Cooperative epithelial phagocytosis enables error correction in the early embryo

Abstract

Errors in early embryogenesis are a cause of sporadic cell death and developmental failure1,2. Phagocytic activity has a central role in scavenging apoptotic cells in differentiated tissues3,4,5,6. However, how apoptotic cells are cleared in the blastula embryo in the absence of specialized immune cells remains unknown. Here we show that the surface epithelium of zebrafish and mouse embryos, which is the first tissue formed during vertebrate development, performs efficient phagocytic clearance of apoptotic cells through phosphatidylserine-mediated target recognition. Quantitative four-dimensional in vivo imaging analyses reveal a collective epithelial clearance mechanism that is based on mechanical cooperation by two types of Rac1-dependent basal epithelial protrusions. The first type of protrusion, phagocytic cups, mediates apoptotic target uptake. The second, a previously undescribed type of fast and extended actin-based protrusion that we call 'epithelial arms', promotes the rapid dispersal of apoptotic targets through Arp2/3dependent mechanical pushing. On the basis of experimental data and modelling, we show that mechanical load-sharing enables the long-range cooperative uptake of apoptotic cells by multiple epithelial cells. This optimizes the efficiency of tissue clearance by extending the limited spatial exploration range and local uptake capacity of non-motile epithelial cells. Our findings show that epithelial tissue clearance facilitates error correction that is relevant to the developmental robustness and survival of the embryo, revealing the presence of an innate immune function in the earliest stages of embryonic development. Main textEarly embryogenesis is prone to cellular errors like mitotic defects induced by cell intrinsic or extrinsic stress factors1,2. This leads to sporadic cell death of progenitor stem cells3-6, assumed to be a major cause of early developmental failures in human pre-implantation development7,8. Stochastic cell death is expected to occur at random locations, vary in cell number and differ from developmentally programmed cell death occurring at later stages in vertebrate embryogenesis, which has predefined spatiotemporal dynamics and specific functions in morphogenetic processes9. Detection and removal of cell corpses requires specific clearance mechanisms as mediated by professional phagocytic cells in adult tissues10. Whether such active mechanisms for efficient apoptotic tissue clearance exist in early blastula and gastrula

Functions of Arp2/3 Complex in the Dynamics of Epithelial Tissues

“…Interestingly, Wu and his colleagues have shown that WASp and the Arp2/3 complex participates in the formation of the phagocytic cup through a Rac-dependent signaling and are required for an efficient apoptotic cell corpse engulfment ( Wu et al, 2017 ). Consistent with these previous data, the Arp2/3 complex is also essential in the apoptotic cell clearance in zebrafish and mouse embryos ( Hoijman et al, 2021 ). Interestingly, in addition to the formation of the phagocytic cup, the Arp2/3 complex also participates in the generation of epithelial arms at the basal part of the epithelium ( Figure 1B ).…”

“…Interestingly, in addition to the formation of the phagocytic cup, the Arp2/3 complex also participates in the generation of epithelial arms at the basal part of the epithelium ( Figure 1B ). These arms push apoptotic cells, which results in the dispersion of apoptotic corpses and improves the overall clearance efficiency by the surrounding epithelial cells ( Hoijman et al, 2021 ). This highlights the major role of the branched actin regulators in epithelial cell cooperation for the elimination of cell corpses.…”

Phagocytic ‘teeth’ and myosin-II ‘jaw’ power target constriction during phagocytosis

“…In addition, the fast forward movement of actin teeth, which underlie target constriction, concomitant with phagocytic cup progression across the target is in stark contrast to lamellipodial focal adhesion complexes (FAs), which are fixed relative to the substratum (Case and Waterman, 2015). The strong target constriction recently observed in complementmediated phagocytosis by peritoneal macrophages in vitro (Walbaum et al, 2021), and in phosphatidylserine-mediated phagocytosis by epithelial cells in zebrafish embryos (Hoijman et al, 2021) suggests that strong normal forces and target constriction are likely a general feature of phagocytosis.…”

A deletion at the polled PC locus alone is not sufficient to cause a polled phenotype in cattle

“…Although this immune response was demonstrated in primary cell lines, one may question if this could translate over into embryos. Little is known about the innate immune response in early embryos, but a recent study unveiled the existence of what can be described as the earliest observable innate immune response in the developing embryo 27 . They discovered that epithelial cells were able to detect, consume, and destroy defective cells, thus aiding in the embryo’s ability to survive.…”