期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 292, 期 21, 页码 8594-8604出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M117.782029
关键词
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资金
- National Science Foundation of China [91639302, 31625019, 91339104, 31271552, 31222038, 31571503, 31501172, 31601168, 81300340]
- Ministry of Science and Technology [2013CB945302, 2016YFC1300600]
- Strategic Priority Research Program of the Chinese Academy of Sciences (CAS) [XDB19000000]
- Youth Innovation Promotion Association of CAS [2015218]
- Key Project of Frontier Sciences of CAS [QYZDB-SSW-SMC003]
- International Cooperation Fund of CAS, Shanghai Zhangjiang Stem Cell Research Project [ZJ2014-ZD002]
- Shanghai Science and Technology Commission [14JC1407400, 16DZ2280800]
- Shanghai Yangfan Project [15YF1414000]
- Rising Star Program [15QA1404300]
- China Postdoctoral Science Foundation [2015M581669, 2016T90387, 2016LH0042]
- President Fund of Shanghai Institutes for Biological Sciences (SIBS)
- AstraZeneca and SanofiSIBS Fellowship
The liver possesses a remarkable capacity to regenerate after damage. There is a heated debate on the origin of new hepatocytes after injuries in adult liver. Hepatic stem/progenitor cells have been proposed to produce functional hepatocytes after injury. Recent studies have argued against this model and suggested that pre-existing hepatocytes, rather than stem cells, contribute new hepatocytes. This hepatocyte-to-hepatocyte model is mainly based on labeling of hepatocytes with Cre-recombinase delivered by the adeno-associated virus. However, the impact of virus infection on cell fate determination, consistency of infection efficiency, and duration of Cre-virus in hepatocytes remain confounding factors that interfere with the data interpretation. Here, we generated a new genetic tool Alb-DreER to label almost all hepatocytes (>99.5%) and track their contribution to different cell lineages in the liver. By pulse-and-chase strategy, we found that pre-existing hepatocytes labeled by Alb-DreER contribute to almost all hepatocytes during normal homeostasis and after liver injury. Virtually all hepatocytes in the injured liver are descendants of pre-existing hepatocytes through self-expansion. We concluded that stem cell differentiation is unlikely to be responsible for the generation of a substantial number of new hepatocytes in adult liver. Our study also provides a new mouse tool for more precise in vivo genetic study of hepatocytes in the field.
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