Liver homeostasis is maintained by midlobular zone 2 hepatocytes
Authors: Yu-Hsuan Lin
Yuemeng Jia
Yonglong Wei
Tao Wang
Hao Zhu
Yunguan G Wang
Jung Yoon
Min Zhu
Meng-Hsiung Hsieh
Shuyuan Zhang
Jeffrey H Albrecht
Tripti Sharma
Zixi Wang
Phuong T Le
Lin Li
Clifford J Rosen
Yu Zhang
Journal: Science (2021)
Discipline: Multidisciplinary
Keywords: liver zones; hepatocytes; fate mapping; metabolic enzymes; periportal zone 1
Affiliations: Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Children's Research Institute Mouse Genome Engineering Core, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Gastroenterology Division, Minneapolis VA Health Care System, Minneapolis, MN 55417, USA., Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, Minneapolis, MN 55455, USA., Maine Medical Center Research Institute, Maine Medical Center, Scarborough, ME 04074, USA., Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. .

Abstract:  The liver is organized into zones in which hepatocytes express different metabolic enzymes. The cells most responsible for liver repopulation and regeneration remain undefined, because fate mapping has only been performed on a few hepatocyte subsets. Here, 14 murine fate-mapping strains were used to systematically compare distinct subsets of hepatocytes. During homeostasis, cells from both periportal zone 1 and pericentral zone 3 contracted in number, whereas cells from midlobular zone 2 expanded in number. Cells within zone 2, which are sheltered from common injuries, also contributed to regeneration after pericentral and periportal injuries. Repopulation from zone 2 was driven by the insulin-like growth factor binding protein 2-mechanistic target of rapamycin-cyclin D1 (IGFBP2-mTOR-CCND1) axis. Therefore, different regions of the lobule exhibit differences in their contribution to hepatocyte turnover, and zone 2 is an important source of new hepatocytes during homeostasis and regeneration. 

Retracted: No

PubPeer comments:
 Pointed out to me by a reader. Full disclosure: I do not have access to the paper, and do not know which figure this is, but the concern seems legit. Two panels, marked with red boxes, appear to overlap with each other.  , 
 Thank you for bringing this to my attention. I see that there is a mistake on our part here--these images are clearly from the same slide. While this does not affect the conclusions, it still needs to be corrected. I am investigating this further today and I will provide an update soon. , 
 We agree that the IHC image in Figure 6H has significant overlap with the Ki-67 image in Figure 6C. We accidentally took this picture from the same control mouse section as the one shown in 6C. This was likely a mistake originating from poor naming of the files, such that two control mice were confused. While this has no impact on the quantification or interpretation of the data, and does not affect the conclusions, we take complete responsibility for this error. We have contacted Science to initiate corrective steps for the image panel in Figure 6H. , 
 Thank you so much, Dr. Zhu, for checking and for correcting this error. Always much appreciated if authors do the right thing! , 
 Thanks Dr. Bik, we would have totally overlooked this had you not made us aware. We are glad you brought it to our attention so that we could deal with it promptly. We believe that this error does not reflect the care and extraordinary effort that the authors took to make this study as rigorous as possible. , 
 September 3 2021 erratum: https: www.science.org doi 10.1126 science.abl8195 Erratum text:  In the Research Article u201cLiver homeostasis is maintained by midlobular zone 2 hepatocytes,u201d the control Ki-67 immunohistochemistry image in Fig. 6H was inadvertently obtained from the control liver Ki-67 slide from Fig. 6C. The Ki-67 image in Fig. 6H has now been replaced with the Ki-67 image from the correct control liver. This replacement does not change the authorsu2019 conclusions. Additionally, fig. S2A was intended to show that for the 11 CreER strains generated, individual mice harboring the same CreER knock-in transgene exhibited consistent fluorescent reporter expression patterns. Four images were incorrectly labeled as coming from independent mice, but these were actually from the same specimens as adjacent images. These images correctly reflected the genotypes stated in the figure but were not from independent mice. Pklr-CreER images 1, 2, and 3 were from the same mouse (images 1 and 2 have now been replaced with images from independent mice), Arg1.1-CreER images 1 and 2 were from the same mouse (image 1 has now been replaced with an image from an independent mouse), and Gls2-CreER images 1 and 2 were from the same mouse (image 1 has now been replaced with an image from an independent mouse). Because expression patterns from independent mice are similar, the corrected figure does not substantially change the appearance of the images nor does it change the conclusions drawn from this figure. So in total four images have been found to be mislabeled. Can the authors confirm if all other data in the paper has been correctly labeled and presented? ,