Guided Cell Migration: A Dynamical Systems Perspective. Wolfgang Losert. Department of Physics, University of Maryland

Transcription

1 Guided Cell Migration: A Dynamical Systems Perspective Wolfgang Losert Department of Physics, University of Maryland

2 Guided Cell Migration is Essential for Living Systems Phil Keller, Janelia Farm Development Parent Nature 2013 Immunity Weiger, M., et al. (2013). PLoS ONE Alberts, B. et al. ( 2002) Wound Healing Cancer Metastasis

3 Cell Migration during Cancer Metastasis Friedl Intravital (2012). Alexander et al. (2008) Histochemistry and Cell Biology

4 Cells Move in Context Physical Environment Guides Migration Friedl Intravital (2012). Bozec et al, Biophysical Journal (2007) Collagen Fibrils: Nanoscale Ropes Colagen Fibers visible Friedl Intravital (2012).

5 Flat Texture Sensing in Epithelial Cells Ridges ~1mm

6 How General is Texture Sensing? Measuring across Phyla 1) Epithelial Migration 2) Amoeboid Migration: Neutrophils and Dictyostelium discoideum

7 Focal Adhesions Migration Mode Typical Cell Size Typical Speed Guided by Ridges Dicty Neutrophils Epithelial Cells Amoeboid Amoeboid Epithelial ~10 µm ~10 µm ~30 µm 10 µm/min 5 µm/min 0.5 µm/min How do cells sense their surrounding on scales of ~100s of nm (much larger than proteins)?

8 The Actin Cytoskeleton is an Excitable System: Waves on 100s of nm Scale Joshua Parker Scaffolding nucleates, grows, and dissolves Joshua Parker Dayel.com Simulations of Actin Waves w/ Anders Carlsson (WashU) Bretschneider, et al 2009

9 Individual Cells Exhibit Actin Waves Boundary Position (a.u.) Lifeact-RFP Labeled High Intensity Low Intensity Back Time (min) 10 μm Front Driscoll et al (2012)

10 Texture Sensing via Actin Waves 5 mm M. Driscoll et al, ACS Nano (2014)

11 Optimal Ridge Spacing for Texture Sensing Fit to Circular Normal Distribution Stochastically driven damped harmonic oscillator? Angle (Radians) Can Guven P a'v 0 a'l 1 L ' (L 0 ') 2 M. Driscoll et al, ACS Nano (2014)

12 HL-60 labeled with actin-yfp

13 Epithelial Cells: Texture Sensing via Actin Waves

14 Exploiting the Biology of Texture Sensing: Cell Differentiation Human bone marrow stem cells change shapes on fiber surfaces (FS) and preferentially differentiate into bone cells on FS. FLAT Surface Kumar et al, Biomaterials (2012) Chen et al, Biomaterials (2016)

15 Exploiting the Physics of Texture Sensing: Asymmetric Textures for Unidirectional Guidance Chemotaxis : Chemical gradient Global gradient Direction of cell migration μm Contact guidance: Physical gradient Local subcellular gradient 3 μm

16 Cells Conform to & Prefer to Migrate Up Sawteeth 3 μm 3 μm ESOTAXIS 20 μm Preferred direction of cell migration Sun, X., et. al. PNAS, 2015

17 Sawteeth refract the Actin Waves Dictyostelium Neutrophils Xiaoyu Sun Meghan Driscoll ESOTAXIS

18 Biased actin polymerization 8 μm Actin Waves in Neutrophils propagate up the slope persistently on 8-μm sawteeth 4 μm 4 μm Time (min) Sun, X., et. al. PNAS,(2015)

19 Probability Cell motion is unidirectionally guided on sawteeth Direction of guidance, 8- μm sawteeth Counts Speed (μm/min) Angle (with respect to the sawteeth)

20 The preferred direction depends on topography 3 μm 3 μm

21 Sensing Texture AND Touching Cells Friedl Intravital (2012).

22 Studying the Sense of Touch in a Model Organism Dictyostelium discoideum Stream 100 μm μm F-actin Labeled C. Wang, et al, Interface (2014)

23 Shape Waves Couple Cell-to-Cell C. Wang et al, Interface, (2014)

24 Motion Inside Streams Cells Migrating for 90 Minutes 300 mm McCann et al, JCS (2011)

25 Boundary Position (a.u.) Leader Cells Exhibit Actin Waves Lifeact-RFP Labeled High Intensity 300 Back Low Intensity 5 μm Front Time (min)

26 Boundary Position (a.u.) Actin Waves are Suppressed in Streaming Cells Lifeact-RFP Labeled A Cell Migrating in Stream High Intensity μm Back Front Time (min) 5 Low Intensity

27 Collective Migration for Epithelial Cells

28 Effects on Collective Cell Migration Simulations: Haicen Yue, Wouter Rappel UCSD Lee R, et al.interface (2017)

29 Changing Coupling of Motility to Velocity of Neighbors Alters Collective Behavior Experiment Simulation Lee R, et al.interface (2017)

30 Summary - Physical Guidance of Cell Migration Guidance via surface topography ESOTAXIS - Dynamic Texture Sensing: Bioinspired textures nucleate and guide actin waves and cell migration in amoeboid and epithelial cells. Consequences of Esotaxis: Unidirectional Motion through Asymmetric Texture Guidance via contact with other cells Cell-cell contact can suppress waves and lead to steady polymerization -> accurate cell-cell guidance Coupling of Motility to motion of neighbors alters large scale collective behavior

31 Cell Acrobatics Team POSITION AVAILABLE Xiaoyu Sun Rachel Lee Matt Hourwitz Sebastian Schmidt Former Students Meghan Driscoll (UT Southwestern) Can Guven (Intel) Chenlu Wang Ava Omidvar PI: Wolfgang Losert Collaborators Carole Parent Anders Carlsson Peter Friedl Roberto Weigert John Fourkas