Tensegrity-Based Mechanical Control of Mammalian Cell Fate Switching and Morphogenesis by Ingber
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Transcript of Tensegrity-Based Mechanical Control of Mammalian Cell Fate Switching and Morphogenesis by Ingber
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Don Ingber, M.D.,Ph.D.Judah Folkman Professor of Vascular BiologyDepts. of Pathology & Surgery, Harvard Medical School
Interim Co-Director, Vascular Biology Program, Childrens Hospital Boston
Interim Co-Director, Harvard Institute for Biologically Inspired Engineering
Tensegrity-Based Mechanical Control ofMammalian Cell Fate Switching and Morphogenesis
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How are living cellsand tissues constructed?
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A Linear View of Tissue Development(Tumor Angiogenesis)
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Local Control during Angiogenesis
Branching Patterns
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Extracellular Matrix
Cells Exert Tension on their Matrix Adhesions
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MicromechanicalControl of Morphogenesis
Underlying Hypothesis:
ECM remodeling changes LOCAL MECHANICS
Increasing ECM flexibility promotes cell stretching
Tension on adhesion receptors &
distortion of the cytoskeleton
alters cellular biochemistry
Localized Growth & Motility(Ingber et al., PNAS78:3901-5, 1981; Ingber & Jamieson, In: Gene Expression During
Normal & Malig. Differ. ,1985; Huang and Ingber, Nature Cell Biol. ,1999)
Cell Stretching
Cell Stretching
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Making Cell Distortion an Independent Variable
GFGF
GF
GF
GF
GF
GFGF
GF
GF
GF
GF
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(with George Whitesides, Chemistry Dept. Harvard U.)
Nanotechnology-Based Microfabrication(Soft Lithography + Self Assembling Monolayers)
PDMS(polydimethyl-siloxane)
Photoresist
Adhesive alkanethiol(methyl-terminated)
NON-adhesive alkanethiol(PEG-terminated)
Silicon
Mask
ECM protein
SUPPORTSAdsorption
RESISTS Protein Adsorption
Au Silicon, Glass
=Stamp
+ ECM Protein
(Singhvi et al., Science1994; Chen et al. Science1997;Chen et al. Methods Mol. Biol. 2000;139: 209-219)
UV
MolecularSelf-Assembly
FlexiblePDMS Stamp
SAM
on the NANOSCALE
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Stretching Cells Makes Them Grow
And Rounded Cells Die
Growth
Cell Distortion
CellF
unctio
n
Death Growth
(Singhvi et al. Science1994; Chen et al. Science1997)
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Capillary Blood Vessel Formation In A Dish
(Dike et al. In Vitro Cell Dev Biol 1999)
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(Parker et al. FASEB J 2002)
Stretch-Dependent Control of Directional Motility
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Actin Stress Fibers(AFM) (F-Actin)
FibronectinFibrils
Focal Adhesions(Vinculin)
Cell Distortion Redirects Molecular Self-AssemblyIn the Cytoskeleton & Extracellular Matrix
(Parker et al. FASEB J2002; Wang et al., Cell Cytosk. Motil. 2002; Brock et al. Langmuir 2003)
TRACTION FORCE MICROSCOPY:
Cell Morphology Stress Map
Guided by Localized Tension Application in Cell Corners
Strain Map
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100um
Physical ECM Pattern Governs Directional Motility
1C-3,3 3L-3,3 8L-3,3
+ PDGF (NO CHEMICAL GRADIENT!) (Xia et al., FASEB J2008)
Migration Paths:
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(Brangwynne et al. In Vitro Cell Dev Biol2000;Huang et al., Cell Cytosk Motil2005)
Local Rules & Physical Determinants
Govern Pattern Formation
(Symmetry Breaking in Mammalian Cells)
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(Huang et al., Cell Motil. Cytosk. 2005)
Patterning Predicted by Whole CellBehaviors
Experimental Results Computational Model
Fibroblast (Low Persistence - No Yin Yang)
Capillary Endothelial Cell (High Persistence - Yin Yang)
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Solublegrowth factors
Morphogenesis
Wound Healing
Spatial heterogeneity ofcell fates drives morphogenesis
die differentiatedivide
Cell Fate Switching Depends on Physicality of Microenvironment
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How are Cells Constructed so that they can Sense Force?
Hypothesis:
Cells are Built Like Tents
Old View:
Cells are like Water Balloons
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he Molecular Networksof the Cytoskeleton
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(Ingber et al., PNAS78:3901-5, 1981; Ingber & Jamieson,1985;
Wang et al. Science1993, PNAS2001; Ingber J. Cell Sci1993, 2003)
Cellular Tensegrity Model
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Resting Tension (Prestress) in Living Stress FibersRevealed using Laser Nano-Surgery (tensed cables)
(Kumar et al., Biophys J. 2006)
300 nm
Retraction of a single actinstress fiber in a living cell
(with Eric Mazur, Dept. Physics, Harvard U.)
