Polyploidy promotes transformation of epithelial cells into non-professional phagocytes

Removal of dead and damaged cells is critical for organismal health. Under stress conditions such as nutritional deprivation, infection, or temperature shift, the clearance of nonessential cells becomes a universal strategy to conserve energy and maintain tissue homeostasis. Typically, this task is performed by professional phagocytes such as macrophages. However, non-professional phagocytes (NPPs) can also adopt a phagocytic fate under specific circumstances. Similar to professional phagocytes, NPPs undergo transitions from immature to mature states and activation, but the precise cellular and molecular mechanisms governing their maturation, induction and phagocytic execution remain largely unknown. A notable example of stress-induced phagocytosis is the removal of germline cells by follicle cell-derived NPPs during oogenesis in Drosophila. In this study, we report that the transformation of follicle cells into NPPs is dependent on Notch signaling activation during mid-oogenesis. Moreover, Notch overactivation is sufficient to trigger germline cell death and clearance (GDAC). We further show that polyploidy, driven by Notch signaling-induced endoreplication, is essential for the transformation of follicle cells into NPPs. Polyploidy facilitates the activation of JNK signaling, which is crucial for the phagocytic behavior of these cells. Additionally, we show that polyploidy in epidermal cells, another type of NPPs, is important for their engulfment of dendrites during induced degeneration. Together, these findings suggest that polyploidy is a critical factor in the transformation of epithelial cells into NPPs, enabling their phagocytic functions, which are essential for maintaining cellular and organismal homeostasis during stress conditions. SIGNIFICANCEThe ability to remove dead and damaged cells is essential for maintaining tissue homeostasis and organismal health. While this task is typically performed by professional phagocytes such as macrophages, non-professional phagocytes (NPPs) can also acquire phagocytic functions during development or in response to stress conditions. Using Drosophila oogenesis as a model, we reveal that the transformation of follicle cells into NPPs is driven by Notch signaling and is critically dependent on polyploidy. Our findings show that polyploidy, induced through Notch signaling-mediated endoreplication, is required for activating JNK signaling, a pathway essential for the phagocytic behavior of NPPs. Furthermore, we show that polyploidy also facilitates the phagocytic activity of epidermal cells in clearing degenerating dendrites. Together, these results suggest that polyploidy plays an important role in enabling epithelial cells to adopt NPP functions and in maintaining tissue and organismal homeostasis under stress conditions.