Mechanobiology Flashcards
Mechanobiology
the study of how physical forces and changes in cell or tissue mechanics contribute to development, physiology and disease
Mechanotransduction
the conversion of a physical force to a biochemical response like mechanosignalling
Mechanosensing
when a protein or cellular structure responds to a physical cue to initiate mechanotransduction
Examples of mechanotransduction in action
blood pressure autoregulation
coronary artery disease- myogenic tone
auditory mechanotransduction + hearing
Shear stress
stress that acts parallel to area
How can mechanical forces promote tumour aggression?
expanding tumour means that there is increased solid stress
combined with the mechanical resistance of the ECM
increases interstitial pressure
impairing lymphatic drainage + drug delivery
Solid stress
refers to the force exerted by the solid structural components of a tissue experiencing growth.
Mechanical control of tumour cell fate
stiffened matrix strengthens cell-ECM interactions in tumour cells
prompts disruption of E-cadherin-mediated cell junctions so beta catenin can translocate into the nucleus
How is tissue stiffness used in diagnoses?
increased stiffness is diagnostic of diseased tissue like liver disease
it can assist intervention and therapeutic decisions like biopsies and treatment
palpation of lumps is often how breast cancer is found
Techniques to measure cellular mechanical forces
atomic force microscopy
optical tweezers
magnetic tweezers
micropipette aspiration
uniaxial stretcher
Atomic force microscopy
method to measure small levels of indentation when cantilever is pushed down so that the more indentation there is the more the angle of the laser at the tip of the cantilever is changed
Piezo channels
mechanosensitive ion channels (mainly Ca2+)
integral membrane proteins usually connected to cytoskeleton
What are piezo channels activated by?
mechanically activated by membrane or cortical tension
stretching of the membrane leads to channel opening
Integrins
major sensors of ECM stiffness
have an extracellular domain, which can be activated in various ways
when force is applied to the ECM they cluster to become focal adhesions
Focal adhesions
contain talin which is a multimodular molecule that can unfold if force is applied
Fibrillar adhesions
matured focal adhesions that have tensin instead of talin
What are the 3 types of mechanosensors?
piezo channels
caveolae
integrins
Caveolae
small invaginations of the plasma membrane due to the binding of caveolin
Cavin 1 and 2
peripheral proteins that can detach from the plasma membrane and are connected to the actin cytoskeleton
What is the function of caveolae?
flatten upon shear stress or increase in membrane tension
reservoirs of extra membrane so when cells are put under stress they don’t tear as they provide extra membrane to stretch
What is the role of cavin complexes?
they dissociate from the membrane when flattened
regulate transcription in the nucleus which leads to biochemical changes
What happens to talin when force is applied?
it unfolds, freeing binding sites for vinculine so they can bind and promote the formation of focal adhesions
Vinculine
connect F-actin to integrins via talin
What is the importance of myosin in integrins?
F-actin alone does not have any contratile activity
myosin molecules sit between them so it can exert force and slide the filaments against each other
Why is the actin-myosin cytoskeleton connected to focal adhesions?
if myosin is pushed in one direction the ECM will push in the opposite direction as it has elasticity
so there is equal and opposite forces
What is the effect of stiffened ECM?
promotes epithelial to mesenchymal transition and invasion
due to increased force from the ECM the cytoskeleton has to push against
Inhibitors that perturb cell-ECM interactions and cell adhesion signalling
TGF beta inhibitors
MMP inhibitors
losartan
LOXL2 inhibitors
integrin inhibitors
Rho inhibitors
What do Rho GTPases cause?
migration, invasion, survival, proliferation → metastasis
Hippo pathway
regulated by mechanotransduction
excess YAP activation leads to organ enlargement
yap and taz negatively regulated by Lats1/2 phosphorylating them
What does negative regulation of yap/taz lead to?
them being degraded so they cannot act as a transcriptional regulator
or bound to 14-3-3 molecule so that they can’t enter the nucleus
What mechanic factors regulate YAP nuclear localisation?
ECM stiffness
cell size
What is the effect of a myosin inhibitor on yap regulation?
contractility is blocked
subcellular localisation of yap is regulated so that it is not in the nucleus
What is important for positive regulation of myosin?
Rho kinase
