Liver stem cell-derived beta-cell surrogates for treatment of type 1 diabetes.
Consistent with the common embryonic origin of liver and pancreas as well the similar glucose-sensing systems in hepatocytes and pancreatic beta-cells, it should not be surprising that liver stem cells/hepatocytes can transdifferentiate into insulin-producing cells under high-glucose culture conditions or by genetic reprogramming. Persistent expression of the pancreatic duodenal homeobox-1 (Pdx1) transcription factor or its super-active form Pdx1-VP16 fusion protein in hepatic cells reprograms these cells into pancreatic beta-cell precursors. In vitro culture at elevated glucose concentrations or in vivo exposure to a hyperglycemia are required for further differentiation and maturation of liver-derived pancreatic beta-cell precursor into functional insulin-producing pancreatic beta-like cells. Under appropriate conditions, multiple pancreatic transcription factors can work in concert to reprogram liver stem/adult liver cells into functional insulin-producing cells. If such autologous liver-derived insulin-producing cells can be made to escape the type 1 diabetes-associated autoimmunity, they may serve as a valuable cell source for future cell replacement therapy without the need for life-long immunosuppression.
Yang
Li-Jun
LJ
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida 32610, USA. yanglj@pathology.ufl.edu
D000818:Animals; D002454:Cell Differentiation; D003922:Diabetes Mellitus, Type 1 / Q000628:therapy*; D022781:Hepatocytes / Q000502:physiology*; D017405:Herpes Simplex Virus Protein Vmw65 / Q000502:physiology; D018398:Homeodomain Proteins / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000502:physiology*; D051379:Mice; D008954:Models, Biological; D051761:Paired Box Transcription Factors / Q000502:physiology; D013234:Stem Cells / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*
D017405:Herpes Simplex Virus Protein Vmw65; D018398:Homeodomain Proteins; C491709:PAX4 protein, human; D051761:Paired Box Transcription Factors; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein