title: Propagating waves of directionality and coordination orchestrate collective cell migration.
abstract: The ability of cells to coordinately migrate in groups is crucial to enable them to travel long distances during embryonic development, wound healing and tumorigenesis, but the fundamental mechanisms underlying intercellular coordination during collective cell migration remain elusive despite considerable research efforts. A novel analytical framework is introduced here to explicitly detect and quantify cell clusters that move coordinately in a monolayer. The analysis combines and associates vast amount of spatiotemporal data across multiple experiments into transparent quantitative measures to report the emergence of new modes of organized behavior during collective migration of tumor and epithelial cells in wound healing assays. First, we discovered the emergence of a wave of coordinated migration propagating backward from the wound front, which reflects formation of clusters of coordinately migrating cells that are generated further away from the wound edge and disintegrate close to the advancing front. This wave emerges in both normal and tumor cells, and is amplified by Met activation with hepatocyte growth factor/scatter factor. Second, Met activation was found to induce coinciding waves of cellular acceleration and stretching, which in turn trigger the emergence of a backward propagating wave of directional migration with about an hour phase lag. Assessments of the relations between the waves revealed that amplified coordinated migration is associated with the emergence of directional migration. Taken together, our data and simplified modeling-based assessments suggest that increased velocity leads to enhanced coordination: higher motility arises due to acceleration and stretching that seems to increase directionality by temporarily diminishing the velocity components orthogonal to the direction defined by the monolayer geometry. Spatial and temporal accumulation of directionality thus defines coordination. The findings offer new insight and suggest a basic cellular mechanism for long-term cell guidance and intercellular communication during collective cell migration.
authors: Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel.
authors: Assaf
authors: A
authors: Zaritsky
authors: Israel Institute for Biological Research, Ness Ziona, Israel.
authors: Doron
authors: D
authors: Kaplan
authors: School of Physics and Astronomy, The Raymond and Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv, Israel.
authors: Inbal
authors: I
authors: Hecht
authors: Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors: Sari
authors: S
authors: Natan
authors: Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel.
authors: Lior
authors: L
authors: Wolf
authors: Department of Chemical Physics, Weizmann Institute of Science, Rehovot, Israel.
authors: Nir S
authors: NS
authors: Gov
authors: School of Physics and Astronomy, The Raymond and Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv, Israel; Center for Theoretical Biological Physics, Rice University, Houston, Texas, United States of America; Research & Development Unit, Assaf Harofeh Medical Center, Zerifin, Israel.
authors: Eshel
authors: E
authors: Ben-Jacob
authors: Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors: Ilan
authors: I
authors: Tsarfaty
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D002450:Cell Communication / Q000502:physiology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D019295:Computational Biology; D004285:Dogs; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D015398:Signal Transduction; D014945:Wound Healing / Q000502:physiology