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Mechanical Continuity in the Cytoskeleton and ECM
RigidDish
Flexible ECM Substrate
T ECM
(Kumar et al, Biophys J 2006)
GFP-Actin
Before Cut: GreenAfter Cut: Magenta
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Microtubules are Semi- Flexible Compression Struts
Curved (Buckled) Microtubules in a Fixed Cell
Live Beating Heart Cell
(Brangwynne et al, J Cell Biol 2006 with
D. Weitz & K. Parker, Harvard U. & F.
Macintosh, Amsterdam)
Constrained BucklingTheory
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Tensegrity predictsAdhesion Receptors
act as Mechanoreceptors
(Ingber and Jamieson, 1985;
Ingber, Curr Opin Cell Biol 1991)
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Magnetic Twisting & Pulling
Cytometry
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D. Stamenovic (Boston U.)A PrioriPredictions now Confirmed:
Stamenovic et al. J. Theor. Biol.1996Coughlin & Stamenovic, J App Mech 1997,1998Stamenovic & Coughlin, J Theor Biol. 1999Stamenovic & Coughlin, J. Biomech. Engin. 2000
Wang & Stamenovic, Am J. Physiol Cell Physiol. 2000Stamenovic,J. Biomech.,2005.
Linear relation between Stiffness and AppliedStress(Wang et al., Science 1993; Wang and Ingber, Biophys. J. 1994))
Cell Mechanics depends on Prestress(Wang & Ingber, Biophys. J. 1994; Lee et al., Am. J.Physiol. 1997)
Linear relation between Stiffness and Prestress(Wang et al., PNAS 2001; Wang & Stamenovic, Am. J. Physiol 2002)
Hysteresivity independent of prestress(Maksym et al.,Am. J. Phys. 2000;Wang et al., PNAS 2001)
Quantitative Prediction of Cellular Elasticity(Stamenovic and Coughlin, J. Biomech. Engineer. 2000)
Prediction of Dynamic Mechanical Behavior(Sultan et al., Ann Biomed Engin. 2004)
Mechanical Contribution of Intermediate Filaments toCell Mechanics(Wang and Stamenovic, Am J Physiol Cell Physiol, 2000)
Microtubules Bear Compression(Keach et al., 1996; Wang et al., 2001; Hu et al., Bioscience, 2004;Brangwynne et al., J Cell Biol 2006)
Mathematical Tensegrity Model of the Cell
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Hierarchical Tensegrity Model(Cell & Nucleus Connected by Tension Elements)
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(Wang et al. PNAS2001)
A local stress can produce DISTANT responses
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Intermediate Filaments are Suspensory Cables
Link other filaments& membrane to thenucleus
From Nickerson and Penman
From R. Goldman
(Maniotis et al. PNAS 1997; Eckes et al. JCS1998)
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Mechanical Control of the Mitotic Spindle Axis
(Maniotis et al., PNAS 1997)
Spindle Axis:
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Tensed Spectrin
Stiff Actin Protofilament
Cortical Membrane as a Prestressed Tensegrity(Vera et al. Annals Biomed. Engin. 2005; with Bob Skelton, UCSD)
www.jacobsschool.ucsd.edu/news_events/releases/release.sfe?id=484
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TE
Tensegrity-Based Hierarchical Integration(computer images by Eddy Xuan, U. Toronto)
(Ingber, FASEB J2006)
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Tensegrity Focuses Force on Molecules in theExtracellular Matrix and Cytoskeleton
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-Cytoskeleton is More than a Mechanical Scaffold
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1 2 3
AB
C
Solid-State Biochemistry on Cytoskeletal Scaffolds(Structure = Catalyst)
4
Cytoskeletal filament
Channeling of Chemical Reactions:DNA replicationRNA ProcessingTranscriptionTranslationGlycolysisSignalTransduction
(Ingber, Cell1993)
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Pulling on IntegrinsActivates Signaling &Gene Transcription
Surface Integrins Mediate
Mechano-Chemical Transduction
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Pulling on Integrins Specifically Activates Ca+2 Influx(Time scale < 10 milliseconds) [Funded by DARPA & NIH]
