Biological Tissues as Active Materials J.F. Joanny Physico-Chimie - - PowerPoint PPT Presentation

Biological Tissues as Active Materials

J.F. Joanny

Physico-Chimie Curie Institut Curie

Les Houches school on Active Matter, Les Houches September 2018

Joanny (Institut Curie) Tissues TAU 1 / 48

Multicellular spheroids Intestinal epithelia Confluent monolayers

Epithelial tissues

Epithelial structure Dividing cells Differentiated cells Apoptotic cells Tissue mechanics Solid-like behavior Liquid-like behavior Viscoelastic liquid, relaxation time T Plastic behavior

Joanny (Institut Curie) Tissues TAU 3 / 48

Outline

1

Homeostatic state of tissues

Joanny (Institut Curie) Tissues TAU 4 / 48

Outline

1

Homeostatic state of tissues

2

Fluidization of tissues by cell division

Joanny (Institut Curie) Tissues TAU 4 / 48

Outline

1

Homeostatic state of tissues

2

Fluidization of tissues by cell division

3

Tissues as active liquids Defects in nematic tissue monolayers Spontaneous flow of tissues

Joanny (Institut Curie) Tissues TAU 4 / 48

Outline

1

Homeostatic state of tissues

2

Fluidization of tissues by cell division

3

Tissues as active liquids Defects in nematic tissue monolayers Spontaneous flow of tissues

4

Muticellular spheroids

Joanny (Institut Curie) Tissues TAU 4 / 48

Outline

1

Homeostatic state of tissues

2

Fluidization of tissues by cell division

3

Tissues as active liquids Defects in nematic tissue monolayers Spontaneous flow of tissues

4

Muticellular spheroids

5

Epithelial tissues, Intestine Vertex models of epithelial layers Intestine

Joanny (Institut Curie) Tissues TAU 4 / 48

Outline

1

Homeostatic state of tissues

2

Fluidization of tissues by cell division

3

Tissues as active liquids Defects in nematic tissue monolayers Spontaneous flow of tissues

4

Muticellular spheroids

5

Epithelial tissues, Intestine Vertex models of epithelial layers Intestine

Joanny (Institut Curie) Tissues TAU 5 / 48

Homeostatic Pressure Basan

Permeable compartments Fluctuations due to cell divisions

Joanny (Institut Curie) Tissues TAU 6 / 48

Possible measurements of homeostatic pressure F.Montel,

• D. Vijgnevic

Tissue growth inside an agarose gel Helmlinger et al. Pressure ∼ 104Pa

Joanny (Institut Curie) Tissues TAU 7 / 48

Possible measurements of homeostatic pressure F.Montel,

• D. Vijgnevic

Tissue growth inside an agarose gel Helmlinger et al. Pressure ∼ 104Pa Semi-permeable membrane (dialysis bags) Cabane Tissue spheroids in micropipettes Guevorkian,Brochard PAA beads as microsensors G.Cappello et al.

Joanny (Institut Curie) Tissues TAU 7 / 48

Possible measurements of homeostatic pressure F.Montel,

• D. Vijgnevic

Tissue growth inside an agarose gel Helmlinger et al. Pressure ∼ 104Pa Semi-permeable membrane (dialysis bags) Cabane Tissue spheroids in micropipettes Guevorkian,Brochard PAA beads as microsensors G.Cappello et al. 2-dimensional tissues Silberzan Stress measurement in a tissue O. Campas et al.

Joanny (Institut Curie) Tissues TAU 7 / 48

Cell proliferation and stress Cheng et al.

Joanny (Institut Curie) Tissues TAU 8 / 48

Possible measurements of homeostatic pressure F.Montel,

• D. Vijgnevic

Tissue growth inside an agarose gel Helmlinger et al. Pressure ∼ 104Pa Semi-permeable membrane (dialysis bags) Cabane Tissue spheroids in micropipettes Guevorkian,Brochard PAA beads as microsensors G.Cappello et al.

Joanny (Institut Curie) Tissues TAU 9 / 48

PAA microsensors

Joanny (Institut Curie) Tissues TAU 10 / 48

Possible measurements of homeostatic pressure F.Montel,

• D. Vijgnevic

Tissue growth inside an agarose gel Helmlinger et al. Pressure ∼ 104Pa Semi-permeable membrane (dialysis bags) Cabane Tissue spheroids in micropipettes Guevorkian,Brochard PAA beads as microsensors G.Cappello et al. 2-dimensional tissues Silberzan Stress measurement in a tissue O. Campas et al.

