Iredale, John

Bird, Thomas Graham

2011-11-14T14:54:08Z

2011-11-14T14:54:08Z

2011-07-05

The liver is the largest solid organ in the body and is frequently the site of injury. During disease, liver injury is usually compensated for by exceptionally efficient regeneration which occurs both from differentiated epithelia and also from an undifferentiated cell population with stem cell like qualities known as hepatic progenitor cells (HPCs). HPCs are particularly active during massive or chronic liver injury and therefore are an attractive target for much needed novel therapies to enhance regeneration in patients for whom the only current effective therapy is liver transplantation. Stem cells in other organs systems are believed to reside in a specialised microenvironment or niche which supports their maintenance and function. To investigate the hypothesis that HPCs are supported by a functional niche and are capable of regenerating hepatocytes, we commenced by establishing a number of murine in vivo models. Having shown a stereotypical niche, consisting of macrophages, myofibroblasts and laminin exists in both animal models and human disease, we investigated the active recruitment of extrahepatic cells into this niche and showed that macrophages are actively recruited from the bone marrow during liver injury. Macrophages were shown to influence HPC behaviour during injury. Furthermore using macrophages as a cellular therapy, induced HPC activation with corresponding changes to liver structure and function. Investigation of signalling pathways revealed and confirmed a TWEAK dependent activation of HPCs following macrophage transfer. Having demonstrated the potential for macrophage therapy via HPC activation, we aimed to study the ability of HPCs to regenerate the hepatic parenchyma. To do so we developed and characterised a novel model of hepatocellular injury and HPC activation. Using the genetic labeling of hepatocytes in this model we were able to show rapid and large scale repopulation of hepatocytes from a precursor source with HPCs being the critical precursor source of hepatocellular regeneration. In addition this process is again dependent on TWEAK signalling, without which HPC mediated regeneration fails resulting in mortality. Therefore HPCs are an attractive biological target for regenerative medicine, and both TWEAK signalling and autologous macrophage infusion offer genuine potential to manipulate these cells as future therapies.

http://hdl.handle.net/1842/5634

en

The University of Edinburgh

Bird, T.G., Lorenzini, S., and Forbes, S.J. (2008). Activation of stem cells in hepatic diseases. Cell Tissue Res 331, 283-300.

Lorenzini, S., Bird, T.G., Boulter, L., Bellamy, C., Samuel, K., Aucott, R., Clayton, E., Andreone, P., Bernardi, M., Golding, M., et al. (2010). Characterization of a stereotypical cellular and extracellular adult liver progenitor cell niche in rodents and diseased human liver. Gut 59, 645-54.

liver regeneration

stem cell

TWEAK

notch

Wnt

bone marrow

Liver regeneration by hepatic progenitor cells

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy