Liver regeneration by hepatic progenitor cells
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Bird2011.doc (155.8Mb)
Date
05/07/2011Author
Bird, Thomas Graham
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Abstract
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.