Cell-in-Cell Structures in the Liver: A Tale of Four E's

Abstract

The liver is our largest internal organ and it plays major roles in drug detoxification and immunity, where the ingestion of extracellular material through phagocytosis is a critical pathway. Phagocytosis is the deliberate endocytosis of large particles, microbes, dead cells or cell debris and can lead to cell-in-cell structures. Various types of cell endocytosis have been recently described for hepatic epithelia (hepatocytes), which are non-professional phagocytes. Given that up to 80% of the liver comprises hepatocytes, the biological impact of cell-in-cell structures in the liver can have profound effects in liver regeneration, inflammation and cancer. This review brings together the latest reports on four types of endocytosis in the liver -efferocytosis, entosis, emperipolesis and enclysis, with a focus on hepatocyte biology.

Keywords: cancer; cell-in-cell; efferocytosis; emperipolesis; enclysis; entosis; liver; regeneration.

FIGURE 1

Hepatocytes are important efferocytes. Comprising up to 80% of the liver mass, hepatocytes engulf apoptotic and necrotic cells via the asialoglycoprotein receptor (ASGR1) (3), and rapidly degrade them. This process may supply the liver with nutrients while maintaining homeostasis by eliminating pro-inflammatory cell debris. CIC structures can also lead to failure of cytokinesis (19) and this can impact hepatocyte ploidy.

FIGURE 2

Entosis in neoplastic hepatocytes. We recently showed that hepatocellular carcinoma cells were able to engulf their live neighbors by entosis (13). Entosis is an important disease pathway in cancer epithelia involving E-cadherin and β-catenin (12). Tumor cells that detach from matrix are prone to entosis, and further research is necessary to measure its implications in patients with hepatocellular carcinoma.

FIGURE 3

Suicidal Emperipolesis. The seminal work by Benseler et al. provided the first evidence for a biological role of the cell-in-cell structures described as emperipolesis, where immune cells were engulfed alive by hepatocytes (11). In this study, autoreactive CD8⁺ T cells were deleted by suicidal emperipolesis in the liver. The mechanism of capture is not understood, however, perturbation of this process led to breach of liver tolerance in mice.

FIGURE 4

Enclysis in health and in hepatocellular carcinoma. Enclysis is the enclosure and lysis of regulatory T cells (Treg) by hepatocytes and hepatocyte cancer cells (13). We showed that Treg cells were captured preferentially compared to non-regulatory CD4⁺ T cells, and also suffered a different fate, as non-regulatory T cells often survived hepatocyte entry.

FIGURE 5

Cell-in-cell structures in healthy and neoplastic hepatocytes. Efferocytosis (apoptotic or necrotic cells), suicidal emperipolesis (autoreactive CD8⁺ T cells) and enclysis (CD4⁺ T cells, Treg) have been reported for non-neoplastic hepatocytes. Neoplastic hepatocytes can also perform efferocytosis and enclysis, and engulf fellow cancer cells that detached from matrix by entosis.