Resident phagocytes promote non-cell-autonomous fragmentation of apoptotic cells.

Phagocytosis of apoptotic cells maintains tissue homeostasis and regulates inflammation. A proposed facilitator of apoptotic cell clearance is the fragmentation of these cells into apoptotic bodies (ApoBDs) through cell-autonomous processes involving caspases and cytoskeletal rearrangement. Although this fragmentation process is considered a hallmark of apoptosis, its progression in tissue environments remains underexplored. Here, we examine the in vivo apoptotic dynamics of mouse thymocytes and pluripotent cells from zebrafish embryos. We show that the in vivo biogenesis of ApoBDs is independent of known cell-intrinsic regulators. Instead, fragmentation depends on actin-rich protrusions from neighboring resident phagocytes, which mechanically compress apoptotic cells to break them into smaller particles. Four-dimensional in vivo tracking of apoptotic cells reveals that both phagocyte-mediated fragmentation and phagocytosis are size sensitive, indicating that apoptotic size reduction mediated by phagocytes enhances their own clearance abilities. This non-cell-autonomous fragmentation ensures rapid apoptotic cell clearance, crucial for maintaining tissue homeostasis in physiological settings.