Cell-in-cell structures in the human liver

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Davies, Scott Philip (2018). Cell-in-cell structures in the human liver. University of Birmingham. Ph.D.

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Abstract

Hepatocytes can capture dead cells. This phenomenon is called efferocytosis. Furthermore, our lab previously observed live CD4+ T cells captured by hepatocytes. This was reminiscent of entosis. This project aimed to further the understanding of the mechanisms and consequences of these processes. In vitro experimentation showed that efferocytosis could be modulated through cytokine treatment and using macropinocytosis inhibitors. Captured cells were also shown to associate with the uncharacterised receptor, SCARF2. Furthermore, efferocytosis was shown to cause multinucleation in hepatocytes. This was demonstrated in vitro, in vivo using mouse models of acute injury, and ex vivo with cauterised donor human tissue. Increased multinucleation was also associated with hepatocellular carcinoma and vascular invasion. Live CD4+ T cell capture occurred at a lower frequency than efferocytosis and required alternative membrane rearrangements. This process also did not share defining characteristics of entosis, such as E-cadherin association or susceptibility to Rho-kinase inhibitors. Furthermore, anti-inflammatory T-regulatory cells were more likely to enter acidic compartments within their captors in vitro. This project has unearthed novel aspects regarding the regulation and molecular processes of hepatocyte cell-in-cell structure formation. Further understanding into the mechanisms of these processes may provide future targets for therapeutic intervention of inflammatory disease and cancer.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):