Apoptosis form and function

Morphology

During apoptosis, a cell typically condenses its nucleus and cytoplasm, its DNA is degraded into many small (200 bp-250 kbp) pieces, marked bleb-bing of the plasma membrane occurs, and, in the final stages, the cell collapses into multiple intact fragments that are eaten by phagocytes before the cellular contents have had a chance to escape (Figure 1). Probably the most striking morphologic feature of apoptosis is the marked condensation and disintegration of the nucleus into numerous, intensely staining, spheres scattered throughout the cytoplasm

Figure 2 Morphological features of (A) a live versus (B) an apoptotic cell. Note particularly the disintegration of the nucleus into numerous discrete fragments.

(Figure 2). This contrasts starkly with the process of necrosis, where the nucleus typically swells to occupy most of the cytoplasm, and the chromatin decreases rather than increases in staining intensity. Plasma

Figure 1 Schematic representation of apoptosis.

membrane blebbing and disintegration of the cell into numerous apoptotic bodies are other highly characteristic features of apoptosis (Figure 3). The collapse of the cell into apoptotic bodies, that retain membrane integrity for several hours, likely facilitates phagocytosis and removal of the dying cell by surrounding phagocytes (Figure 1). In essence, apoptosis represents a clean and efficient way of removing unwanted or diseased cells while minimizing an inflammatory response.

Recognition and removal of apoptotic cells by phagocytes

Changes to the composition of the plasma membrane have long been suspected to mediate early recognition of apoptotic cells by phagocytes - thereby triggering their safe removal. In many ways this stage of apoptosis is the most critical, since the essential functional difference between an apoptotic and a necrotic cell is that the former is somehow recognized as being in the throes of death several hours before any cytoplasmic contents leak out. Necrotic cells, on the other hand, undergo early lysis, thereby

Figure 3 Transmission electron micrographs of a healthy (top) versus an apoptotic (bottom) mouse hepatocyte. Apoptosis was induced by ligation of CD95 (Fas/APO-1) on these cells with cross-iinking antibody. Note the dramatic collapse of the apoptotic cell into many discrete apoptotic bodies (arrows) and the marked condensation of the chromatin (arrowheads). N, indicates the position of the nucleus in the live cell. (Reproduced with permission from Ni etal. (1994) Experimental Cell Research 215: 332-337. Figure kindly provided by Professor Shigekazu Nagata.)

Figure 3 Transmission electron micrographs of a healthy (top) versus an apoptotic (bottom) mouse hepatocyte. Apoptosis was induced by ligation of CD95 (Fas/APO-1) on these cells with cross-iinking antibody. Note the dramatic collapse of the apoptotic cell into many discrete apoptotic bodies (arrows) and the marked condensation of the chromatin (arrowheads). N, indicates the position of the nucleus in the live cell. (Reproduced with permission from Ni etal. (1994) Experimental Cell Research 215: 332-337. Figure kindly provided by Professor Shigekazu Nagata.)

causing damage to surrounding cells and eliciting an inflammatory response. When apoptotic cells are formed in culture, where there are no phagocytic cells around to eat them, they eventually undergo secondary necrosis, which would probably be just as damaging as primary necrosis were it to occur in vivo. Thus, the membrane changes that signal to phagocytes that a cell is undergoing apoptosis are of paramount importance in this process.

Membrane changes that occur on apoptotic cells have proved elusive. To date it appears that there are two main alterations that occur on the surface of apoptotic cells that may be mutually exclusive in their usage. One mechanism used by apoptotic cells to signal their plight to surrounding cells is to export phosphatidylserine - a lipid normally confined to the inner plasma membrane leaflet on healthy cells - to the external surface of the plasma membrane. This appears to trigger phagocytosis of these cells, presumably by recognition of surface phosphatidyl-serine via a putative phosphatidylserine receptor on the macrophage. The other mechanism that has been comparatively well characterized involves the appearance of, an as yet unidentified, thrombospon-din-binding ligand on the surface of the apoptotic cell. This ligand is bound by thrombospondin-bearing macrophages (thrombospondin being bound to the macrophage via a vitronectin receptor-CD36 interaction) and facilitates uptake of the apoptotic cell by the latter. Interestingly, the CD36-associated mechanism also appears to operate in Drosophila, as recent studies have discovered a CD36-related molecule (Croquemort) involved in macrophage removal of apoptotic cells in this organism. Other apoptosis-associated membrane changes have also been described, such as alterations to the carbohydrate composition of the plasma membrane, but these changes remain poorly characterized.

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