The fingering patterns in the epithelial layer control the gap closure rate via curvature-mediated force

Closing gaps in cellular monolayers is a fundamental aspect of both morphogenesis and wound healing. This closure can be achieved through leader cell crawling or actomyosin-based contraction, depending on the size of the gap. Here, we focus on wounds whose closure is driven by interfacial instabilities, featuring both leader cell-driven fingers and actin-mediated contraction. Our proposed model predicts a positive correlation between the frequency of fingering and the overall speed of boundary closure. This fingering frequency is precisely regulated through the orchestration of cell density-driven pressure, cell-cell repulsions, and the initial curvature of the wound boundary. Our findings demonstrate an inverse correlation between fingering frequency and boundary curvatures, indicating a “self-control” mechanism for closure rates independent of the initial curvatures of the wound periphery. Notably, changes in curvature caused by fingering formation generate force that aids in the healing process.

[1]  St. Lucia.,et al.  Cell segregation via differential collision modes between heterotypic cell populations , 2022, Molecular biology of the cell.

[2]  G. Gompper,et al.  Instability and fingering of interfaces in growing tissue , 2020, New Journal of Physics.

[3]  Michael F Staddon,et al.  Wound Healing Coordinates Actin Architectures to Regulate Mechanical Work , 2019, Nature Physics.

[4]  J. Casademunt,et al.  Active Fingering Instability in Tissue Spreading. , 2019, Physical review letters.

[5]  U. Schwarz,et al.  Mechanical interactions among followers determine the emergence of leaders in migrating epithelial cell collectives , 2018, Nature Communications.

[6]  Visar Ajeti,et al.  Cooperation of dual modes of cell motility promotes epithelial stress relaxation to accelerate wound healing , 2018, PLoS Comput. Biol..

[7]  Wouter-Jan Rappel,et al.  Contact inhibition of locomotion determines cell–cell and cell–substrate forces in tissues , 2016, Proceedings of the National Academy of Sciences.

[8]  A. Kabla,et al.  Gap geometry dictates epithelial closure efficiency , 2015, Nature Communications.

[9]  Chwee Teck Lim,et al.  Mechanics of epithelial closure over non-adherent environments , 2015, Nature Communications.

[10]  P. Korrapati,et al.  Role of Dermatopontin in re-epithelialization: Implications on keratinocyte migration and proliferation , 2014, Scientific Reports.

[11]  William Thielicke,et al.  PIVlab – Towards User-friendly, Affordable and Accurate Digital Particle Image Velocimetry in MATLAB , 2014 .

[12]  Olivera Stojadinovic,et al.  Epithelialization in Wound Healing: A Comprehensive Review. , 2014, Advances in wound care.

[13]  M. Ben Amar,et al.  Re-epithelialization: advancing epithelium frontier during wound healing , 2014, Journal of The Royal Society Interface.

[14]  A. Buguin,et al.  Interplay of RhoA and mechanical forces in collective cell migration driven by leader cells , 2014, Nature Cell Biology.

[15]  P. Silberzan,et al.  Border forces and friction control epithelial closure dynamics. , 2014, Biophysical journal.

[16]  Chwee Teck Lim,et al.  Epithelial bridges maintain tissue integrity during collective cell migration. , 2014, Nature materials.

[17]  Xavier Trepat,et al.  Propulsion and navigation within the advancing monolayer sheet , 2013, Nature materials.

[18]  J. Klarlund.  Dual modes of motility at the leading edge of migrating epithelial cell sheets , 2012, Proceedings of the National Academy of Sciences.

[19]  M. Sheetz,et al.  Cell crawling mediates collective cell migration to close undamaged epithelial gaps , 2012, Proceedings of the National Academy of Sciences.

[20]  Jonathan E. Gale,et al.  Live-cell delamination counterbalances epithelial growth to limit tissue overcrowding , 2012, Nature.

[21]  David A. Weitz,et al.  Physical forces during collective cell migration , 2009 .

[22]  P. Chavrier,et al.  Collective migration of an epithelial monolayer in response to a model wound , 2007, Proceedings of the National Academy of Sciences.

[23]  M. Sheetz,et al.  Two distinct modes of myosin assembly and dynamics during epithelial wound closure , 2007, The Journal of Cell Biology.

[24]  F. Saija,et al.  Phase diagram of softly repulsive systems: the Gaussian and inverse-power-law potentials. , 2005, The Journal of chemical physics.

[25]  Miki Ebisuya,et al.  ERK Activation Propagates in Epithelial Cell Sheets and Regulates Their Migration during Wound Healing , 2004, Current Biology.

[26]  T. Schöneberg,et al.  Single‐cell epithelial defects close rapidly by an actinomyosin purse string mechanism with functional tight junctions , 2002, The Journal of physiology.

[27]  Paul Martin,et al.  Dynamic analysis of dorsal closure in Drosophila: from genetics to cell biology. , 2002, Developmental cell.

[28]  Ben Fabry,et al.  Traction fields, moments, and strain energy that cells exert on their surroundings. , 2002, American journal of physiology. Cell physiology.

[29]  Louise P. Cramer,et al.  An epithelial cell destined for apoptosis signals its neighbors to extrude it by an actin- and myosin-dependent mechanism , 2001, Current Biology.

[30]  Paul Martin,et al.  Mechanisms of epithelial fusion and repair , 2001, Nature Cell Biology.

[31]  Gabriel Fenteany,et al.  Signaling pathways and cell mechanics involved in wound closure by epithelial cell sheets , 2000, Current Biology.

[32]  W. Bement,et al.  Wound-induced assembly and closure of an actomyosin purse string in Xenopus oocytes , 1999, Current Biology.

[33]  I. Gipson,et al.  Actin 'purse string' filaments are anchored by E-cadherin-mediated adherens junctions at the leading edge of the epithelial wound, providing coordinated cell movement. , 1998, Journal of cell science.

[34]  C. Nobes,et al.  Rho, Rac, and Cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia , 1995, Cell.

[35]  P. Forscher,et al.  A novel cytoskeletal structure involved in purse string wound closure and cell polarity maintenance , 1993, The Journal of cell biology.

[36]  Paul Martin,et al.  Actin cables and epidermal movement in embryonic wound healing , 1992, Nature.

[37]  Charles A. Johnson.  Generalization of the Gibbs-Thomson equation , 1965 .