mechanotransduction Flashcards
(8 cards)
elastic modulus
Elastic modulus (Young’s modulus, E): Measure of resistance to deformation, size-independent.
Units: Pascals (Pa = N/m²)
Higher E = stiffer material.
Stiffness order (lowest to highest):
Fluid → blood/mucus → brain → muscle → plastic → glass → bone
Cells generate internal force via actomyosin contraction, and respond to external stiffness through:
Focal adhesions
ECM-integrin-cytoskeleton pathway
Nucleus (via LINC complex)
Tissue stiffness values (approximate):
Material Elastic Modulus (E)
Water ~0 Pa
Mucus/Blood ~10–100 Pa
Brain tissue ~100–1,000 Pa
Muscle ~10,000 Pa (10 kPa)
Osteoid (pre-bone) ~30 kPa
Mature Bone ~10⁷ Pa (10 MPa)
Plastic ~10⁹ Pa
Glass ~10¹⁰–10¹¹ P
tensegrity
Tensegrity Theory in Cells
The tensegrity model (short for “tensional integrity”) proposes that cells maintain their structure through a balance of tensile (pulling) and compressive (pushing) forces.
In this model:
The actin cytoskeleton provides tension
Microtubules and ECM attachments resist compression
Scientific support:
Experiments using magnetic beads and cytoskeletal inhibitors show that disrupting one part of the system (e.g., actin or integrins) affects forces throughout the cell, consistent with tensegrity principles.
This model helps explain why mechanical signals at the membrane can cause rapid changes inside the nucleus.
cues
Intrinsic vs Extrinsic Cues + Feedback Loop
Extrinsic cues: External mechanical and biochemical signals (e.g., ECM stiffness, substrate elasticity, cell density, shear stress).
Intrinsic cues: Internal cellular machinery (e.g., cytoskeletal tension, gene expression, organelle positioning).
Feedback loop: Cells sense ECM stiffness → cytoskeleton adjusts tension → this tension is transmitted to the nucleus → changes chromatin organization, transcription factor localization → alters gene expression → which in turn modifies how the cell responds to the environment.
stem cell mechanosensitivity and lineage commitment
Stem Cell Mechanosensitivity & Lineage Commitment
Speed of mechanical vs chemical signals:
Mechanical signals act within seconds (e.g., cytoskeletal strain, YAP/TAZ shuttling)
Soluble cues (like growth factors) act over minutes–hours
➤ Implication: Mechanical cues can “prime” cells before soluble factors arrive — crucial in development and tissue repair
Plating density & cell–cell interactions:
High-density plating → more cell-cell interactions, less spreading → favors adipogenesis
Low-density plating → more spreading, more tension → favors osteogenesis
Cell shape and cytoskeletal tension:
Well-spread cells = more stress fibres = osteogenic
Rounded cells = less tension = adipogenic
Inhibiting tension (e.g., with blebbistatin or Y-27632) can block stiffness-guided differentiation
chemical inhibitors
Chemical Inhibitors Used in Studies
Drug Target Effect
Blebbistatin Myosin II Blocks actomyosin contractility
Y-27632 Rho-associated kinase (ROCK) Reduces cell tension
Cytochalasin D Actin polymerization Disrupts cytoskeleton
➤ All of these reduce tension → bias stem cells away from stiff-lineage fate (osteogenic, myogenic)
Gene expression correlates with stiffness.
Blocked by blebbistatin → proves dependence on internal force generation.
matrix stiffness and diffeentiation outcomes
Polyacrylamide gels used to tune stiffness
On stiff matrices:
Larger, more stable focal adhesions
Stronger actin stress fibres
Higher YAP/TAZ nuclear localization
Favor osteogenesis, myogenesis
On soft matrices:
Weaker adhesions
Less tension
YAP/TAZ remain in cytoplasm
Favor neurogenesis or adipogenesis
Example:
Cardiomyocytes beat normally only when substrate stiffness matches natural heart tissue (~10 kPa)
Stiffer substrate → arrhythmic beating
Infarcted myocardium = stiffer → altered cell behavior
🧬 Marker expression matches native tissue stiffness:
Brain-like softness → neural markers
Muscle stiffness (~10 kPa) → myogenic markers
Stiff like bone → osteogenic markers
mechanoregulation in development
Mechanoregulation in Development – Hippo Pathway
YAP/TAZ = key mechanotransducers in Hippo pathway
Their localization (nucleus vs cytoplasm) depends on:
Substrate stiffness
Cell shape
Actin cytoskeleton tension
In stem cells:
YAP/TAZ nuclear = active = promotes proliferation & osteogenesis
Cytoplasmic = inactive = favors differentiation or apoptosis
organoids
Organoid and Intestinal Stem Cell Mechanobiology
Intestinal organoids recapitulate tissue stiffness gradients
Stem cell zone (crypt): softer → promotes stemness
Villous region: stiffer → promotes differentiation
Mechanical cues + biochemical gradients drive spatially regulated stem cell behavior
