Mechanobiology Flashcards
What is mechanotransduction
Conversion of a physical force to a biochemical response
What is mechanosensing?
When a protein or cellular structure responds to a physical cue to initiate mechanotransduction. E.g a cell responding to surface stiffness
What is the signal cascade from mechonosensing?
- Mechanosensing with adhesion receptors
- Signal transduction
- Signal integration in the nucleus. Chromosome rearrangement
- Cellular response
How is blood pressure regulated?
Mechanoresponse to expanding/contracting blood vessels to keep blood pressure constant. When bloodflow is large, the diameter contracts to limit bloodflow to certain organs
Explain auditory mechanotransduction
Movement from sound bends cilia. Ion channels open and cause depolarisation.
How does lung on a chip imitate the gas exchange surface in lungs?
The system has a membrane flanked by endothelium and epithelium. A vacuum is introduced into the side chambers, stretching the cell layers, forming tight junctions
What are organs on chips used to study?
Inflammation, e.g adding TNFα
Neutrophils migrating from endothelial to epithelial layer to engulf bacteria
Why can nanoparticles enter through the alveoli epithelium?
Lungs can undergo mechanical stretching
What is the stiffness equation?
Stress / Strain (Pa)
What is the equation for stress?
F / A (Pa)
What is the equation for strain?
ΔL / L
What can increased tissue stiffness be an indicator of?
Chronic liver disease and cancer. The higher the stiffness in chronic liver disease, the higher the stage.
How is ECM stiffness usually altered around cancerous cells?
EMTs happen, so cell-cell adhesion is disrupted. Actomyosin contractility and cell-ECM adhesion increase
How are cellular mechanical forces measured?
Atomic force microscopy
Micropipette aspiration
Optical tweezers
Magnetic tweezers
Explain atomic force microscopy
A sensitive arm scans a sample and a laser beam is shone on it to show indentation.
What opens Piezo Channels?
Actin which pulls on the membrane or cytoskeleton
What are piezo channels?
Mechanically activated ion channels, mainly Ca2+
38TM
Open under stress like a sliding door
How does integrin act as a mechanosensor?
When integrins cluster into focal adhesions, thy bind to the ECM. Force in the ECM is exerted on talin, releasing its vinculin binding sites. Actin is connected to vinculin and changes the cytoskeleton.
What happens when force is put on integrin?
Ligand binding is stronger, allowing a conformational change to take place
How does caveolae act as a mechanosensor?
They flatten out upon stretching, preventing the cell tearing.
Filamin A mediates links to stress fibres and is regulated by Cav1
What proteins shape caveolae?
Caveolins
Cavins
pacsin2
What proteins regulate caveolae dynamics?
Dyn2
EDH2
Filamin A
What happens when ECM stiffens?
Snail is upregulated which is a transcription factor of EMTs
Epithelial - Mesenchymal Transition and invasion.
What can be used to inhibit EMTs?
Prevent ECM stiffening with TGF-β inhibitors
Integrin inhibitors
Inhibitors which interfere with ECM post translational modifications
Rho kinases to tackle signal transduction
What does excessive YAP activation lead to?
Organ enlargement
How is YAP regulated?
Downstream kinases
What do YAP/TAZ and Yorkie regulate via the hippo pathway?
Proliferation
Cell survival
Cell competition
Stem cell maintenance
Metastasis
Regeneration
What regulates nuclear localisaiton of the transcriptional regulator YAP?
ECM stiffness and cell size
How can YAP activity be measured?
mRNA expression of its downstream molecules
What is a positive regulator of myosin in the hippo pathway?
Rho kinases
