Group leader: 

Stuart J Forbes

Position: 

Professor of Transplantation and Regenerative Medicine; Associate Director; Theme leader Liver Stem Cell Biology and Tissue Repair; Consultant Hepatologist Scottish Liver Transplant Unit

Contact: 

Stuart [dot] forbes [at] ed [dot] ac [dot] uk

Aims

• To understand the role of stem cells in liver regeneration, fibrosis and cancer.
• To use this knowledge to develop novel treatments for liver disease.

Background

Liver disease is the 5th commonest cause of death in the UK and the deaths from cirrhosis are rapidly rising. Currently the only curative option for end-stage liver disease is liver transplantation. Donor organ availability cannot even meet current demand and many patients die whilst waiting for a suitable organ. Alternative therapeutic strategies are urgently required for the treatment of advanced liver disease.

The normal liver regenerates through division of mature hepatocytes. However, in chronic liver injury this capacity is lost. Fortunately we have a second tier of cells that can regenerate the liver- the Hepatic Progenitor Cells (HPCs or oval cells). These bipotential progenitor cells can give rise to both hepatocytes and biliary epithelium but may also be a potential source of liver cancer.

Image shows liver progenitor cells (red) in their niche (green). Image credit Dr Luke Boulter.

Approaches and progress

Our program of research concentrates on understanding how the Hepatic Progenitor Cells regenerate the liver in chronic disease and how this process becomes deranged in the development of liver cancer. By understanding what controls this process we aim to be able to promote healthy liver regeneration and reduce the formation of liver cirrhosis and cancer.

We are also developing pre-clinical and clinical tools to stimulate liver regeneration and reduce scarring using cell therapy. In particular we have found that bone marrow derived macrophages can promote liver regneration and reduce scarring and this is being developed as a clinical therapy (funded by the Medical Research Council). We have a clinical research program of “stem cell therapy for cirrhosis” funded by the Jules Thorn Trust and Scottish Enterprise.


Image above shows liver cells (red with nuclei in blue) in the early damaged liver with liver stem cells in green migrating to the damaged areas. In the healthy liver, the liver stem cells are only found surrounding the bile ducts close to the blood vessels (black area, on right with some red blood cells in orange). Image credit Dr Luke Boulter.

Collaborations
Collaborators within the Centre include John Iredale (Liver injury and the mechanisms of fibrosis regression), Marc Turner (clinical stem cell therapy protocols) and Sally Lowell (Notch Signalling in the liver). Outwith the Centre collaborations include Owen Sansom (The Beatson Insitute Glagsgow, transgenic models of adult stem cell biology) and Tania Roskams (Leuven, progenitor cells and gene expression in human liver disease).

Selected publications

• Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease. 2012. Boulter L, Govaere O, Bird TG, Radulescu S, Ramachandran P, Antonella Pellicoro A, Ridgway RA, Seo SS, Spee B, Van Rooijen N, Sansom OJ, Iredale JP, Lowell S, Roskams T & J Forbes SJ. Nature Medicine, published online 04 March 2012. doi:10.1038/nm.2667. Press release.
• Ly6Chi monocytes direct alternatively activated pro-fibrotic macrophage regulation of lung fibrosis. MA. Gibbons, AC MacKinnon, P Ramachandran, K Dhaliwal, R Duffin, AT. Phythian-Adams, N van Rooijen, C Haslett, SE. Howie, AJ Simpson, N Hirani, J Gauldie, JP Iredale, T Sethi and SJ Forbes. Am J Respir Crit Care Med. 2011 Jun 16. [Epub ahead of print]
  
• Macrophage therapy for murine liver fibrosis recruits host effector cells improving fibrosis, regeneration and function. Thomas JA, Pope C, Wojtacha D, Robson AJ, Gordon-Walker TT, Hartland S, Ramachandran P, Van Deemter M, Hume DA, Iredale JP, Forbes SJ. Hepatology. 2011 Mar 23. doi: 10.1002/hep.24315. [Epub ahead of print]
  
• Kallis YN, Forbes SJ. 2009. The bone marrow and liver fibrosis: friend or foe? Gastroenterology 137(4):1218-1221.
• Russo FP, Alison MR, Bigger BW, Amofah E, Florou A, Amin F, Bou-Gharios G, Jeffery R, Iredale JP, Forbes SJ. 2006. The bone marrow functionally contributes to liver fibrosis. Gastroenterology 130(6):1807-1821.
• Vig P, Russo FP, Edwards RJ, Tadrous PJ, Wright NA, Thomas HC, Alison MR, Forbes SJ. 2006. The sources of parenchymal regeneration following chronic hepatocellular liver injury in mice. Hepatology 43(2):316-324.
• Duffield JS, Forbes SJ, Costandinou CM, Clay S, Partolina M, Vuthoori S, Shengji Wu S, Lang R and Iredale JP. 2005. Rapid communication: Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. Journal of Clinical Investigation 115(1):56-65.
• Forbes SJ, Russo F, Rey V, Burra P, Rugge M, Wright NA and Alison MR. 2004. Rapid communication: a significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis. Gastroenterology 126(4):955-963.

Funding

• Jules Thorn Trust
• Wellcome Trust
• Medical Research Council
• Cancer Research UK
• Scottish Enterprise

Prof Forbes is also a member of the University of Edinburgh's MRC Centre for Inflammation Research and the NHS Scottish Liver Transplant Unit.