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

L. Boulter; O. Govaere; T.G. Bird; S. Radulescu; P. Ramachandran; A. Pellicoro; R. Ridgway; S.S. Seo; B. Spee; N. van Rooijen; O.J. Sansom; J.P. Iredale; S. Lowell; T.A. Roskams; S.J. Forbes

doi:10.1038/nm.2667

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

L. Boulter
, O. Govaere
, T.G. Bird
, S. Radulescu
, P. Ramachandran
, A. Pellicoro
, R. Ridgway
, S.S. Seo
, B. Spee
, N. van Rooijen
, O.J. Sansom
, J.P. Iredale
, S. Lowell
, T.A. Roskams
, S.J. Forbes

extern

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Nat Med. 2012 Mar 4;18(4):572-9. doi: 10.1038/nm.2667. Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Boulter L, Govaere O, Bird TG, Radulescu S, Ramachandran P, Pellicoro A, Ridgway RA, Seo SS, Spee B, Van Rooijen N, Sansom OJ, Iredale JP, Lowell S, Roskams T, Forbes SJ. Source Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK. 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. Comment in Neighborhood watch orchestrates liver regeneration. [Nat Med. 2012]

Original language	Undefined/Unknown
Pages (from-to)	572-579
Number of pages	8
Journal	Nature Medicine
Volume	18
Issue number	4
DOIs	https://doi.org/10.1038/nm.2667
Publication status	Published - 2012

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SDG 3 Good Health and Well-being

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Macrophage-derived Wnt
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Cite this

Boulter, L., Govaere, O., Bird, T. G., Radulescu, S., Ramachandran, P., Pellicoro, A., Ridgway, R., Seo, S. S., Spee, B., van Rooijen, N., Sansom, O. J., Iredale, J. P., Lowell, S., Roskams, T. A., & Forbes, S. J. (2012). Macrophage-derived Wnt opposes notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Nature Medicine, 18(4), 572-579. https://doi.org/10.1038/nm.2667

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title = "Macrophage-derived Wnt opposes notch signaling to specify hepatic progenitor cell fate in chronic liver disease",

abstract = "Nat Med. 2012 Mar 4;18(4):572-9. doi: 10.1038/nm.2667. Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Boulter L, Govaere O, Bird TG, Radulescu S, Ramachandran P, Pellicoro A, Ridgway RA, Seo SS, Spee B, Van Rooijen N, Sansom OJ, Iredale JP, Lowell S, Roskams T, Forbes SJ. Source Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK. 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. Comment in Neighborhood watch orchestrates liver regeneration. [Nat Med. 2012]",

author = "L. Boulter and O. Govaere and T.G. Bird and S. Radulescu and P. Ramachandran and A. Pellicoro and R. Ridgway and S.S. Seo and B. Spee and \{van Rooijen\}, N. and O.J. Sansom and J.P. Iredale and S. Lowell and T.A. Roskams and S.J. Forbes",

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Boulter, L, Govaere, O, Bird, TG, Radulescu, S, Ramachandran, P, Pellicoro, A, Ridgway, R, Seo, SS, Spee, B, van Rooijen, N, Sansom, OJ, Iredale, JP, Lowell, S, Roskams, TA & Forbes, SJ 2012, 'Macrophage-derived Wnt opposes notch signaling to specify hepatic progenitor cell fate in chronic liver disease', Nature Medicine, vol. 18, no. 4, pp. 572-579. https://doi.org/10.1038/nm.2667

TY - JOUR

T1 - Macrophage-derived Wnt opposes notch signaling to specify hepatic progenitor cell fate in chronic liver disease

AU - Boulter, L.

AU - Govaere, O.

AU - Bird, T.G.

AU - Radulescu, S.

AU - Ramachandran, P.

AU - Pellicoro, A.

AU - Ridgway, R.

AU - Seo, S.S.

AU - Spee, B.

AU - van Rooijen, N.

AU - Sansom, O.J.

AU - Iredale, J.P.

AU - Lowell, S.

AU - Roskams, T.A.

AU - Forbes, S.J.

PY - 2012

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N2 - Nat Med. 2012 Mar 4;18(4):572-9. doi: 10.1038/nm.2667. Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Boulter L, Govaere O, Bird TG, Radulescu S, Ramachandran P, Pellicoro A, Ridgway RA, Seo SS, Spee B, Van Rooijen N, Sansom OJ, Iredale JP, Lowell S, Roskams T, Forbes SJ. Source Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK. 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. Comment in Neighborhood watch orchestrates liver regeneration. [Nat Med. 2012]

AB - Nat Med. 2012 Mar 4;18(4):572-9. doi: 10.1038/nm.2667. Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Boulter L, Govaere O, Bird TG, Radulescu S, Ramachandran P, Pellicoro A, Ridgway RA, Seo SS, Spee B, Van Rooijen N, Sansom OJ, Iredale JP, Lowell S, Roskams T, Forbes SJ. Source Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK. 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. Comment in Neighborhood watch orchestrates liver regeneration. [Nat Med. 2012]

U2 - 10.1038/nm.2667

DO - 10.1038/nm.2667

M3 - Article

SN - 1078-8956

VL - 18

SP - 572

EP - 579

JO - Nature Medicine

JF - Nature Medicine

IS - 4

ER -