Joanny (Institut Curie) Tissues TAU 11 / 48

Oils droplets

Epithelial and mesenchymal cell

Joanny (Institut Curie) Tissues TAU 12 / 48

Tissue Competition and sorting

Joanny (Institut Curie) Tissues TAU 13 / 48

Outline

1

Homeostatic state of tissues

2

Fluidization of tissues by cell division

3

Tissues as active liquids Defects in nematic tissue monolayers Spontaneous flow of tissues

4

Muticellular spheroids

5

Epithelial tissues, Intestine Vertex models of epithelial layers Intestine

Joanny (Institut Curie) Tissues TAU 14 / 48

Coupling between stress and cell division

Cell division coupled to stress Fink, Cuvelier Fink, Cuvelier

Joanny (Institut Curie) Tissues TAU 15 / 48

Cell diffusion

Cell diffusion in an aggregate Division and apoptosis noise Cell conservation law dρ

dt = ρ(kd − ka)(ρ) − ρvγγ + ξ(t)

Correlation ξ(r, t)ξ(r′, t′) = (ka + kd)ρδ(t − t′)δ(r − r′) Diffusion constant proportional to kd if K/pρ ≫ 1

Joanny (Institut Curie) Tissues TAU 16 / 48

Epiboly J. Ranft, T. Risler

CP Heisenberg et al.

Joanny (Institut Curie) Tissues TAU 17 / 48

Tissue simulations J. Elgeti, M. Basan

Joanny (Institut Curie) Tissues TAU 18 / 48

Outline

1

Homeostatic state of tissues

2

Fluidization of tissues by cell division

3

Tissues as active liquids Defects in nematic tissue monolayers Spontaneous flow of tissues

4

Muticellular spheroids

5

Epithelial tissues, Intestine Vertex models of epithelial layers Intestine

Joanny (Institut Curie) Tissues TAU 19 / 48

Confluent elongated cells G. Duclos, P. Silberzan

Nematic order of Spindle shaped cells Spindle-shaped cells: NIH 3T3, RPE1, C2 C12 Elongated cells show nematic order: head-tail symmetry Different defects expected for polar and nematic cells Spontaneous cell flow due to activity Defect motion

Joanny (Institut Curie) Tissues TAU 20 / 48

Defect motion in cell monolayers

Only +1/2 and −1/2 defects Spontaneous motions of +1/2 defects −1/2 defects do not move Annihilation between +1/2 and −1/2 defects

Joanny (Institut Curie) Tissues TAU 21 / 48

Cell Monolayers confined to a disk

Defect relaxation Tangential boundary condition Relaxation to two +1/2 defects Activity negligible

Joanny (Institut Curie) Tissues TAU 22 / 48

Cell orientation in a confined disk C. Erlenkamper

Free energy minimization 2 defects in a passive nematic

• disk. Ignore activity

Minimize elastic energy with two defects at a radius r0 F =

• dxK

2 (∇θ)2 Minimum of the free energy r0 = 0, 67R Excellent agreement with experiment Effective temperature independent

• f R

Joanny (Institut Curie) Tissues TAU 23 / 48

Spontaneous tissue flow G. Duclos, V. Yashunsky, P. Silberzan

Experiment Stripe width 50µm to 800µm Cell orientation PIV Velocity and cell orientation

Joanny (Institut Curie) Tissues TAU 24 / 48

Active gel theory C. Blanch-Mercader

Spontaneous flow Fredericks transition Theoretical developments Substrate friction: screening length λ = (η/ξ)1/2 Transverse flow related to cell division Chiral effects

Joanny (Institut Curie) Tissues TAU 25 / 48

Outline

1

Homeostatic state of tissues

2

Fluidization of tissues by cell division

3

Tissues as active liquids Defects in nematic tissue monolayers Spontaneous flow of tissues

4

Muticellular spheroids

5

Epithelial tissues, Intestine Vertex models of epithelial layers Intestine

Joanny (Institut Curie) Tissues TAU 26 / 48

Interfacial tension of a tissue

Relaxation measurements Steinberg et al.,

• F. Montel

Relaxation measurements Steinberg et al. Neural Retina relaxation Liquid description Typical relaxation time τa ∼ 100s small compared to division rates Liquid limit ˜ σαβ = 2η˜ vαβ Viscosity η = Eτa, Modulus E ∼ 1000 Pa

Joanny (Institut Curie) Tissues TAU 27 / 48

Cortical tension

Optical Imaging Charras Actomyosin layer Polymerization from the surface (formins) Treadmilling time ∼ 30s Cortex tension Electron microscopy Medalia Dense actin layer Thickness ∼ 1µm Filaments parallel to the cell surface

