Directed migration of mesenchymal cells: where signaling and the cytoskeleton meet.

Cell migration directed by spatial cues, or taxis, is a primary mechanism for orchestrating concerted and collective cell movements during development, wound repair, and immune responses. Compared with the classic example of amoeboid chemotaxis, in which fast-moving cells such as neutrophils are directed by gradients of soluble factors, directed migration of slow-moving mesenchymal cells such as fibroblasts is poorly understood. Mesenchymal cells possess a distinctive organization of the actin cytoskeleton and associated adhesion complexes as its primary mechanical system, generating the asymmetric forces required for locomotion without strong polarization. The emerging hypothesis is that the molecular underpinnings of mesenchymal taxis involve distinct signaling pathways and diverse requirements for regulation.

[1]  Min Zhao,et al.  Electrical signals control wound healing through phosphatidylinositol-3-OH kinase-gamma and PTEN. , 2006, Nature.

[2]  I. Schneider,et al.  Directed cell migration in multi-cue environments. , 2013, Integrative biology : quantitative biosciences from nano to macro.

[3]  Chuan-Hsiang Huang,et al.  Eukaryotic chemotaxis: a network of signaling pathways controls motility, directional sensing, and polarity. , 2010, Annual review of biophysics.

[4]  Wolfgang Huber,et al.  Directional tissue migration through a self-generated chemokine gradient , 2013, Nature.

[5]  Frank B. Gertler,et al.  Ena/VASP: towards resolving a pointed controversy at the barbed end , 2009, Journal of Cell Science.

[6]  N. Sharpless,et al.  Loss of Arp2/3 induces an NF-κB–dependent, nonautonomous effect on chemotactic signaling , 2013, The Journal of cell biology.

[7]  Daniel Kalman,et al.  Rac and Cdc42 play distinct roles in regulating PI(3,4,5)P3 and polarity during neutrophil chemotaxis , 2003, The Journal of cell biology.

[8]  Shin Ishii,et al.  Quantification of Local Morphodynamics and Local GTPase Activity by Edge Evolution Tracking , 2008, PLoS Comput. Biol..

[9]  P. Micke,et al.  Exploring the tumour environment: cancer-associated fibroblasts as targets in cancer therapy , 2005, Expert opinion on therapeutic targets.

[10]  Matthew D. Welch,et al.  A nucleator arms race: cellular control of actin assembly , 2010, Nature Reviews Molecular Cell Biology.

[11]  A. Shuttleworth,et al.  Mesenchymal stem cell migration is regulated by fibronectin through α5β1-integrin-mediated activation of PDGFR-β and potentiation of growth factor signals , 2011, Journal of Cell Science.

[12]  Thomas A. Mustoe, MD, FACS,et al.  Growth factors and wound healing: platelet-derived growth factor as a model cytokine. , 1991, Annual review of medicine.

[13]  J. Haugh Deterministic model of dermal wound invasion incorporating receptor-mediated signal transduction and spatial gradient sensing. , 2006, Biophysical journal.

[14]  K. Beningo,et al.  Nascent Focal Adhesions Are Responsible for the Generation of Strong Propulsive Forces in Migrating Fibroblasts , 2001, The Journal of cell biology.

[15]  S. Narumiya,et al.  Cdc42 and Rac Family GTPases Regulate Mode and Speed but Not Direction of Primary Fibroblast Migration during Platelet-Derived Growth Factor-Dependent Chemotaxis , 2009, Molecular and Cellular Biology.

[16]  Kenneth M. Yamada,et al.  Cell migration in 3D matrix. , 2005, Current opinion in cell biology.

[17]  E. Schaefer,et al.  Paxillin phosphorylation at Ser273 localizes a GIT1–PIX–PAK complex and regulates adhesion and protrusion dynamics , 2006, The Journal of cell biology.

[18]  Michael Sixt,et al.  Interstitial Dendritic Cell Guidance by Haptotactic Chemokine Gradients , 2013, Science.

[19]  Yukinori Endo,et al.  A Rac switch regulates random versus directionally persistent cell migration , 2005, The Journal of cell biology.

[20]  Sergey V. Plotnikov,et al.  Force Fluctuations within Focal Adhesions Mediate ECM-Rigidity Sensing to Guide Directed Cell Migration , 2012, Cell.

[21]  E. Holland,et al.  Platelet-derived growth factor (PDGF) and glial tumorigenesis. , 2006, Cancer letters.

[22]  Pere Roca-Cusachs,et al.  Mechanical guidance of cell migration: lessons from chemotaxis. , 2013, Current opinion in cell biology.

[23]  Robert H. Insall,et al.  Understanding eukaryotic chemotaxis: a pseudopod-centred view , 2010, Nature Reviews Molecular Cell Biology.

[24]  Erik S. Welf,et al.  Migrating fibroblasts reorient directionality by a metastable, PI3K-dependent mechanism , 2012, The Journal of cell biology.

