 LEPCs acquired the phenotype of pancreatic endocrine progenitor cells rather than giving rise to insulin-producing cells directly. EGFP/Pdx-1 LEPCs proliferated vigorously and expressed the crucial transcription factors involved in beta cell development, including Ngn3, NeuroD, Nkx2.2, Nkx6.1, Pax4, Pax6, Isl1, MafA and endogenous Pdx-1, but did not secrete insulin. When cultured in high glucose/low serum medium supplemented with cytokines, EGFP/Pdx-1 LEPCs stopped proliferating and gave rise to functional beta cells without any evidence of exocrine or other islet cell lineage differentiation. When transplanted into diabetic SCID mice, EGFP/Pdx-1 LEPCs ameliorated hyperglycemia by secreting insulin in a glucose regulated manner. Considering the limited availability of beta cells, we propose that our experiments will provide a framework for utilizing the immortal liver progenitor cells as a renewable cell source for the generation of functional pancreatic beta cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Culture Techniques
  • Cell Proliferation
  • Cell Transplantation
  • Epithelial Cells
  • Hepatocytes / cytology*
  • Homeodomain Proteins / biosynthesis*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / physiology
  • Hyperglycemia / therapy
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / cytology*
  • Insulin-Secreting Cells / transplantation
  • Mice
  • Mice, SCID
  • Stem Cells / cytology*
  • Trans-Activators / biosynthesis*
  • Trans-Activators / genetics
  • Trans-Activators / physiology
  • Transcription Factors / biosynthesis

Substances

  • Homeodomain Proteins
  • Insulin
  • Trans-Activators
  • Transcription Factors
  • pancreatic and duodenal homeobox 1 protein