title: Autonomy and Non-autonomy of Angiogenic Cell Movements Revealed by Experiment-Driven Mathematical Modeling.
abstract: Angiogenesis is a multicellular phenomenon driven by morphogenetic cell movements. We recently reported morphogenetic vascular endothelial cell (EC) behaviors to be dynamic and complex. However, the principal mechanisms orchestrating individual EC movements in angiogenic morphogenesis remain largely unknown. Here we present an experiment-driven mathematical model that enables us to systematically dissect cellular mechanisms in branch elongation. We found that cell-autonomous and coordinated actions governed these multicellular behaviors, and a cell-autonomous process sufficiently illustrated essential features of the morphogenetic EC dynamics at both the single-cell and cell-population levels. Through refining our model and experimental verification, we further identified a coordinated mode of tip EC behaviors regulated via a spatial relationship between tip and follower ECs, which facilitates the forward motility of tip ECs. These findings provide insights that enhance our mechanistic understanding of not only angiogenic morphogenesis, but also other types of multicellular phenomenon.
authors.affiliation: Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Sugihara
authors.affiliation: Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan; International Research Center for Medical Sciences, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Chiyoda-ku, Tokyo 102-0076, Japan. Electronic address: nkanako@kumamoto-u.ac.jp.
authors.forename: Koichi
authors.initials: K
authors.lastname: Nishiyama
authors.affiliation: Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan.
authors.forename: Shigetomo
authors.initials: S
authors.lastname: Fukuhara
authors.affiliation: Department of Retinal Vascular Biology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Uemura
authors.affiliation: Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Arima
authors.affiliation: Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Higashi-Hiroshima, Hiroshima 739-8526, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Kobayashi
authors.affiliation: Department for Innovative Methods of Computing, Center for Information Services and High Performance Computing (ZIH), Technische Universität Dresden, 01062 Dresden, Germany.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Köhn-Luque
authors.affiliation: Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Mochizuki
authors.affiliation: International Research Center for Medical Sciences, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan; Cancer Institute of Singapore, National University of Singapore Centre for Translational Medicine, 14 Medical Drive, 12-01, Singapore 117599, Singapore.
authors.forename: Toshio
authors.initials: T
authors.lastname: Suda
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
authors.forename: Hisao
authors.initials: H
authors.lastname: Ogawa
authors.affiliation: Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Chiyoda-ku, Tokyo 102-0076, Japan; Institute for Biology and Mathematics of Dynamical Cell Processes (iBMath), the University of Tokyo, 3-8-1 Komaba, Meguro-ku, Tokyo 153-8914, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kurihara
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D004625:Embryo, Nonmammalian / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D018919:Neovascularization, Physiologic / Q000187:drug effects; D012160:Retina / Q000187:drug effects / Q000378:metabolism; D059008:Time-Lapse Imaging; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D015027:Zebrafish / Q000254:growth & development
chemical_list: D042461:Vascular Endothelial Growth Factor A