[25]  Marc W. Kirschner,et al.  A PtdInsP3- and Rho GTPase-mediated positive feedback loop regulates neutrophil polarity , 2002, Nature Cell Biology.

[26]  E. Kunkel,et al.  Integrating Conflicting Chemotactic Signals , 1999, The Journal of cell biology.

[27]  Miguel Vicente-Manzanares,et al.  Myosin IIA/IIB restrict adhesive and protrusive signaling to generate front–back polarity in migrating cells , 2011, The Journal of cell biology.

[28]  Erik S. Welf,et al.  In chemotaxing fibroblasts, both high-fidelity and weakly biased cell movements track the localization of PI3K signaling. , 2011, Biophysical journal.

[29]  M. Mercola,et al.  Distribution and functions of platelet-derived growth factors and their receptors during embryogenesis. , 1997, International review of cytology.

[30]  P. Fisher,et al.  Quantitative analysis of cell motility and chemotaxis in Dictyostelium discoideum by using an image processing system and a novel chemotaxis chamber providing stationary chemical gradients , 1989, The Journal of cell biology.

[31]  D. Breitsprecher,et al.  Essential and nonredundant roles for Diaphanous formins in cortical microtubule capture and directed cell migration , 2014, Molecular biology of the cell.

[32]  Kenneth M. Yamada,et al.  Myosin IIA regulates cell motility and actomyosin–microtubule crosstalk , 2007, Nature Cell Biology.

[33]  C. Parent,et al.  A cell's sense of direction. , 1999, Science.

[34]  Elgene Lim,et al.  Protein kinase C α is a central signaling node and therapeutic target for breast cancer stem cells. , 2013, Cancer cell.

[35]  P. Iglesias,et al.  An Excitable Signal Integrator Couples to an Idling Cytoskeletal Oscillator to Drive Cell Migration , 2013, Nature Cell Biology.

[36]  C. Heldin,et al.  PDGF receptors as targets in tumor treatment. , 2007, Advances in cancer research.

[37]  M. Kirschner,et al.  Activation of the WAVE complex by coincident signals controls actin assembly. , 2009, Molecular cell.

[38]  A. Huttenlocher,et al.  Integrin-mediated adhesion regulates cell polarity and membrane protrusion through the Rho family of GTPases. , 2001, Molecular biology of the cell.

[39]  Johanna Andrae,et al.  Role of platelet-derived growth factors in physiology and medicine. , 2008, Genes & development.

[40]  Toshio Ohhashi,et al.  PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis. , 2004, Cancer cell.

[41]  P. A. Dimilla,et al.  Vascular smooth muscle cell durotaxis depends on substrate stiffness gradient strength. , 2009, Biophysical journal.

[42]  E. Butcher,et al.  Chemokines in the systemic organization of immunity , 2003, Immunological reviews.

[43]  D. Discher,et al.  Crawling from soft to stiff matrix polarizes the cytoskeleton and phosphoregulates myosin-II heavy chain , 2012, The Journal of cell biology.

[44]  Denis Wirtz,et al.  Water Permeation Drives Tumor Cell Migration in Confined Microenvironments , 2014, Cell.

[45]  Chang Shin Park,et al.  Kinetic Analysis of Platelet-derived Growth Factor Receptor/Phosphoinositide 3-Kinase/Akt Signaling in Fibroblasts* , 2003, Journal of Biological Chemistry.

[46]  J. Edelberg,et al.  Translation of PDGF cardioprotective pathways , 2007, Cardiovascular Toxicology.

[47]  John S. Condeelis,et al.  Chemotaxis in cancer , 2011, Nature Reviews Cancer.

[48]  T. Meyer,et al.  A local coupling model and compass parameter for eukaryotic chemotaxis. , 2005, Developmental cell.

[49]  K. Hahn,et al.  Spatiotemporal dynamics of RhoA activity in migrating cells , 2006, Nature.

[50]  M. Sixt,et al.  Rapid leukocyte migration by integrin-independent flowing and squeezing , 2008, Nature.

[51]  K. Siminovitch,et al.  The mDial Formin Is Required for Neutrophil Polarization, Migration, and Activation of the LARG/RhoA/ROCK Signaling Axis during Chemotaxis1 , 2009, The Journal of Immunology.

[52]  Min Zhao,et al.  Electrical signals control wound healing through phosphatidylinositol-3-OH kinase-γ and PTEN , 2006, Nature.

[53]  M. Dembo,et al.  Traction force microscopy of migrating normal and H-ras transformed 3T3 fibroblasts. , 2001, Biophysical journal.

[54]  Gaudenz Danuser,et al.  Coordination of Rho GTPase activities during cell protrusion , 2009, Nature.

