Cell-in-cell phenomenon: A New Paradigm in Life Sciences

Abstract

Cell-in-cell, a phenomenon characterized by one or more viable cells entering actively into another cell, was observed more than a century and has only attracted more attention in recent years and is becoming a new hot topic in the biological field, owing its biological significance in evolutionary as well as physiological and pathological relevance in development, homeostasis and diseases. In this paper we focus on the diversity, evolutionary conservatism and clinical implication of cell-in-cell as well as latest opinions on the research strategies. Based on the findings from our laboratory and other research groups three working models of cell-in-cell are also proposed.

Fig. (1)

A cell-in-cell selection model. Diagram depicts effector cell (red cell) penetrates into the cytoplasm of host cell (green cell) to form cell-in-cell structure. After cell-in-cell interaction between effector cell and host cell, some effector cells display self-degradation in different pathways, entosis, cannibalism or emperitosis (upper panel), while others release from the host cell and acquire new properties (low panel), resulting different biological activities.

Fig. (2)

A cell-in-cell stress model. In this model, effector cell/cells (red cell) inside host cell (green cell) may change the biological properties of the host cell through cell-in-cell interactions, which may result in sequentially the niche changes around the host cell and systemic immune shifting. For example, expressing up-regulating molecules on the host cell membrane may induce inflammation (up panel); otherwise, expressing co-inhibitory molecules on the host cell membrane may induce immune tolerance (middle panel). In some cases, entered effector cell /cells change genomes of the host cell, thereby providing a new way to form new cells with different biological features (low panel). There are different pathways leading to multigenomes in host cell:cytokinesis failure of host cell due to cell-in-cell structure results in polypolid cell formation and subsequent following bipopar division often leads to chromosome missegregation and produce aneuploidy; cell fusion between effector cell and host cell can lead to metastatic cell formation; in other case, effector cell can penetrates into the nuclei of host cell and may result in genetic information exchange; finally through all the above ways, somatic cell genomes may be changed from one genome into multiple genomes.

Fig. (3)

Cell penetration in cell-in-cell structure may be highly directional. Three different types of cells form special cell-in-cell structure. In the mix-culture, cell A (green cell, white arrow) can be penetrated by both cell B (black cell, yellow arrow) and cell C (red cell, pink arrow). However, we hardly can observe cell A penetrates into cell B or cell C.

Fig. (4)

A nested cell-in-cell structure. One cell (low red cell, pink arrow) penetrates into the second host cell (middle cell, white arrow), both of them penetrate into the third one (upper green cell, yellow arrow).

Fig. (5)

Cell-in-cell structures formation could occur cross species. A granulocyte (red cell) with a typical doughnut nucleus (blue: DAPI) from C57BL/6 mice penetrates into a human CNE-2 cell (green cell).