title: Conversion of Terminally Committed Hepatocytes to Culturable Bipotent Progenitor Cells with Regenerative Capacity.
abstract: A challenge for advancing approaches to liver regeneration is loss of functional differentiation capacity when hepatocyte progenitors are maintained in culture. Recent lineage-tracing studies have shown that mature hepatocytes (MHs) convert to an immature state during chronic liver injury, and we investigated whether this conversion could be recapitulated in vitro and whether such converted cells could represent a source of expandable hepatocytes. We report that a cocktail of small molecules, Y-27632, A-83-01, and CHIR99021, can convert rat and mouse MHs in vitro into proliferative bipotent cells, which we term chemically induced liver progenitors (CLiPs). CLiPs can differentiate into both MHs and biliary epithelial cells that can form functional ductal structures. CLiPs in long-term culture did not lose their proliferative capacity or their hepatic differentiation ability, and rat CLiPs were shown to extensively repopulate chronically injured liver tissue. Thus, our study advances the goals of liver regenerative medicine.
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Katsuda
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Masaki
authors.initials: M
authors.lastname: Kawamata
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Keitaro
authors.initials: K
authors.lastname: Hagiwara
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Ryou-U
authors.initials: RU
authors.lastname: Takahashi
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Fernando D
authors.initials: FD
authors.lastname: Camargo
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. Electronic address: tochiya@ncc.go.jp.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ochiya
mesh_terms: D000577:Amides / Q000494:pharmacology; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000187:drug effects; D002678:Chimera / Q000378:metabolism; D004171:Diploidy; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000293:injuries / Q000473:pathology; D008115:Liver Regeneration / Q000187:drug effects; D051379:Mice; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D012038:Regeneration / Q000187:drug effects; D015203:Reproducibility of Results; D054852:Small Molecule Libraries / Q000494:pharmacology; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D013882:Thiosemicarbazones / Q000494:pharmacology; D013997:Time Factors
chemical_list: C507011:A-83-01; D000577:Amides; C473711:Chir 99021; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D054852:Small Molecule Libraries; D013882:Thiosemicarbazones; C108830:Y 27632
keywords: bipotentiality; in vitro reprogramming; liver progenitor cell; liver repopulation; small molecule