Microenvironmental influences of apoptosis in vivo and in vitro.

The apoptosis program of physiological cell death elicits a range of non-phlogistic homeostatic mechanisms-"recognition, response and removal"-that regulate the microenvironments of normal and diseased tissues via multiple modalities operating over short and long distances. The molecular mechanisms mediate intercellular signaling through direct contact with neighboring cells, release of soluble factors and production of membrane-delimited fragments (apoptotic bodies, blebs and microparticles) that allow for interaction with host cells over long distances. These processes effect the selective recruitment of mononuclear phagocytes and the specific activation of both phagocytic and non-phagocytic cells. While much evidence is available concerning the mechanisms underlying the recognition and responses of phagocytes that culminate in the engulfment and removal of apoptotic cell bodies, relatively little is yet known about the non-phagocytic cellular responses to the apoptosis program. These responses regulate inflammatory and immune cell activation as well as cell fate decisions of proliferation, differentiation and death. Here, we review current knowledge of these processes, considering especially how apoptotic cells condition the microenvironments of normal and malignant tissues. We also discuss how apoptotic cells that persist in the absence of phagocytic clearance exert inhibitory effects over their viable neighbors, paying particular attention to the specific case of cell cultures and highlighting how new cell-corpse-clearance devices-Dead-Cert Nanoparticles-can significantly improve the efficacy of cell cultures through effective removal of non-viable cells in the absence of phagocytes in vitro.