YIA Candidate Australasian Extracellular Vesicles Conference 2020

YIA Presentation: Unexpected role of ion channels in apoptotic body formation and cell clearance (#23)

Thanh Kha Phan 1 , Rochelle Tixeira 1 , Bo Shi 1 , Niall D Geoghegan 2 , Kelly L Rogers 2 , Ivan KH Poon 1
  1. La Trobe Institute for Molecular Sciences, La Trobe University, Bundoora, VIC, Australia
  2. Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia

Dying cells often break into smaller membrane-bound vesicles, called apoptotic bodies (ApoBD), via apoptotic cell disassembly, an essential physiological or pathophysiological event downstream of apoptosis. Emerging evidence implies the importance of ApoBD formation in mediating efficient phagocytic removal of apoptotic debris and facilitating intercellular communication through trafficking of biomolecules and pathogen-derived materials. In contrast to long-lasting belief, our recent findings have demonstrated that apoptotic cell disassembly is a tightly-regulated and temporally-controlled three-step process: (i) membrane blebbing, (ii) formation of thin apoptotic membrane protrusion promoting bleb separation and (iii) protrusion fragmentation to form ApoBD. Latest studies from our laboratory suggest the direct relationship between ApoBD formation and dead cell clearance efficiency, which is crucial to maintain homeostasis and prevent clearance-associated pathogenesis such as chronic inflammation and autoimmunity. However, detailed insights into the underlying mechanism of apoptotic cell disassembly undoubtedly require further investigations. Using lattice light-sheet microscopy, we vividly showed that extracellular calcium influx preceded disassembly step of apoptotic cell, blockade of which, using specific inhibitors against voltage-gated calcium channels and potassium channels, abolishes ApoBD formation. Intriguingly, calcium channel and potassium channels work in tandem to induce calcium influx, resulting in plasma membrane depolarisation. The resulting electrochemical force across the untethered membrane, ultimately leads to protrusion formation and cell disassembly. Our findings therefore provide further molecular and mechanobiochemical insights into dying cell disassembly and its relevance to cell clearance.