MagneticPulses
Force Dependence Force & Integrin Dependence
(Matthews et al., in review)
0
0.025
0.05
0.075
0.1
RGD
AcLDL
HDL
RGD+Gd3+
C
alcium(
F/Fo)
Force (pN)
100 450 850 2000
Cytoskeletal Strain Calcium (FLUO4)
BEAD
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Activation of G proteins and cAMP Signaling by Mechanical ForceTransmitted Across Integrin Receptors
Gene Transcription
Mechanical Control of Gene Transcription
cAMP LevelsPKA Translocation
CREB Activation
+ TWIST
(Meyer et al., Nature Cell Biol. 2000)
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Focal Adhesion is a Nanoscale Mechanochemical Machine
Stress
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Mechanochemical Transduction
Alter CSK Organization
Cellular Tensegrity Model
Tensegrity provides a mechanism to INTEGRATEboth LOCAL and DISTANT structural responses
when forces are transmittedthrough the cytoskeleton
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Signal Integration through Cell Distortion:Cells Act Locally, but Think Globally
Growth
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The Small GTPase Rho Mediates Shape Control of Growth
TENSION
Rho
ROCK
(Huang et al., Mol. Biol. Cell, 1998; Huang & Ingber, Exp Cell Res. 2002; Numaguchi et al.,
Angiogenesis 2003; Mammoto et al., J. Biol. Chem. 2004;Mammoto et al., J. Cell Sci. 2007)
Filaminp190RhoGAP
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MicromechanicalControl of Morphogenesis
Underlying Hypothesis:
ECM remodeling changes LOCAL MECHANICS
Increasing ECM flexibility promotes cell stretching
Tension on adhesion receptors &
distortion of the cytoskeletonalters cellular biochemistry
Localized Growth & Motility(Ingber et al., PNAS78:3901-5, 1981; Ingber & Jamieson, In: Gene Expression DuringNormal & Malig. Differ. ,1985; Huang and Ingber, Nature Cell Biol. ,1999)
Cell Stretching
Cell Stretching
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CNF-1
(200 ng/ml)
Control
CNF-1(2-20 ng/ml)
Time (hrs): 0 48
0
20
40
60
80
100
120
140
160
180
200
0 2 20 200
%BudIncrease
CNF-1 (ng/ml)
Bud Inducing Activity
Developmental Control Requires a Fine Balance of Forces
Tension
Tension
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c
mc
c
ce
c
mc
c
ce
Control CNF-1 (20 ng/ml) Y27632 (40 uM)
Epitheliogenesis & Angiogenesis in Embryonic Lungcan be Controlled by Altering Cytoskeletal Tension
(Moore et al, Dev. Dynamics2005)
TENSION TENSION
Epi
Epi
Epi
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Extracellular Matrix & Cytoskeleton not just structural supportsthey also are KEY DEVELOPMENTAL REGULATORS
Because they mediate MECHANICAL SIGNALING
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GRB
Sos
Ras
c-raf
MEK1/2
MAPK(erk1/2)
MEKK1
NFkB
Sek1(MKK4)
SAPK=JNK
ATF2
CREB
Rac
CaMKII
MKK3/6
p38=HOG
Akt
PIP3
p70S6
PLC
mycElk
IKK
FAK
src
Rho
Cdc42
PAK
IkB
Shc
p90rsk
JunFos
Stat3
Ca2+
Bad
MLC
G
FRAP
PDK
Rap1
Jak1
Stat1
Jak2
Bcl-2
caspase 9
caspase 2
FADD
caspase 8
mitochodrialcyt C release
PKC
PKA
Apaf-1
PTEN
TCF
APC
-catenin
TCF-Lef
PI3K
RAIDD
NIK
TRAF
TAK1Smad2
Smad4
Smad7
cyclin E
cyclin DpRb E2F
p27cdk4,6
cdk2
-catenin
a-actinin
cyclin A
INKp21
caspase 3,6,7
Extracellular signals
IRS-1Pyk2 cAMP
B-Raf
But Where is the Specificity? [SOFTWARE Challenge]
growthapoptosis
differentiationmotility
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Cell Distortion
Apoptosis Differentiation Growth
Cell Fate Switching: A Biological Phase Transition
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C
Stable Functional States Emerge from Dynamic Information Networks(work from Complexity Field by Stuart Kauffman)
A B
C D 2 4 = 16
A B
D
A B
C D
mini DNA chip
If genes were independent:
All expression configurations
are equally possible.
A B
C D
If genes are interacting via Logic F(x)s:
A B
C DA B
C D
Stable
Attractor
state
Regulatory interactions CONSTRAIN paths!
