Key Points
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In mammalian systems, the internalization of one cell by another is most commonly associated with the phagocytic engulfment of apoptotic cells. However, alternative mechanisms of cell internalization also exist and, unlike phagocytosis, these alternative mechanisms target viable cells for internalization, forming what are referred to as cell-in-cell structures.
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Cell-in-cell structures can form between various host and target cell types. Unlike apoptotic cells that are engulfed by phagocytosis and rapidly degraded, internalized cells within cell-in-cell structures remain viable for extended periods of time and exhibit various possible fates, including release or division inside the host, and cell death.
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Although hundreds of reports document cell-in-cell phenomena occurring between diverse cell types, these structures can be generally grouped into two classes: those in which target cells internalize into hosts of different cell types (heterotypic cell-in-cell structures), which often occur between leukocyte target cells and non-leukocyte hosts, and those in which the target and host cell are of the same cell type (homotypic cell-in-cell structures), which often occur in human tumours.
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Neither the mechanisms responsible for the generation of cell-in-cell structures nor their physiological roles are well understood. Based on existing data, we propose that these structures fall into three different groups that include both heterotypic and homotypic interactions: some structures seem to form transiently owing to normal or pathological transit of one cell through another (for example, transcellular migration of leukocytes), other structures might be generated to perform a specific physiological function (for example, for thymocyte maturation within thymic nurse cells), and other structures probably form fortuitously as a result of the admixture of adhesion-compatible cell types (for example, in human tumours).
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Although these classifications begin to clarify the nature of these unusual cell structures, much remains to be understood regarding their physiological functions, including their more precise roles in haematopoietic cell maturation, or the consequences of cell-in-cell formation in human tumours, which exhibit both heterotypic and homotypic types of structures. That internalized cells and hosts exhibit various fates probably underscores the complex roles that these processes have in normal physiology and pathophysiology.
Abstract
For decades, authors have described unusual cell structures, referred to as cell-in-cell structures, in which whole cells are found in the cytoplasm of other cells. One well-characterized process that results in the transient appearance of such structures is the engulfment of apoptotic cells by phagocytosis. However, many other types of cell-in-cell structure have been described that involve viable non-apoptotic cells. Some of these structures seem to form by the invasion of one cell into another, rather than by engulfment. The mechanisms of cell-in-cell formation and the possible physiological roles of these processes will be discussed.
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We apologize to those authors whose work was not referenced here. We thank E. S. Cibas for critical reading of the manuscript.
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Glossary
- Extravasate
-
The action of a cell (for example, a leukocyte or tumour cell) passing out of a vessel through an endothelial cell layer to enter into a tissue.
- Demarcation membrane system
-
A large membrane network in the cytoplasm of megakaryocytes that is formed by tubular invagination of the plasma membrane and is proposed to be the source of proplatelet membranes.
- α-granules
-
Secretory granules that are found in megakaryocytes and platelets and contain growth factors, clotting factors and the adhesion molecule P-selectin.
- Thymic cortex
-
The outer region of the thymus that contains large numbers of immature thymocytes, in which early events in T-cell development occur, including positive and negative selection.
- Uropod
-
A tail structure that is characteristic of certain types of polarized migrating cells, such as lymphocytes.
- FERM domain
-
A conserved binding domain that is shared by many proteins (for example, Band4.1, ezrin, radixin, moesin and FAK), which function as linkers between transmembrane proteins and the cytoskeleton. The FERM domain binds to transmembrane proteins and other signalling proteins.
- Caveolae
-
Small invaginations of the plasma membrane (50–100 nm), marked by caveolin-1 protein, that are rich in cholesterol and have a role in signal transduction and endocytosis. Certain cell types, such as endothelial cells, can also contain tubular-vesicular channels of caveolae.
- Ascites
-
Fluid accumulation in the peritoneal cavity, which lines the abdomen.
- Pleural fluid
-
Fluid in the pleural cavity, which surrounds the lungs.
- Autophagy
-
The digestive process by which cells degrade their own components, including damaged organelles.
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Overholtzer, M., Brugge, J. The cell biology of cell-in-cell structures. Nat Rev Mol Cell Biol 9, 796–809 (2008). https://doi.org/10.1038/nrm2504
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DOI: https://doi.org/10.1038/nrm2504
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