Joanny (Institut Curie) Tissues TAU 28 / 48

Metastatic Inefficiency

5 10 15 20 25 30 0.02 0.04 0.06 0.08 0.1 0.12 0.14

5 10 15 20

Critical Cell Number Probability

Probability Time [d] n

c3 20 40 60 80 100 120 10 50 90 130 170 210 250 290 330 370 More

Size Interval Number of Tumors n

c1

t 1

d 0.08 0.06 0.04 0.02

t 1 4

d

Joanny (Institut Curie) Tissues TAU 29 / 48

Spheroid growth

F .Montel, M.Delarue Growth experiments Indirect experiments

◮ Dialysis bag ◮ Pressure exerted by dextran

Direct experiments

◮ Spheroid in contact with dextran

solutions

◮ No penetration of dextran in

spheroid

Joanny (Institut Curie) Tissues TAU 30 / 48

Surface growth

Pressure dependence ∂tV = (kd − ka)V + 4π( 3 4π )

2/3

δksλV 2/3 Nutrient effect Elgeti

Joanny (Institut Curie) Tissues TAU 31 / 48

Cell flow

Injection of fluorescent nano-particles Incompressible fluid Velocity field ∇ · v = k(r)

Joanny (Institut Curie) Tissues TAU 32 / 48

Particle distribution

Transport by cell flow ∂tρ + ∇ vρ = 0 Negligible diffusion Density ρ(r, t) = ρ0(˜ r, 0) e−(k+δk)t if r > R − λ ˜ r 3 = e−(k+δk)t r 3 + t

0 δk(R(t′) − λ)3 e−(k+δk)t′ dt′

Joanny (Institut Curie) Tissues TAU 33 / 48

Volume change after a pressure step

Growing spheroid with no applied pressure Pressure step 5000 Pa after 4 days Volume and anisotropy from correlations between nuclei position

Joanny (Institut Curie) Tissues TAU 34 / 48

Active hydrodynamics of tissues

Radially polarized cell cells Active gel hydrodynamics with active stress depending on pressure Power law decay of density δn

n = ∆P(3+βe) 3K

• r

R0

βe βe = −0.6

Joanny (Institut Curie) Tissues TAU 35 / 48

Volume decrease and cell division

Decrease in cell division rate, no change in apoptosis

◮ Decrease in cell diameter at

center after 5 min.

◮ P27 Overexpression after 1 day ◮ Decrease in cell division after 4

days

◮ Cell proliferation arrest in G1

phase

◮ Joanny (Institut Curie) Tissues TAU 36 / 48

Interaction spheroid-macrophages P. Benaroch, J. Nikolic

Multicomponent spheroid M. Benamar, J. Ackermann Cancer Immunotherapy Cancer cells, Interstitial fluid and extracellular matrix, Dead cells

Joanny (Institut Curie) Tissues TAU 37 / 48

Heterogeneous spheroid

Spinodal decomposition Interacting components, effective free energy for two components Include cell division Unstable composition inside the spheroid 3 component systems; non dividing macrophages

Joanny (Institut Curie) Tissues TAU 38 / 48

Outline

1

Homeostatic state of tissues

2

Fluidization of tissues by cell division

3

Tissues as active liquids Defects in nematic tissue monolayers Spontaneous flow of tissues

4

Muticellular spheroids

5

Epithelial tissues, Intestine Vertex models of epithelial layers Intestine

Joanny (Institut Curie) Tissues TAU 39 / 48

Epithelial monolayers

Epithelia are protective layers lining organs Can be multilayers or monolayers of cells Tight junctions between cells 80% of cancers originate in epithelia (carcinoma) Cell Shape in monolayered epithelia Columnar epithelium; intestine Squamous epithelium: lung Cuboidal epithelium: kidney tubules Intermediate structures : pseudo-stratified epithelium

Joanny (Institut Curie) Tissues TAU 40 / 48

Vertex model of Epithelia Jülicher et al.

Joanny (Institut Curie) Tissues TAU 41 / 48

Joanny (Institut Curie) Tissues TAU 42 / 48

3-dimensional vertex model of epithelial tissue layers

Tissue monolayers Phase diagram

Joanny (Institut Curie) Tissues TAU 43 / 48

Crypts and Villi

Joanny (Institut Curie) Tissues TAU 44 / 48

Intestine and Colon

Small intestine: Weak coupling to curvature Colon: Strong coupling to curvature

Joanny (Institut Curie) Tissues TAU 45 / 48

Diagram of villi structures

Transition between structures

Joanny (Institut Curie) Tissues TAU 46 / 48

Compartment formation in crypts

Dynamics of crypts Stokes equation η∇2v − ∇Π − ζv = 0 Kinetics of cell differentiation and division ∂S ∂t + ∇(Sv) = kS − kdS Stem cell localization at bottom of crypts kdx = kx

Joanny (Institut Curie) Tissues TAU 47 / 48

Organoids Clevers

Joanny (Institut Curie) Tissues TAU 48 / 48