PDGF Facilitates Direct Lineage Reprogramming of Hepatocytes to Functional β-Like Cells Induced by Pdx1 and Ngn3

Cell Transplant. 2016 Oct;25(10):1893-1909. doi: 10.3727/096368916X691439.

Abstract

Islet transplantation has been proven to be an effective treatment for patients with type 1 diabetes, but a lack of islet donors limits the use of transplantation therapies. It has been previously demonstrated that hepatocytes can be converted into insulin-producing β-like cells by introducing pancreatic transcription factors, indicating that direct hepatocyte reprogramming holds potential as a treatment for diabetes. However, the efficiency at which functional β-cells can be derived from hepatocyte reprogramming remains low. Here we demonstrated that the combination of Pdx1 and Ngn3 can trigger reprogramming of mouse and human liver cells to insulin-producing cells that exhibit the characteristics of pancreatic β-cells. Treatment with PDGF-AA was found to facilitate Pdx1 and Ngn3-induced reprogramming of hepatocytes to β-like cells with the ability to secrete insulin in response to glucose stimulus. Importantly, this reprogramming strategy could be applied to adult mouse primary hepatocytes, and the transplantation of β-like cells derived from primary hepatocyte reprogramming could ameliorate hyperglycemia in diabetic mice. These findings support the possibility of developing transplantation therapies for type 1 diabetes through the use of β-like cells derived from autologous hepatocyte reprogramming.

Keywords: Glucagon-like peptide-1 (GLP-1); Hepatocyte transdifferentiation; Lineage reprogramming; Platelet-derived growth factor (PDGF); Type 1 diabetes mellitus; β-Cells.

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Blood Glucose / analysis
  • Cell Transdifferentiation / drug effects
  • Cells, Cultured
  • Cellular Reprogramming / drug effects*
  • Diabetes Mellitus, Experimental / chemically induced
  • Diabetes Mellitus, Experimental / pathology
  • Diabetes Mellitus, Experimental / therapy
  • Exenatide
  • Genetic Vectors / genetics
  • Genetic Vectors / metabolism
  • Glucagon-Like Peptide 1 / pharmacology
  • Glucagon-Like Peptide-1 Receptor / genetics
  • Glucagon-Like Peptide-1 Receptor / metabolism
  • Glucose / pharmacology
  • Hepatocytes / cytology
  • Hepatocytes / metabolism
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Humans
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / transplantation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Mice, Transgenic
  • Microscopy, Fluorescence
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Peptides / pharmacology
  • Platelet-Derived Growth Factor / pharmacology*
  • Receptor, Platelet-Derived Growth Factor alpha / genetics
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Venoms / pharmacology

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Blood Glucose
  • Glucagon-Like Peptide-1 Receptor
  • Homeodomain Proteins
  • Insulin
  • Nerve Tissue Proteins
  • Neurog3 protein, mouse
  • Peptides
  • Platelet-Derived Growth Factor
  • Trans-Activators
  • Venoms
  • pancreatic and duodenal homeobox 1 protein
  • platelet-derived growth factor A
  • Glucagon-Like Peptide 1
  • Exenatide
  • Receptor, Platelet-Derived Growth Factor alpha
  • Glucose