Yeh-Chuin Poh Department of Mechanical Science and Engineering 5 th May 2011
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Yeh-Chuin Poh Department of Mechanical Science and Engineering5th May 2011
Mechanical Force Effects on Cellular Functions
May 2011
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Introduction
2May 2011
What is “mechanotransduction”?
The process and mechanisms by which living cells sense mechanical forces and convert them into biochemical signals.
-S. Na et al, Science Signaling 2008
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Introduction: Forces are Important in Living Cells
3May 2011
Forces play a major role in biological functions like:Cell spreadingCell migration (wound healing)Cell contractionCell division
Regulates cell functionsGene expressionProtein synthesisCell proliferation
Ingber, Nat. Rev. Mol. Cell. Biol., 2005
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Cells Respond to External Mechanical Stimuli
4May 2011
Wu, CC et al., PNAS, 2007
Katsumi, A et al., JCB, 2002Kurpinski, K et al., PNAS, 2006
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Cells Respond to External Mechanical Stimuli
5May 2011
Hahn and Schwartz, Nat Rev Mol Cell Bio 2009
Discher et al, Science Rev 2009
Discher et al, Science 2005
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Force Unfolding of Proteins and Opening of Ion Channels Within Cells
6May 2011
C Johnson et al., Science, 2009
-spectrin undergoes force induced structure change exposing binding sites for ligands.
Mechanosensitive ion channels
Vogel & Sheetz, Nat Rev Mol Cell Biol, 2006
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Stress Induced Src Activation is Rapid
7May 2011
0 1 2 3
1.0
1.1
1.2
+EGF
No
rmal
ized
em
issi
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rat
io
Time (s)
+
0 3 100 200 3001.0
1.2
1.4
EGF
No
rmal
ized
emis
sio
n r
atio
Time (s)
12 s 20 s
+Stress
+EGF
0 1 2 3
1.0
1.1
1.2
+EGF
No
rmal
ized
em
issi
on
rat
io
Time (s)
+
0 3 100 200 3001.0
1.2
1.4
EGF
No
rmal
ized
emis
sio
n r
atio
Time (s)
12 s 20 s
+Stress
+EGF
S Na et al., PNAS, 2008
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Rac Signaling Pathway
8May 2011
M Ouyang et al., PNAS, 2008
Plasma membrane
PDGF
PD
GF
R
Src
Rac
Extracellular
Cytoplasm
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Stressed Induced Rac Signaling Pathway is Different from Soluble Factor
9May 2011
Poh et al., PLoS ONE, 2009
Overlay
0.5
3.0
0.3 s 1.0 s 5.0 s
-Stress +Stress
Brightfield
+PP1 (10 M, 1 hr)
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E-cadherin are mechanosensors
10May 2011
Vinculin potentiates E-cadherin mechanosensing and is recruited to actin-anchored sites within adherens junctions in a myosin II–dependent manner
Le Duc et al., JCB, 2010
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Mechanical Effects on Stem Cells
11May 2011
• Maintain Pluripotency in ESCs mouse human LIF bFGF 2i mTOR
• Induce differentiationa. RAb. SaB-vitamin Cc. Proprietary chemicalsd. Endogenous factorse. Natural products
• iPS cell reprogamming with defined factorsa. Yamanaka coktailb. Other defined factors Lutolf MP et al., Nat Biotechnol, 2005
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Mechanical Effects on Stem Cells
12May 2011
Force
Discher, DE et al., Science, 2009
ForcePlu
ripot
ency
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Substrate Rigidity Dictates Mesenchymal Stem Cells Differentiation Lineage
13May 2011
Engler et al, Cell 2006
Neurogenic Myogenic Osteogenic
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Soft Substrate Promotes Self-Renewal of Embryonic Stem Cells
14May 2011
F Chowdhury et al, PLoS ONE 2010
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Cell Shape Affects Human Mesenchymal Stem Cell Differentiation Lineage
15May 2011
Chen, CS et al., Dev. Cell, 2004
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Topography Controls Adult Stem Cell Fate
16May 2011
Chen, CS et al., Dev. Cell, 2004
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Direct Mechanical Stress Induces Embryonic Stem Cell Differentiation
17May 2011
Chowdhury et al, Nat Mat 2009
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Stress Induced Spreading of Embryonic Stem Cell
18May 2011
Chowdhury et al, Nat Mat 2009
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Biomaterials in Stem Cell Differentiation
19May 2011
OrthomimeticsTM received CE Mark of approval for the repair or articular cartilage and bone. Currently undergoing clinical trial.
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20May 2011
Conclusion• Cells respond to mechanical stimuli by altering cell shape, migration, contraction
and division
• Cell signaling pathways induced by mechanical stress and soluble factors are different
• Mechanical environment (shape, substrate rigidity, forces, topography) affects stem cells differentiation lineage
• Directed differentiation of stem cells requires both chemical and mechanical cues
• Substrate rigidity may also promote embryonic stem cell self-renewal
• Stem cells have promising therapeutic advantages. We need better mechanistic understanding of developmental and homeostatic conditions (physiological, pathological)
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Thank you for your attention!
May 2011
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22May 2011
Y. Wang et al. Nature 2005
GC CFP SH2 substrate YFP
Plasma membrane
Membrane-targeted Src reporter
433 nm
SH2
Src + ATP
476 nm433 nm
527 nm
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23May 2011