Apoptosis and Compensatory Proliferation Signaling Are Coupled by CrkI-Containing Microvesicles

Apoptosis has been implicated in compensatory proliferation signaling (CPS), whereby dying cells induce proliferation in neighboring cells as a means to restore homeostasis. The nature of signaling between apoptotic cells and their neighboring cells remains largely unknown. Here we show that a fraction of apoptotic cells produce and release CrkI-containing microvesicles (distinct from exosomes and apoptotic bodies), which induce proliferation in neighboring cells upon contact. We provide visual evidence of CPS by videomicroscopy. We show that purified vesicles in vitro and in vivo are sufficient to stimulate proliferation in other cells. Our data demonstrate that CrkI inactivation by ExoT bacterial toxin or by mutagenesis blocks vesicle formation in apoptotic cells and inhibits CPS, thus uncoupling apoptosis from CPS. We further show that c-Jun amino-terminal kinase (JNK) plays a pivotal role in mediating vesicle-induced CPS in recipient cells. CPS could have important ramifications in diseases that involve apoptotic cell death. [Display omitted] •Apoptotic cells release vesicles that stimulate proliferation in neighboring cells•These vesicles are distinct from exosomes and apoptotic bodies•CrkI inactivation inhibits vesicle formation in apoptotic cells and blocks CPS•Vesicle-induced proliferation requires JNK activity in neighboring cells Apoptotic cells can induce proliferation in neighboring cells, a process known as compensatory proliferation. Gupta, Goldufsky, Wood et al. now show that a fraction of apoptotic cells produce and release CrkI-containing microvesicles, distinct from exosomes and apoptotic bodies, that stimulate proliferation in bystander cells upon contact.