Luigi PreziosiDept Mathematical Sciences

Politecnico di Torino

luigi.preziosi@polito.itHttp://calvino.polito.it/~preziosi

Modelling the Interactions of Cells with the Environment

Index

How do cells interact mechanically with the environment?

Why is it important?

What has been done from the modeling point of view?

Index

How do cells interact mechanically with the environment?

Why is it important?

What has been done from the modeling point of view?

Biological background

The cytoskeleton is an intricate network of protein filaments that extends throughout the cytoplasm.

Biological background

The cytoskeleton is an intricate network of protein filaments that extends throughout the cytoplasm.

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

The actin cytoskeleton

• Keratocyte

• Keratocyte fragment

A. Verkhovsky

www.youtube.com/watch?v=saYK4Xseg2g

T

Actin polymerisation (Pantaloni and Carlier, 2002)

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

• 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

Cell crawling

• Motion of a melanoma cell

• Motion of a fibroblastOriginal at: cellix.imba.oeaw.ac.at/fileadmin/conferences/Videotour_CellMotility/fig3.mov

(Burridge & Chrzanowska-Wodnick)

(Burridge et al. Trends Cell Biol. 7, 342-347, 1997)

Cell crawling

Cell crawling

• 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

Extra-cellular matrix

Extra-cellular matrix

(P. Friedl)

Index

How do cells interact mechanically with the environment?

Why is it important?

What has been done from the modeling point of view?

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

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

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

Insufficient mechanosensing

Excessive ECM

Enhanced ECM breakdown

Cell hypercontractility

Loss of contact inhibitionMatrix Metallo Proteinases

Excessive production of ECM

Diseases of mechanotransduction

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

Butcher, Alliston & Weaver, A tense situation: forcing tumour progression

Nat Rev Cancer 9, 108-122 (2009)

Tumour-stroma interaction

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

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)

Mechano-reciprocity

Mechano-reciprocity

Franzè, The mechanical control of nervous system developmentDevelopment 140, 3069-3077 (2013)

Mechano-reciprocity

Building stem cell niches

Jones & Wagers, No place like home: Anatomy and function of the stem cell niche, Nature Rev 9, 11-22 (2008)

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)

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)

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)

T

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)

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

Interaction with ECM micropatterns

Théry, ... & JulicherExperimental and theoretical study of mitotic spindle orientationNature 447, 493-497 (2007)

Interaction with ECM micropatterns

Building a proper artificial ECM

Building a proper artificial ECM

Stevens & George, “Exploring and engineering the cell surface interface”, Science 310, 1135-1138 (2005)

Tissue engineering: building the stem cell nicheTissue engineering: building the stem cell niche

Tactile sensors

Flow sensors