Dying epithelial cells tell their neighbors to evict them by releasing the lipid sphingosine-1-phosphate (S1P), Gu et al. report.
Healthy cells form an actomyosin ring around adjacent apoptosing cells to push them out of an epithelial layer without leaving any gaps in the tissue. But the signal sent by dying cells to their neighbors has remained mysterious. Gu et al. found that S1P—a lipid produced by apoptotic cells—was sufficient to induce actin cable assembly and that blocking S1P production by inhibiting sphingosine kinase prevented the extrusion of dying epithelial cells.
On the other hand, neighbors of the apoptotic cells needed the S1P receptor S1P2 to expel the dying cells from their midst. Inhibiting or knocking down the receptor prevented epithelial monolayers from evicting dying cells in vitro, and zebrafish lacking S1P2 couldn't extrude apoptotic cells from their epidermis. S1P2 is a G protein–coupled receptor that likely stimulates actomyosin ring assembly by activating the Rho GTPase.
Gu et al. also found that surrounding cells take up the S1P produced by their dying neighbors. Since S1P promotes cell survival, this internalization may ensure that these cells stay alive to take the evicted cell's place. Senior author Jody Rosenblatt now wants to investigate how S1P is transferred between neighboring cells. She is also interested in whether defects in this pathway lead to dysfunctional epithelia in asthma and other diseases and whether S1P signaling contributes to the extrusion of living epithelial cells in both normal development and cancer metastasis.