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Review
. 2016 Dec 20;17(12):2144.
doi: 10.3390/ijms17122144.

Apoptosis in Cellular Society: Communication between Apoptotic Cells and Their Neighbors

Yuhei Kawamoto  1   2 , Yu-Ichiro Nakajima  3   4 , Erina Kuranaga  5   6   7
Affiliations
Review

Apoptosis in Cellular Society: Communication between Apoptotic Cells and Their Neighbors

Yuhei Kawamoto et al. Int J Mol Sci. .

Abstract

Apoptosis is one of the cell-intrinsic suicide programs and is an essential cellular behavior for animal development and homeostasis. Traditionally, apoptosis has been regarded as a cell-autonomous phenomenon. However, recent in vivo genetic studies have revealed that apoptotic cells actively influence the behaviors of surrounding cells, including engulfment, proliferation, and production of mechanical forces. Such interactions can be bidirectional, and apoptosis is non-autonomously induced in a cellular community. Of note, it is becoming evident that active communication between apoptotic cells and living cells contributes to physiological processes during tissue remodeling, regeneration, and morphogenesis. In this review, we focus on the mutual interactions between apoptotic cells and their neighbors in cellular society and discuss issues relevant to future studies of apoptosis.

Keywords: apoptosis; engulfment; mechanical force; non-cell autonomous effects; proliferation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic illustration of the apoptosis signaling pathway in Drosophila and mammals. The same colors and shapes represent functional homologous in both Drosophila melanogaster and mammals. In Drosophila, RHG proteins (Rpr, Hid, and Grim) produced by apoptotic stimuli inhibit the function of DIAP1 (Drosophila inhibitor of apoptosis protein 1). Dark (apaf-1 homologue) forms a complex (apoptosome) with the initiator caspase Dronc. Effector caspases DrICE and Dcp-1 are activated by the apoptosome, and the activated effector caspases promote cell death. Eiger (Drosophila TNFα ortholog) induces the JNK (c-Jun N-terminal kinase)-mediated cell-death pathway through Grindelwald (TNF receptor). In mammals, Smac and HtrA2 released from mitochondria block the function of IAP (Inhibitor of apoptosis protein). Mitochondria also secretes cytochrome c (cyt c), and the apoptosome which is consisted of cyt c, Apaf-1, and pro-caspase-9 activates effector caspases, such as Caspase-3 and Caspase-7. Cell death via initiator caspase-8 requires the activation of death ligands and receptor signaling (TNFα-TNF receptor and Fas-Fas ligand). TNFα, tumor necrosis factor α.
Figure 2
Figure 2
The mutual interaction between apoptotic cells and engulfing cells: (A) The process of macrophage priming. Naive macrophages cannot engulf pathogens. Apoptotic cells induce the non-autonomous activation of macrophages, and uptake of these cells leads to their transformation into mature macrophages; (B) Model for NC death in Drosophila oogenesis. Stretch follicle cells (FCs) contact nurse cell (NC) remnants during late oogenesis and non-autonomously promote NC death. In stretched FCs, the engulfment gene Draper becomes activated by the Ced-12-JNK signal. Ced-12 also contributes to NC death in parallel with the JNK-Draper pathway.
Figure 3
Figure 3
The control of cell numbers in tissue by non-autonomous effects of proliferation and apoptosis. (A) Apoptosis-induced proliferation. Apoptotic cells secrete mitogenic signals (e.g., Wnt, BMP and EGF) that induce the proliferation of neighboring cells (yellow hexagons) and contribute to tissue regeneration; (B) Proliferating cells induce non-autonomous apoptosis. Slow-growing cells are eliminated by their surrounding fast-growing cells. This event, called cell competition, is essential for the maintenance of tissue homeostasis.
Figure 4
Figure 4
The interaction between apoptosis and mechanical force. (A) Apoptosis-induced morphogenetic changes in Drosophila leg joint formation. Apoptotic cells pull their neighbors toward the basal side during delamination at the presumptive joint area. In their neighboring cells, the actomyosin cable accumulates in the apical cortical area. The apical surface of surrounding cells undergoes apical constriction; (B) Model for mechanical tension-induced cell competition. In cultured mammalian epithelial cells, compaction by overcrowding induces apoptosis in polarity-deficient cells, which is mediated by the upregulation of p53. The yellow hexagons represent normal cells.
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