Mechanobiology

Question 1

Mechanobiology

Answer 1

the study of how physical forces and changes in cell or tissue mechanics contribute to development, physiology and disease

Question 2

Mechanotransduction

Answer 2

the conversion of a physical force to a biochemical response like mechanosignalling

Question 3

Mechanosensing

Answer 3

when a protein or cellular structure responds to a physical cue to initiate mechanotransduction

Question 4

Examples of mechanotransduction in action

Answer 4

blood pressure autoregulation
coronary artery disease- myogenic tone
auditory mechanotransduction + hearing

Question 5

Shear stress

Answer 5

stress that acts parallel to area

Question 6

How can mechanical forces promote tumour aggression?

Answer 6

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

Question 7

Solid stress

Answer 7

refers to the force exerted by the solid structural components of a tissue experiencing growth.

Question 8

Mechanical control of tumour cell fate

Answer 8

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

Question 9

How is tissue stiffness used in diagnoses?

Answer 9

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

Question 10

Techniques to measure cellular mechanical forces

Answer 10

atomic force microscopy
optical tweezers
magnetic tweezers
micropipette aspiration
uniaxial stretcher

Question 11

Atomic force microscopy

Answer 11

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

Question 12

Piezo channels

Answer 12

mechanosensitive ion channels (mainly Ca2+)
integral membrane proteins usually connected to cytoskeleton

Question 13

What are piezo channels activated by?

Answer 13

mechanically activated by membrane or cortical tension
stretching of the membrane leads to channel opening

Question 14

Integrins

Answer 14

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

Question 15

Focal adhesions

Answer 15

contain talin which is a multimodular molecule that can unfold if force is applied

Question 16

Fibrillar adhesions

Answer 16

matured focal adhesions that have tensin instead of talin

Question 17

What are the 3 types of mechanosensors?

Answer 17

piezo channels
caveolae
integrins

Question 18

Caveolae

Answer 18

small invaginations of the plasma membrane due to the binding of caveolin

Question 19

Cavin 1 and 2

Answer 19

peripheral proteins that can detach from the plasma membrane and are connected to the actin cytoskeleton

Question 20

What is the function of caveolae?

Answer 20

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

Question 21

What is the role of cavin complexes?

Answer 21

they dissociate from the membrane when flattened
regulate transcription in the nucleus which leads to biochemical changes

Question 22

What happens to talin when force is applied?

Answer 22

it unfolds, freeing binding sites for vinculine so they can bind and promote the formation of focal adhesions

Question 23

Vinculine

Answer 23

connect F-actin to integrins via talin

Question 24

What is the importance of myosin in integrins?

Answer 24

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

Question 25

Why is the actin-myosin cytoskeleton connected to focal adhesions?

Answer 25

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

Question 26

What is the effect of stiffened ECM?

Answer 26

promotes epithelial to mesenchymal transition and invasion
due to increased force from the ECM the cytoskeleton has to push against

Question 27

Inhibitors that perturb cell-ECM interactions and cell adhesion signalling

Answer 27

TGF beta inhibitors
MMP inhibitors
losartan
LOXL2 inhibitors
integrin inhibitors
Rho inhibitors

Question 28

What do Rho GTPases cause?

Answer 28

migration, invasion, survival, proliferation → metastasis

Question 29

Hippo pathway

Answer 29

regulated by mechanotransduction
excess YAP activation leads to organ enlargement
yap and taz negatively regulated by Lats1/2 phosphorylating them

Question 30

What does negative regulation of yap/taz lead to?

Answer 30

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

Question 31

What mechanic factors regulate YAP nuclear localisation?

Answer 31

ECM stiffness
cell size

Question 32

What is the effect of a myosin inhibitor on yap regulation?

Answer 32

contractility is blocked
subcellular localisation of yap is regulated so that it is not in the nucleus

Question 33

What is important for positive regulation of myosin?

Answer 33

Rho kinase