Reversal of hepatocyte senescence after continuous in vivo cell proliferation.
A better understanding of hepatocyte senescence could be used to treat age-dependent disease processes of the liver. Whether continuously proliferating hepatocytes could avoid or reverse senescence has not yet been fully elucidated. We confirmed that the livers of aged mice accumulated senescent and polyploid hepatocytes, which is associated with accumulation of DNA damage and activation of p53-p21 and p16(ink4a)-pRB pathways. Induction of multiple rounds continuous cell division is hard to apply in any animal model. Taking advantage of serial hepatocyte transplantation assays in the fumarylacetoacetate hydrolase-deficient (Fah(-/-)) mouse, we studied the senescence of hepatocytes that had undergone continuous cell proliferation over a long time period, up to 12 rounds of serial transplantations. We demonstrated that the continuously proliferating hepatocytes avoided senescence and always maintained a youthful state. The reactivation of telomerase in hepatocytes after serial transplantation correlated with reversal of senescence. Moreover, senescent hepatocytes harvested from aged mice became rejuvenated upon serial transplantation, with full restoration of proliferative capacity. The same findings were also true for human hepatocytes. After serial transplantation, the high initial proportion of octoploid hepatocytes decreased to match the low level of youthful liver.


CONCLUSIONS
These findings suggest that the hepatocyte "ploidy conveyer" is regulated differently during aging and regeneration. The findings of reversal of hepatocyte senescence could enable future studies on liver aging and cell therapy.
Department of Cell Biology, Second Military Medical University, Shanghai, P.R. China; Center for Stem Cell and Medicine, Graduate School, Second Military Medical University, Shanghai, P.R. China.
Min-Jun
MJ
Wang
Fei
F
Chen
Jian-Xiu
JX
Li
Chang-Cheng
CC
Liu
Hai-Bin
HB
Zhang
Yong
Y
Xia
Bing
B
Yu
Pu
P
You
Dao
D
Xiang
Lian
L
Lu
Hao
H
Yao
Uyunbilig
U
Borjigin
Guang-Shun
GS
Yang
Kirk J
KJ
Wangensteen
Zhi-Ying
ZY
He
Xin
X
Wang
Yi-Ping
YP
Hu
D000818:Animals; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000502:physiology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D005434:Flow Cytometry; D022781:Hepatocytes / Q000166:cytology* / Q000502:physiology / Q000637:transplantation*; D006867:Hydrolases / Q000235:genetics; D007763:Lac Operon; D008099:Liver / Q000166:cytology / Q000502:physiology; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D011123:Polyploidy; D019098:Telomerase / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; D019098:Telomerase; D006867:Hydrolases; C020156:fumarylacetoacetase