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The role of Arid1a and Tet1 in ductal cell-driven liver regeneration



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Mckie, Mikel Alexander  ORCID logo


Title: The role of Arid1a and Tet1 in ductal cell-driven regeneration Author: Mikel Alexander Mckie

The liver has several robust and potent mechanisms of repair after damage despite slow homeostatic turnover. In cases of extreme toxic damage, where the hepatocyte compartment is severely compromised and unable to proliferate, a bi-potent ductal population arises that is able to expand and differentiate into both hepatocytes and ductal cells. The regulation of the activation of this ductal progenitor population is poorly understood. We have taken advantage of 3D organoid cultures that model the activation of bi-potent ductal progenitors to identify potential candidates involved in organoid establishment and maintenance. Using knock down experiments, we identified the epigenetic modifiers Arid1a and Tet1 as important candidates for ductal progenitor maintenance and establishment, respectively, in vitro. Further in vitro analysis of several genetic models of Arid1a showed that reduction but not ablation of Arid1a results in enhanced proliferation and survival of organoid culture. In addition, Arid1a defective organoids lacked the ability to differentiate into functional hepatocytes in vitro. Therefore, Arid1a is important for regulating the differentiation and proliferative nature of ductal progenitors in vitro. On the other hand, we found that reduction or loss of Tet1 resulted in abolished establishment and maintenance of organoid culture, suggesting an important role of Tet1 in the activation of the progenitor state from a mature ductal cell. In line with this, we found that a hypomorphic mouse model of Tet1 showed a significantly reduced ductal regenerative response when challenged with acute liver damage. Furthermore, chronically damaged hypomorphic mice maintained significant fibrosis over WT mice. Finally, ductal specific genetic ablation of Tet1 coupled with lineage tracing showed that Tet1 mutant ductal cells formed significantly smaller regenerative hepatocyte clusters. As a result, Tet1 is crucial for the activation and function of ductal bi-potent progenitors both in vivo and in vitro. Taken together, the role of Arid1a and Tet1 in organoid culture and liver regeneration suggests that regulation of the epigenetic landscape is crucial to determine cell fate decisions during the damage-regeneration response.





Huch, Meritxell


Liver Regeneration, Organoids, Epigenetics


Doctor of Philosophy (PhD)

Awarding Institution

University of Cambridge
MRC doctoral training grant (grant no. MR/K50127X/1)