TY - JOUR
T1 - Conversion of Terminally Committed Hepatocytes to Culturable Bipotent Progenitor Cells with Regenerative Capacity
AU - Katsuda, Takeshi
AU - Kawamata, Masaki
AU - Hagiwara, Keitaro
AU - Takahashi, Ryou u.
AU - Yamamoto, Yusuke
AU - Camargo, Fernando D.
AU - Ochiya, Takahiro
N1 - Funding Information:
We thank Hirokazu Ohata for assistance with FACS experiments; Ayako Inoue, Takumi Sonoda, and Yumi Kawamura for their technical assistance; Luc Gailhouste and Juntaro Matsuzaki for critically reading our manuscript; and Yuko Fujiwara (National Cancer Center Research Institute) for assistance with the microarray experiments. We thank Chise Tateno and her colleagues (PhoenixBio Co., Ltd) for assistance with the transplantation experiments and their valuable advices. We thank Hideki Nishikawa (Keyence Corporation) for assistance with the microscopic analyses. We thank DS Pharma Biomedical Co., Ltd, for their technical assistance. This research was supported by the Research Program on Hepatitis (16fk0310505h0005) from Japan Agency for Medical Research and Development (AMED).
Publisher Copyright:
© 2017 Elsevier Inc.
PY - 2017/1/5
Y1 - 2017/1/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85006263481&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85006263481&partnerID=8YFLogxK
U2 - 10.1016/j.stem.2016.10.007
DO - 10.1016/j.stem.2016.10.007
M3 - Article
C2 - 27840021
AN - SCOPUS:85006263481
SN - 1934-5909
VL - 20
SP - 41
EP - 55
JO - Cell stem cell
JF - Cell stem cell
IS - 1
ER -