modelling the interactions of cells with the environment
TRANSCRIPT
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Luigi PreziosiDept Mathematical Sciences
Politecnico di Torino
[email protected]://calvino.polito.it/~preziosi
Modelling the Interactions of Cells with the Environment
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Index
How do cells interact mechanically with the environment?
Why is it important?
What has been done from the modeling point of view?
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Index
How do cells interact mechanically with the environment?
Why is it important?
What has been done from the modeling point of view?
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Biological background
The cytoskeleton is an intricate network of protein filaments that extends throughout the cytoplasm.
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Biological background
The cytoskeleton is an intricate network of protein filaments that extends throughout the cytoplasm.
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Functions of the cytoskeleton
• Structural support for the cytoplasm
• Causes changes in cell shape• Drives cell division• Causes cell movements• Causes muscle contraction• Controls location of
organelles• Provides transport between
organelles
• Structural support for the cytoplasm
• Causes changes in cell shape• Drives cell division• Causes cell movements• Causes muscle contraction• Controls location of
organelles• Provides transport between
organelles
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The actin cytoskeleton
• Keratocyte
• Keratocyte fragment
A. Verkhovsky
www.youtube.com/watch?v=saYK4Xseg2g
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Actin polymerisation (Pantaloni and Carlier, 2002)
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Actin filaments
Actin filaments are concentrated beneath the plasma membrane (cell cortex) and give the cell mechanical strength.
Assembly of actin filaments can determine cell shape and cause cell movement.
Association of actin filaments with myosin can form contractile structures.
www.sci.sdsu.edu/movies/actin_myosin_gif.html
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• Motor proteins bind to actin filaments and microtubules and move by cycles of conformational changes using energy from ATP.
• One end of the protein can bind to specific cellular components.
myosinOriginal at: www.youtube.com/watch?v=vJ9ffKeUCvE&hl=it
Motor proteins
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Cell crawling
• Motion of a melanoma cell
• Motion of a fibroblastOriginal at: cellix.imba.oeaw.ac.at/fileadmin/conferences/Videotour_CellMotility/fig3.mov
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(Burridge & Chrzanowska-Wodnick)
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(Burridge et al. Trends Cell Biol. 7, 342-347, 1997)
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Cell crawling
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Cell crawling
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• Focal contacts and microtubulin
• Animation focal contact and cytoskeleton
• Making a focal contact(cellix.imba.oeaw.ac.at/fileadmin/conferences/Videotour_CellMotility/fig40.mov fig26.mov fig15.mov)
Focal contacts
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Extra-cellular matrix
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Extra-cellular matrix
(P. Friedl)
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Index
How do cells interact mechanically with the environment?
Why is it important?
What has been done from the modeling point of view?
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Mechanosensing = How cells sense mechanical forcesMechano-transduction = How cells respond to mechanical signals,
either directly or via the activation of signalling pathways
Macroscopicforce
Cell traction
Macroscopicforce
Mechanosensing & mechanotransduction
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Guilak, … & Chen, Control of stem cells by physical interaction with the ECM,
Cell Stem Cell 5, 17-26 (2009)
Sun, Chen, Fu, Forcing stem cells to behave: A biophysical perspective of the cellular microenvironment
Ann. Rev. Biophys. 41, 519-542 (2012)
Mechanosensing = How cell celse mechanical forces Mechano-transduction = How cell respond to mechanical signals,
either directly or via the activation of pathways
Mechanosensing & mechanotransduction
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Ingber, Mechanobiology and diseases of mechanotransductionAnnals Medicine 35, 1-14 (2009)
Abnormal ECM accumulation
Stretching of mesangial cells through ECM and integrins due to glomerular hypertension
Abnormal conversion of mechanical stress into intracellular gradients of electrical activity
Stretch activated signalling cascades due to stents and grafts
Dementhia
Vasculature feels and adapt to shear and pressure
Diseases of mechanotransduction
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Insufficient mechanosensing
Excessive ECM
Enhanced ECM breakdown
Cell hypercontractility
Loss of contact inhibitionMatrix Metallo Proteinases
Excessive production of ECM
Diseases of mechanotransduction
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Tumour-stroma interaction
Kass, Erler, Dembo & Weaver, Mammary epithelial cell: Influence of ECM composition and organization during development and tumorigenesisInt J Biochem Cell Biol 39, 1987-94 (2007)
Relations between ECM stiffness and cell tensile stress influences Proliferation Apoptosis Migration
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Butcher, Alliston & Weaver, A tense situation: forcing tumour progression
Nat Rev Cancer 9, 108-122 (2009)
Tumour-stroma interaction
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Control of stem cell fate: Genetic and molecular mediators (growth factors, transcription factors, …)
ECM interaction
ECM elasticity ECM morphology ECM mediated stress
Jones & Wagers, No place like home: Anatomy and function of the stem cell niche
Nature Rev 9, 11-22 (2008)
Tissue engineering: Controlling stem cell fate
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Mechano-reciprocity
It mantains tensional homeostasis in the tissue Is necessary for development and tissue-specific differentiation Its loss promotes disease progression, including liver fibrosis, atherosclerosis and cancer
Butcher, Alliston, Weaver, A tense situation: forcing tumour progression
Nat Rev Cancer 9, 108-122 (2009)
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Mechano-reciprocity
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Mechano-reciprocity
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Franzè, The mechanical control of nervous system developmentDevelopment 140, 3069-3077 (2013)
Mechano-reciprocity
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Building stem cell niches
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Jones & Wagers, No place like home: Anatomy and function of the stem cell niche, Nature Rev 9, 11-22 (2008)
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Lindvall, Kokaia, Stem cells in human neurodegenerative disorders: Time for clinical translation?J. Clinical Inv 120, 29-40 (2010)Progress stem cells for the treatment of neurological disorders, Nature 441 1094-1096 (2006)
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Lindvall, Kokaia, Stem cells in human neurodegenerative disorders: Time for clinical translation?J. Clinical Inv 120, 29-40 (2010)Progress stem cells for the treatment of neurological disorders, Nature 441 1094-1096 (2006)
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Lindvall, Kokaia, Stem cells in human neurodegenerative disorders: Time for clinical translation?J. Clinical Inv 120, 29-40 (2010)Progress stem cells for the treatment of neurological disorders, Nature 441 1094-1096 (2006)
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Lindvall, Kokaia, Stem cells in human neurodegenerative disorders: Time for clinical translation?J. Clinical Inv 120, 29-40 (2010)Progress stem cells for the treatment of neurological disorders, Nature 441 1094-1096 (2006)
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Interaction with ECM micropatterns
Guilak, … & Chen, Control of stem cell fate by physical interaction with the ECMCell Stem Cell 5, 17-26 (2009)
Cell-ECM contact are regulators of cell function
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Interaction with ECM micropatterns
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Théry, ... & JulicherExperimental and theoretical study of mitotic spindle orientationNature 447, 493-497 (2007)
Interaction with ECM micropatterns
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Building a proper artificial ECM
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Building a proper artificial ECM
Stevens & George, “Exploring and engineering the cell surface interface”, Science 310, 1135-1138 (2005)
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Tissue engineering: building the stem cell nicheTissue engineering: building the stem cell niche
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Tactile sensors
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Flow sensors