The scavenger cell hypothesis of apoptosis: apoptosis redefined as a process by which a cell in living tissue is destroyed by phagocytosis.

Current literature on the definition and description of apoptosis is very confusing and erratic, due to voluminous studies in recent decades using cell culture technique. Apoptosis has evolved as a programmed mechanism of cell demise to get rid of the cells that are no longer needed by the body. The most important reason for a creature to use this mechanism to kill cells is to avoid inflammatory response that causes tissue damage and ensuing scar formation, as seen in necrosis. To reach this aim, the dying cell communicates, at early stages of the dying process, with macrophages or its neighboring cells that have phagocytotic ability, coined collectively as scavenger cells herein. The dying cell is swiftly engulfed by a scavenger cell without leaking any noxious cellular components into the intercellular space to provoke an inflammatory response. Thus, apoptosis is a process involving at least one other cell type and is actually a mechanism occurring in live tissue. Most studies of apoptosis in recent decades neglect this fundamental point and use cell culture system with a single cell type in the medium, in which avoidance of inflammatory response and tissue damage is no longer a reason. In culture, the dying cell has no way to signal scavenger cells to engulf itself and thus needs to demobilize a series of special mechanisms, which have no need in live tissue, to complete the suicidal process and clearance of its own corpse. These "otherwise-no-need" mechanisms seem to involve activation of executor caspases by cytochrome c, and the activated caspases mediate late processes of apoptosis in vitro. However, because the late processes of apoptosis in vivo actually occur in a phagosome of scavenger cell, it may be phagosomal enzymes, but not executor caspases of the apoptotic cell origin, that are really involved in apoptosis. Therefore, I propose a "scavenger cell hypothesis of apoptosis" to redefine apoptosis as an in vivo mechanism of cell death, and suggest that programmed cell death in culture in a third cell demise mechanism besides necrosis and apoptosis that should be defined using other nomenclatures.