Enhanced direct conversion of fibroblasts into hepatocyte-like cells by Kdm2b.
Cell fate conversion of terminally differentiated cells by defined transcription factors between different lineages is a new approach to produce new cells that have the capability to repair or replace diseased and damaged tissues. Previous studies have demonstrated that this inefficient process can be facilitated by the inclusion of additional factors. Here we report that Kdm2b, a histone demethylase, has the capability to promote conversion of fibroblasts to functional induced hepatocyte-like (iHep) cells in combination with previously reported hepatic lineage transcription factors, Hnf4α and Foxa3. This approach led to increased numbers of epithelial-like colonies, hepatic markers and functionality which included periodic acid-Schiff (PAS) positive colonies, CYP450 activity, low-density lipoprotein and indocyanine green (ICG) uptake, as well as Albumin secretion. Additionally, the transplanted iHep cells were engraftable, expressed Albumin, and contributed to the recovery of a carbon tetrachloride-injured mouse model. These results have not only identified an important epigenetic factor for iHep generation, but also brought new insight into the molecular nature of hepatogenesis and future biomedical applications for liver diseases.
Department of Molecular Medicine, School of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran.
Kobra
K
Zakikhan
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
Cellular and Molecular Research Center, Department of Pharmacology, School of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran.
Marjan
M
Nassiri-Asl
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; D000067470:Cellular Reprogramming Techniques / Q000379:methods; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D051543:Hepatocyte Nuclear Factor 3-gamma / Q000378:metabolism*; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism*; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D051379:Mice
D044783:F-Box Proteins; C496506:Foxa3 protein, mouse; D051557:Hepatocyte Nuclear Factor 4; C496593:Hnf4a protein, mouse; D051543:Hepatocyte Nuclear Factor 3-gamma; D056484:Jumonji Domain-Containing Histone Demethylases; C524747:Kdm2b protein, mouse
Direct conversion; Induced hepatocyte-like cells; Kdm2b; Transdifferentiation