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Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease

Nature Medicine volume 18, pages 572–579 (2012)Cite this article

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Abstract

During chronic injury a population of bipotent hepatic progenitor cells (HPCs) become activated to regenerate both cholangiocytes and hepatocytes. Here we show in human diseased liver and mouse models of the ductular reaction that Notch and Wnt signaling direct specification of HPCs via their interactions with activated myofibroblasts or macrophages. In particular, we found that during biliary regeneration, expression of Jagged 1 (a Notch ligand) by myofibroblasts promoted Notch signaling in HPCs and thus their biliary specification to cholangiocytes. Alternatively, during hepatocyte regeneration, macrophage engulfment of hepatocyte debris induced Wnt3a expression. This resulted in canonical Wnt signaling in nearby HPCs, thus maintaining expression of Numb (a cell fate determinant) within these cells and the promotion of their specification to hepatocytes. By these two pathways adult parenchymal regeneration during chronic liver injury is promoted.

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Figure 1: Spatial regulation of the HPC niche is dependent on adult disease pattern.
Figure 2: Modulation of the Notch pathway in vitro and in vivo affects biliary regeneration.
Figure 3: Numb represses the Notch signaling pathway and allows hepatocyte differentiation.
Figure 4: The Wnt pathway drives exit of mHPCs from a biliary fate into a hepatocyte phenotype.
Figure 5: Macrophages are a source of canonical Wnt ligand in the regenerating adult liver.
Figure 6: Ablation of Macrophages in vivo results in the respecification of mHPCs.

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  • 15 March 2012

     In the version of this article initially published online, the last sentence of the abstract incorrectly stated the study focused on a process involved in the recovery from acute liver injury when, in fact, chronic liver injury was meant. The error has been corrected for all versions of this article.

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Acknowledgements

Clodronate (Cl2MDP) was a gift of Roche Diagnostics (Mannheim, Germany). Thanks to R. Aucott (UK Medical Research Council (MRC)/University of Edinburgh Centre for Inflammation Research) for the donation of mouse hepatic fibroblasts. Krt19CreERT mice were a kind gift from G. Gu (Vanderbilt University), and the Ctnnb1ΔEx3 strain was provided by O. Sansom (The Beatson Institute for Cancer Research, Glasgow). S.J.F. is supported by the MRC, Sir Jules Thorn Trust and Wellcome Trust; L.G.B. is funded through an MRC project grant and was supported through an MRC studentship.

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Authors and Affiliations

  1. Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK

    Luke Boulter, Tom G Bird, Sang Soo Seo, Sally Lowell & Stuart J Forbes

  2. Medical Research Council Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK

    Luke Boulter, Tom G Bird, Prakash Ramachandran, Antonella Pellicoro, John P Iredale & Stuart J Forbes

  3. Department of Morphology and Molecular Pathology, The Catholic University of Leuven, Leuven, Belgium

    Olivier Govaere, Nico Van Rooijen & Tania Roskams

  4. The Beatson Institute for Cancer Research, Glasgow, UK

    Sorina Radulescu, Rachel A Ridgway & Owen J Sansom

  5. Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands

    Bart Spee

  6. Department of Molecular Cell Biology, Vrije Universiteit Medisch Centrum, Faculty of Medicine, Amsterdam, The Netherlands

    Nico Van Rooijen

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  1. Luke Boulter
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Contributions

L.B., O.G., T.G.B., P.R. and A.P. designed experiments and generated data, J.P.I., S.L., T.R. and S.J.F. designed experiments; S.S.S. generated the three-dimensional images; N.V.R. generated and supplied the clodronate liposomes; S.R., R.A.R. and B.S. generated data; L.B. and O.G. analyzed the data; L.B. prepared the manuscript; O.J.S., J.P.I., S.L., T.R. and S.J.F. edited the manuscript; J.P.I., T.R. and S.J.F. provided experimental funding.

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Correspondence to Stuart J Forbes.

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The authors declare no competing financial interests.

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Boulter, L., Govaere, O., Bird, T. et al. Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Nat Med 18, 572–579 (2012). https://doi.org/10.1038/nm.2667

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