title: Modeling cell apoptosis for simulating three-dimensional multicellular morphogenesis based on a reversible network reconnection framework.
abstract: Morphogenesis in multicellular organisms is accompanied by apoptotic cell behaviors: cell shrinkage and cell disappearance. The mechanical effects of these behaviors are spatiotemporally regulated within multicellular dynamics to achieve proper tissue sizes and shapes in three-dimensional (3D) space. To analyze 3D multicellular dynamics, 3D vertex models have been suggested, in which a reversible network reconnection (RNR) model has successfully expressed 3D cell rearrangements during large deformations. To analyze the effects of apoptotic cell behaviors on 3D multicellular morphogenesis, we modeled cell apoptosis based on the RNR model framework. Cell shrinkage was modeled by the potential energy as a function of individual cell times during the apoptotic phase. Cell disappearance was modeled by merging neighboring polyhedrons at their boundary surface according to the topological rules of the RNR model. To establish that the apoptotic cell behaviors could be expressed as modeled, we simulated morphogenesis driven by cell apoptosis in two types of tissue topology: 3D monolayer cell sheet and 3D compacted cell aggregate. In both types of tissue topology, the numerical simulations successfully illustrated that cell aggregates gradually shrank because of successive cell apoptosis. During tissue shrinkage, the number of cells in aggregates decreased while maintaining individual cell size and shape. Moreover, in case of localizing apoptotic cells within a part of the 3D monolayer cell aggregate, the cell apoptosis caused the global tissue bending by pulling on surrounding cells. In case of localizing apoptotic cells on the surface of the 3D compacted cell aggregate, the cell apoptosis caused successive, directional cell rearrangements from the inside to the surface. Thus, the proposed model successfully provided a basis for expressing apoptotic cell behaviors during 3D multicellular morphogenesis based on an RNR model framework.
authors.affiliation: Laboratory for in vitro Histogenesis, Center for Developmental Biology (CDB), RIKEN, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan. okuda@cdb.riken.jp.|Laboratory for Organogenesis and Neurogenesis, Center for Developmental Biology (CDB), RIKEN, Kobe, Japan. okuda@cdb.riken.jp.
authors.forename: Satoru
authors.initials: S
authors.lastname: Okuda
authors.affiliation: Department of Biomechanics, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Inoue
authors.affiliation: Laboratory for in vitro Histogenesis, Center for Developmental Biology (CDB), RIKEN, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan.
authors.forename: Mototsugu
authors.initials: M
authors.lastname: Eiraku
authors.affiliation: Department of Biomechanics, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan.
authors.forename: Taiji
authors.initials: T
authors.lastname: Adachi
authors.affiliation: Laboratory for Organogenesis and Neurogenesis, Center for Developmental Biology (CDB), RIKEN, Kobe, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Sasai
mesh_terms: D017209:Apoptosis; D048429:Cell Size; D003198:Computer Simulation; D008954:Models, Biological; D009024:Morphogenesis
keywords: Apoptotic force; Cell apoptosis; Computational biomechanics; Multicellular morphogenesis; Reversible network reconnection model; Three-dimensional vertex model