Forced expression of Hnf1b/Foxa3 promotes hepatic fate of embryonic stem cells.
Embryonic stem (ES) cell-derived hepatocytes have the potential to be used for basic research, regenerative medicine, and drug discovery. Recent reports demonstrated that in addition to conventional differentiation inducers such as chemical compounds and cytokines, overexpression of lineage-specific transcription factors could induce ES cells to differentiate to a hepatic fate. Here, we hypothesized that lentivirus-mediated inducible expression of hepatic lineage transcription factors could enhance mouse ES cells to hepatocyte-like cells. We screened the effects of candidate transcription factors Hnf1b, Hnf1a, Hnf4a, Foxa1, Foxa3 and Hex, and determined that the combination of Hnf1b/Foxa3 promoted expression of several hepatic lineage-specific markers and proteins, in addition to glycogen storage, ICG uptake, and secretion of albumin and urea. The differentiated cells were engraftable and expressed albumin when transplanted into a carbon tetrachloride-injured mouse model. These results demonstrated the crucial role of Hnf1b and Foxa3 in hepatogenesis in vitro and provided a valuable tool for the efficient differentiation of HLCs from ES cells.
Cellular and Molecular Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran.
Neda
N
Yahoo
Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
Behshad
B
Pournasr
Department of Biological Sciences and Biotechnology, School of Science, University of Kurdistan, Sanandaj, Iran.
Jalal
J
Rostamzadeh
Cellular and Molecular Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran.
Mohammad Saeed
MS
Hakhamaneshi
Dentofacial Deformities Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Asghar
A
Ebadifar
Cellular and Molecular Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran. Electronic address: farfath@gmail.com.
Fardin
F
Fathi
Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran; Department of Developmental Biology, University of Science and Culture, ACECR, Tehran, Iran. Electronic address: Baharvand@RoyanInstitute.org.
Hossein
H
Baharvand
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D051539:Hepatocyte Nuclear Factor 1-beta / Q000378:metabolism*; D051543:Hepatocyte Nuclear Factor 3-gamma / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology* / Q000502:physiology*; D051379:Mice
C496506:Foxa3 protein, mouse; C496496:Hnf1b protein, mouse; D051543:Hepatocyte Nuclear Factor 3-gamma; D051539:Hepatocyte Nuclear Factor 1-beta
Embryonic stem cells; Forced expression; Hepatic transcription factors; Hepatic-lineage induction