Homework VII - Biomaterials Science Essentially, all organisms from bacteria to humans are mechanosensitive. Physical forces are known to regulate an enormous amount of processes which play an important role in homeostasis. Thus, the main questions around this topic evolved from its importance to how it is possible to transduce mechanical stimulus into biochemical responses. IST - 4th Year - 2nd Semester - Biomedical Engineering.

1. Biomaterials Science – 4th year | 2nd Semester
Luís Rita | 78680
Cells’ Mechanotransduction – Molecular Mechanisms
Mechanotransduction
Essentially, all organisms from bacteria to humans are mechanosensitive. Physical forces are known to regulate an enormous amount
of processes which play an important role in homeostasis. Thus, the main questions around this topic evolved from its importance to
how it is possible to transduce mechanical stimulus into biochemical responses.
In a microscopic scope, mechanotransduction is believed to play an important role in proliferation, differentiation, sorting and
migration of cells. Later, changes at this level entail embryonic morphogenesis effects (physical folding, extension and cavitation events)
and developmentof specific pathological conditions like aneurysm, bone loss (especiallyrelevantin astronauts), atherosclerotic plaques,
among others.
Different tissues will react differently to stimulus, although the general mechanism can be described in 4 different steps,
developed below. Note that, their interaction is considerably tight, so it’s sometimes tricky to know exactly when any of them
started/ceased.
1. Force Transmission
Forces can have multiple origins. Both external (such as the ones induced by gravity or exercise) or internal (e.g. blood flowing across
endothelium, stretch of vessels owing to blood pressure and microscopic forces that occur when contracting cells pull on surrounding
extracellular matrix or each other) can be divided in tensile, compressive or even
shear stresses that are among the examples given before.
Though, to understand the effects of these on cells and ECM, one must
consider the balance of all external and cell-generated forces as a whole and their
magnitudes.
2. Force Transduction
The most well-known structures that translate mechanical stimuli in biochemical
responses are present in Fig. 1. Specifically, this is usually done by some specific
molecular mechanisms of transduction: Stretch-sensitive ion channels can alter its
conformation and changes its opening and closing rates when the membrane bilayer
distorts due to cytoskeleton (Fig. 2 - B) or external stresses (Fig. 2 - A, patch clamp
technique, permeates the cellular membrane); Distortion of an enzyme (Fig. 2 - C) or
molecular motors can alter its catalytic activity and, for example, inhibit cleavage of
a given substrate; Tension application to individual proteins (Fig. 2 - D) can produce
unfolding of discrete peptide domains within the molecules, influencing their elastic
properties, as well as exposing previously masked binding sites; The chemical
potential of proteins that form biopolymers may alter when the filaments are
compressed or tensed. Release of end-on compression of a cytoskeletal microtubule,
for example (Fig. 2 - E), results in tubulin monomer addition and polymer elongation.
3. Signal Propagation
One way of propagating signal generated by one of the structures in Fig. 1 is through
chemicals release. When mechanical stimulation of articular chondrocytes induces a
cytosolic Ca2+
increase, that may permeate gap junctions. This becomes an
intercellular messenger mediating cell-to-cell communication.
Mechanical loads exerted at the macroscale trickle down to produces changes
in connective tissue and ECM that result in production of stresses at the microscale that produce global structural rearrangements of
the individual molecular components that comprise the ECM, as well as the interconnected cytoskeletons and nuclei of adherent cells.
4. Cellular Response
The primordial responses are at the level of protein translation. By changing the rate at which this occurs, we may promote fibrosis,
intimal hyperplasia, osteoporosis, hemolysis or phenotype changings (e.g. muscle hypertrophy).
[Case Study 1] Very sensitive cells to mechanical stresses are the stem cells. It was verified in cardiac stem cells that mechanical
stress suppressed their growth and proliferation, enhancing their release of inflammatory cytokines and angiogenic factors, improving
myogenic differentiation.
[Case Study 2] This study aimed to identify the influence of mechanical stress in cartilage and chondrocytes. Mechanical stress
was verified to affect the chondrocyte phenotype, thereby altering the expression of chondrocyte ECM.
Fig. 1 – Force Transduction Structures.
Fig. 2 – Force Transduction Mechanisms.