[55]  Rafael Sirera,et al.  The Role of Tumor Stroma in Cancer Progression and Prognosis: Emphasis on Carcinoma-Associated Fibroblasts and Non-small Cell Lung Cancer , 2011, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[56]  A. Leask Potential Therapeutic Targets for Cardiac Fibrosis: TGF&bgr;, Angiotensin, Endothelin, CCN2, and PDGF, Partners in Fibroblast Activation , 2010, Circulation research.

[57]  Greg M. Allen,et al.  Article Electrophoresis of Cellular Membrane Components Creates the Directional Cue Guiding Keratocyte Galvanotaxis , 2022 .

[58]  K. Hahn,et al.  Localized Rac activation dynamics visualized in living cells. , 2000, Science.

[59]  Shawn M. Gomez,et al.  Arp2/3 Is Critical for Lamellipodia and Response to Extracellular Matrix Cues but Is Dispensable for Chemotaxis , 2012, Cell.

[60]  Jingsong Xu,et al.  Divergent Signals and Cytoskeletal Assemblies Regulate Self-Organizing Polarity in Neutrophils , 2003, Cell.

[61]  O. Weiner,et al.  Regulation of cell polarity during eukaryotic chemotaxis: the chemotactic compass. , 2002, Current opinion in cell biology.

[62]  Alexandra Jilkine,et al.  A Comparison of Mathematical Models for Polarization of Single Eukaryotic Cells in Response to Guided Cues , 2011, PLoS Comput. Biol..

[63]  A. Singer,et al.  Cutaneous wound healing. , 1999, The New England journal of medicine.

[64]  Miguel Vicente-Manzanares,et al.  Regulation of protrusion, adhesion dynamics, and polarity by myosins IIA and IIB in migrating cells , 2007, The Journal of cell biology.

[65]  Kenneth M. Yamada,et al.  Random versus directionally persistent cell migration , 2009, Nature Reviews Molecular Cell Biology.

[66]  A. Ham,et al.  VASP is a CXCR2-interacting protein that regulates CXCR2-mediated polarization and chemotaxis , 2009, Journal of Cell Science.

[67]  Richard Superfine,et al.  The Rho GEFs LARG and GEF-H1 regulate the mechanical response to force on integrins , 2011, Nature Cell Biology.

[68]  J. Bear,et al.  New insights into the regulation and cellular functions of the ARP2/3 complex , 2012, Nature Reviews Molecular Cell Biology.

[69]  B. Rubino,et al.  The role of epithelial-mesenchymal transition in cancer pathology. , 2007, Pathology.

[70]  Nadine Peyriéras,et al.  Inhibitory signalling to the Arp2/3 complex steers cell migration , 2013, Nature.

[71]  J. Haugh,et al.  PI3K-dependent cross-talk interactions converge with Ras as quantifiable inputs integrated by Erk , 2009, Molecular systems biology.

[72]  Anna Huttenlocher,et al.  Differential regulation of protrusion and polarity by PI3K during neutrophil motility in live zebrafish. , 2010, Developmental cell.

[73]  J. Bonner,et al.  EGF and PDGF receptor tyrosine kinases as therapeutic targets for chronic lung diseases. , 2006, Current molecular medicine.

[74]  Jason M. Haugh,et al.  Quantitative elucidation of a distinct spatial gradient-sensing mechanism in fibroblasts , 2005, The Journal of cell biology.

[75]  B. Kuhlman,et al.  A genetically-encoded photoactivatable Rac controls the motility of living cells , 2009, Nature.

[76]  Luke N. Olson,et al.  Oscillatory Behavior of Neutrophils under Opposing Chemoattractant Gradients Supports a Winner-Take-All Mechanism , 2014, PloS one.

[77]  Stephen W. Lewellis,et al.  Precise SDF1-mediated cell guidance is achieved through ligand clearance and microRNA-mediated decay , 2013, The Journal of cell biology.

[78]  P. Friedl,et al.  The Journal of Cell Biology , 2002 .

[79]  Mingming Wu,et al.  Dendritic cell chemotaxis in 3D under defined chemokine gradients reveals differential response to ligands CCL21 and CCL19 , 2011, Proceedings of the National Academy of Sciences.

[80]  Patricia J Keely,et al.  Mammary gland ECM remodeling, stiffness, and mechanosignaling in normal development and tumor progression. , 2011, Cold Spring Harbor perspectives in biology.

[81]  Dorit Hanein,et al.  The Arp2/3 complex is required for lamellipodia extension and directional fibroblast cell migration , 2012, The Journal of cell biology.

[82]  Olivier Pertz,et al.  Neutrophil polarization: spatiotemporal dynamics of RhoA activity support a self-organizing mechanism. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[83]  Z. Werb,et al.  The extracellular matrix: A dynamic niche in cancer progression , 2012, The Journal of cell biology.

[84]  M. Dembo,et al.  Cell movement is guided by the rigidity of the substrate. , 2000, Biophysical journal.