Apoptotic extracellular vesicle formation via local phosphatidylserine exposure drives efficient cell extrusion

Akihito Kira; Ichiko Tatsutomi; Keisuke Saito; Machiko Murata; Izumi Hattori; Haruna Kajita; Naoko Muraki; Yukako Oda; Saya Satoh; Yuta Tsukamoto; Seisuke Kimura; Kenta Onoue; Shigenobu Yonemura; Satoko Arakawa; Hiroki Kato; Tsuyoshi Hirashima; Kohki Kawane

doi:10.1016/j.devcel.2023.05.008

Apoptotic extracellular vesicle formation via local phosphatidylserine exposure drives efficient cell extrusion

Dev Cell. 2023 Jul 24;58(14):1282-1298.e7. doi: 10.1016/j.devcel.2023.05.008. Epub 2023 Jun 13.

Authors

Akihito Kira¹, Ichiko Tatsutomi¹, Keisuke Saito¹, Machiko Murata¹, Izumi Hattori¹, Haruna Kajita¹, Naoko Muraki¹, Yukako Oda², Saya Satoh³, Yuta Tsukamoto³, Seisuke Kimura⁴, Kenta Onoue⁵, Shigenobu Yonemura⁶, Satoko Arakawa⁷, Hiroki Kato³, Tsuyoshi Hirashima⁸, Kohki Kawane⁹

Affiliations

¹ Department of Frontier Life Sciences, Faculty of Life Sciences, Kyoto Sangyo University, Kyoto 603-8555, Japan.
² Department of Cell Growth and Differentiation, Center for iPS Cell Research & Application, Kyoto University, Kyoto 606-8507, Japan.
³ Institute of Cardiovascular Immunology, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany.
⁴ Department of Industrial Life Sciences, Faculty of Life Sciences, Kyoto Sangyo University, Kyoto 603-8555, Japan; Center for Plant Sciences, Kyoto Sangyo University, Kyoto 603-8555, Japan.
⁵ Laboratory for Ultrastructural Research, RIKEN Center for Biosystems Dynamics Research, Hyogo 650-0047, Japan.
⁶ Laboratory for Ultrastructural Research, RIKEN Center for Biosystems Dynamics Research, Hyogo 650-0047, Japan; Department of Cell Biology, Tokushima University Graduate School of Medicine, Tokushima 770-8503, Japan.
⁷ Research Core, Institute of Research, Tokyo Medical and Dental University, Tokyo 113-8510, Japan; Department of Pathological Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
⁸ Mechanobiology Institute, National University of Singapore, Singapore 117411, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore; Japan Science and Technology Agency, PRESTO, Saitama 332-0012, Japan. Electronic address: [email protected].
⁹ Department of Frontier Life Sciences, Faculty of Life Sciences, Kyoto Sangyo University, Kyoto 603-8555, Japan. Electronic address: [email protected].

PMID: 37315563
DOI: 10.1016/j.devcel.2023.05.008

Abstract

Cell extrusion is a universal mode of cell removal from tissues, and it plays an important role in regulating cell numbers and eliminating unwanted cells. However, the underlying mechanisms of cell delamination from the cell layer are unclear. Here, we report a conserved execution mechanism of apoptotic cell extrusion. We found extracellular vesicle (EV) formation in extruding mammalian and Drosophila cells at a site opposite to the extrusion direction. Lipid-scramblase-mediated local exposure of phosphatidylserine is responsible for EV formation and is crucial for executing cell extrusion. Inhibition of this process disrupts prompt cell delamination and tissue homeostasis. Although the EV has hallmarks of an apoptotic body, its formation is governed by the mechanism of microvesicle formation. Experimental and mathematical modeling analysis illustrated that EV formation promotes neighboring cells' invasion. This study showed that membrane dynamics play a crucial role in cell exit by connecting the actions of the extruding cell and neighboring cells.

Keywords: EV; PS; apoptosis; apoptotic body; cell death; cell extrusion; delamination; epithelium; extracellular vesicle; phosphatidylserine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / physiology
Drosophila / metabolism
Endocytosis
Extracellular Vesicles* / metabolism
Mammals / metabolism
Phosphatidylserines* / metabolism

Substances

Phosphatidylserines