A B
C D
A B
C D
Attractor
stateBasin of attraction
Gene activity State Space (for 6-gene network):
C
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Boolean Network of Cell Cycle Control
(Huang & Ingber,
Exp Cell Res 2000)
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HELA Cell Cycle(data from Whitfield et al., Mol. Biol. Cell2002)
Simultaneous Dynamic Analysis of Whole Gene Arraywith Genome Expression Dynamics Inspector (GEDI)
(Eichler, Huang & Ingber, Bioinformatics2003)
Available at: www.childrenshospital.org/research/ingber/
Existing Method:
Time 1
Time 2
Time 3
New Method:
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Dictyostelium Development(data from Van Driessche et al., Development2002)
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Evidence that Cell Fates are High Dimensional Attractors
Precursor
(HL60)
Differentiated
neutrophil
HL60 cells =Promyelocytic
Precursor (Stem)
Cells
Neutrophil Differentiation was induced by:
1. all-trans Retinoic Acid (AtRA)[SPECIFIC HORMONE]
2. Dimethyl Sulfoxide (DMSO)[NON-SPECIFIC SOLVENT]
(Huang et al., Phys Rev Lett2005; Chang et al. BMC Bioinform 2006)
(work of Sui Huang and Hannah Chang)
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Cell Fates are High Dimensional Attractors
Precursor
(HL60)
Differentiated
neutrophil
Initial divergence and
terminal convergence of thetwo trajectories in > 70%
(2773 genes) of the state
space dimensions
< D >
c
0 20 40 60 80 100 120 140 1600.6
0.7
0.8
0.9
1
1.1
1.2
1.3
mean of intertrajectory
gene expression differences, < D
>
Time (hr)
GEDI Analysis:
-50 -40 -30 -20 -10 0 10 20 30 40 50-50
-40
-30
-20
-10
0
10
20
30
40
PC1
PC2
0h
8h
24h
168h
24h
8h
PCA Analysis:
(Huan et al. Ph s Rev Lett2005 Chan et al. BMC Bioinform 2006)
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Dynamic Networks: Simplicity in Complexity
GRBSos
Ras
c-raf
MEK1/2
MAPK(erk1/2)
MEKK1
NFkB
Sek1(MKK4)
SAPK=JNK
ATF2
cAMP
PKA
CREB
rac
CaMKII
MKK3/6
p38=HOG
Akt
PI3K
p70S6
PLCg
c-mycElk
IKK
FAKsrc
rhocdc42
PAK
IkB
Shc
p90rsk
JunFos
PKC
Stat3
Ca2+
Pyk2
Bad
MLC
G
FRAP(TOR)PDK
rap
RafB
Jak1TykStat1
Jak2
1 CYTOKINE activates > 100 of genes
FGF-R PDGF-R
g e n o m e
2 different GF RECEPTORS activatesame set of 60 genes to induce growth
(Fambrough et al., 1999)
(Waddington, 1956)
SPECIFIC & NON-SPECIFIC STIMULI
produce same cell FATE switches
Cell Distortion
Apoptosis Differen. Growth
MUTUAL EXCLUSIVITY
of cell fates in Embryogenesis
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Solublegrowth factors
Micromechanics and Collective Behavior
Govern Pattern Formation
Morphogenesis
Wound Healing
Spatial heterogeneity ofcell fates drives morphogenesis
die differentiatedivide
Cell fate switching depends on physicality of microenvironment
Normal Fractal Patterns TumorDisorganization
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Biomimetic Multicellular Robot Swarms(Radhika Nagpal, SEAS; D. Ingber, HMS)[NSF Funded]
Bioinspired Algorithms for robust and complex
shape formation using modular (multicellular) robots
Distributed Homeostasis Desired shape is described relative to the environment
Individual robots use local sensing to adapt their behavior
Inspired by homeostasis in biology and tissue remodeling
in response to environment needs
(Yu et al., IEEE Intl. Conf. on Intelligent Robots and Systems 2007)
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Sui Huang (U. Calgary)
Ning Wang (U. Illinois)
Dimitrije Stamenovic (BU)
George Whitesides (HU)
Eric Mazur (HU)
David Weitz (HU)
Radhika Nagpal (HU)
David Mooney (HU) HIBIE Interim Co-Director
Ingber Lab (Harvard/CH)Francis Alenghat (resident BWH)
Cliff Brangwynne (grad. stud. HU)
Amy BrockHannah Chang
Chris Chen (U. Penn)
Sanjay Kumar (U.C. Berkeley)Tanmay Lele (U. Florida)
Akiko Mammoto
Bob MannixBen Matthews
Chris Meyer (Dental Practice)
Martin MontoyaDarryl Overby (Tulane)
Kevin Kit Parker (Harvard)
Jay PendseTom Polte
Julia Sero
Charles ThodetiWEBSITE:Google search Ingber Lab