Article | Published:

Self-renewing diploid Axin2+ cells fuel homeostatic renewal of the liver

Nature volume 524, pages 180185 (13 August 2015) | Download Citation

Abstract

The source of new hepatocytes in the uninjured liver has remained an open question. By lineage tracing using the Wnt-responsive gene Axin2 in mice, we identify a population of proliferating and self-renewing cells adjacent to the central vein in the liver lobule. These pericentral cells express the early liver progenitor marker Tbx3, are diploid, and thereby differ from mature hepatocytes, which are mostly polyploid. The descendants of pericentral cells differentiate into Tbx3-negative, polyploid hepatocytes, and can replace all hepatocytes along the liver lobule during homeostatic renewal. Adjacent central vein endothelial cells provide Wnt signals that maintain the pericentral cells, thereby constituting the niche. Thus, we identify a cell population in the liver that subserves homeostatic hepatocyte renewal, characterize its anatomical niche, and identify molecular signals that regulate its activity.

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Gene Expression Omnibus

Data deposits

The data discussed in this publication have been deposited in NCBI’s Gene Expression Omnibus and are accessible through GEO Series accession number GSE68806.

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Acknowledgements

These studies were supported by the Howard Hughes Medical Institute and a grant from the Reed-Stinehart foundation. R.N. is an investigator with the Howard Hughes Medical Institute. B.W. was supported by F32DK091005. We thank D. M. Bissell and T. Desai for comments on the manuscript, V. Waehle for assistance in preparing RNA samples for RNA-seq, M. Britton for RNA-seq analysis, and P. Lovelace for assistance with FACS.

Author information

Affiliations

  1. Department of Developmental Biology, Howard Hughes Medical Institute, Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305, USA

    • Bruce Wang
    • , Ludan Zhao
    • , Matt Fish
    • , Catriona Y. Logan
    •  & Roel Nusse
  2. Department of Medicine and Liver Center, University of California San Francisco, San Francisco, California 94143, USA

    • Bruce Wang

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Contributions

B.W. carried out the experiments. D.Z. performed qRT–PCR analysis. M.F. performed in situ hybridization. C.Y.L. performed RNA-seq analysis. B.W. and R.N. designed the study, analysed data and wrote the paper. All authors discussed the results and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Bruce Wang or Roel Nusse.

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https://doi.org/10.1038/nature14863

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