Mechanobiology is an emerging field of science at the interface of biology, engineering, chemistry and physics. It focuses on how physical forces and changes in the mechanical properties of cells and tissues contribute to development, cell differentiation,
physiology
Physiology (; ) is the scientific study of functions and mechanisms in a living system. As a sub-discipline of biology, physiology focuses on how organisms, organ systems, individual organs, cells, and biomolecules carry out the chemical ...
, and disease. Mechanical forces are experienced and may be interpreted to give biological responses in cells. The movement of joints, compressive loads on the
cartilage
Cartilage is a resilient and smooth type of connective tissue. In tetrapods, it covers and protects the ends of long bones at the joints as articular cartilage, and is a structural component of many body parts including the rib cage, the neck an ...
and bone during exercise, and shear pressure on the blood vessel during blood circulation are all examples of mechanical forces in human tissues. A major challenge in the field is understanding
mechanotransduction
In cellular biology, mechanotransduction ('' mechano'' + '' transduction'') is any of various mechanisms by which cells convert mechanical stimulus into electrochemical activity. This form of sensory transduction is responsible for a number of ...
—the molecular mechanisms by which cells sense and respond to mechanical signals. While medicine has typically looked for the genetic and biochemical basis of disease, advances in mechanobiology suggest that changes in cell mechanics,
extracellular matrix
In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide stru ...
structure, or mechanotransduction may contribute to the development of many diseases, including
atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheroma, atheromatous plaque. At onset there are usu ...
,
fibrosis
Fibrosis, also known as fibrotic scarring, is a pathological wound healing in which connective tissue replaces normal parenchymal tissue to the extent that it goes unchecked, leading to considerable tissue remodelling and the formation of perma ...
,
asthma
Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, cou ...
,
osteoporosis
Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone ...
,
heart failure
Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...
, and
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
. There is also a strong mechanical basis for many generalized medical disabilities, such as lower back pain, foot and postural injury, deformity, and
irritable bowel syndrome
Irritable bowel syndrome (IBS) is a "disorder of gut-brain interaction" characterized by a group of symptoms that commonly include abdominal pain and or abdominal bloating and changes in the consistency of bowel movements. These symptoms may ...
.
Load sensitive cells
Fibroblasts
Skin
fibroblast
A fibroblast is a type of cell (biology), biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework (Stroma (tissue), stroma) for animal Tissue (biology), tissues, and plays a critical role in wound ...
s are vital in development and wound repair and they are affected by mechanical cues like tension, compression and shear pressure. Fibroblasts synthesize structural proteins, some of which are mechanosensitive and form integral part of the
extracellular Matrix
In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide stru ...
(ECM) e. g
collagen
Collagen () is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whole ...
types I, III, IV, V VI,
elastin
Elastin is a protein that in humans is encoded by the ''ELN'' gene. Elastin is a key component of the extracellular matrix in gnathostomes (jawed vertebrates). It is highly elastic and present in connective tissue allowing many tissues in the bod ...
, lamin etc. In addition to the structural proteins, fibroblasts make
Tumor-Necrosis-Factor- alpha (TNF-α),
Transforming-Growth-Factor-beta (TGF-β) and
matrix metalloproteases that plays in tissue in tissue maintenance and remodeling.
Chondrocytes
Articular
cartilage
Cartilage is a resilient and smooth type of connective tissue. In tetrapods, it covers and protects the ends of long bones at the joints as articular cartilage, and is a structural component of many body parts including the rib cage, the neck an ...
is the connective tissue that protects bones of load-bearing joints like knee, shoulder by providing a lubricated surface. It deforms in response to compressive load, thereby reducing stress on bones. This mechanical responsiveness of articular cartilage is due to its biphasic nature; it contains both the solid and fluid phases. The fluid phase is made up of water -which contributes 80% of the wet weight – and inorganic ions e. g Sodium ion, Calcium ion and Potassium ion. The solid phase is made up of porous ECM. The proteoglycans and interstitial fluids interact to give compressive force to the cartilage through negative electrostatic repulsive forces. The ion concentration difference between the extracellular and intracellular ions composition of chondrocytes result in hydrostatic pressure. During development, mechanical environment of joint determines surface and topology of the joint. In adult, moderate mechanical loading is required to maintain cartilage; immobilization of joint leads to loss of proteoglycans and cartilage atrophy while excess mechanical loading results in degeneration of joint.
Nuclear mechanobiology
The
nucleus
Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to:
*Atomic nucleus, the very dense central region of an atom
*Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA
Nucle ...
is also responsive to mechanical signals which are relayed from the extracellular matrix through the cytoskeleton by the help of Linker of Nucleoskeleton and Cytoskeleton LINC-associated proteins like KASH and SUN. Examples of effect of mechanical responses in the nucleus involve:
* Hyperosmotic challenge results in chromosome condensation and translocation and activation of the
Ataxia Telangiectasia and Rad3-related (ATR) to the nuclear peripheral region while mechanical stretching due to hypo-osmotic challenge and compression re-localizes and activates
cPLA2 to the nuclear membrane.
* High nuclear tension on the
Lamin A
Pre-lamin A/C or lamin A/C is a protein that in humans is encoded by the ''LMNA'' gene. Lamin A/C belongs to the lamin family of proteins.
Function
In the setting of ZMPSTE24 deficiency, the final step of lamin processing does not occur, res ...
hinders the access of kinases , thereby suppressing its degradation etc.
Mechanobiology of embryogenesis
The embryo is formed by self-assembly through which cells differentiate into tissues performing specialized functions. It was previously believed that only chemical signals give cues that control spatially oriented changes in cell growth, differentiation and fate switching that mediate morphogenetic controls. This is based on the ability of chemical signals to induce biochemical responses like tissue patterning in distant cells. However, it is now known that mechanical forces generated within cells and tissues provide regulatory signals.
During the division of the fertilized
oocyte
An oocyte (, ), oöcyte, or ovocyte is a female gametocyte or germ cell involved in reproduction. In other words, it is an immature ovum, or egg cell. An oocyte is produced in a female fetus in the ovary during female gametogenesis. The female ...
, cells aggregate and the compactness between cells increases with the help of actomyosin-dependent cytoskeletal traction forces and their application to adhesive
receptors
Receptor may refer to:
*Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a n ...
in neighboring cells, thereby leading to formation of solid balls called
Morula
A morula (Latin, ''morus'': mulberry) is an early-stage embryo consisting of a solid ball of cells called blastomeres, contained in mammals, and other animals within the zona pellucida shell. The blastomeres are the daughter cells of the zygote ...
. The spindle positioning within symmetrically and asymmetrically dividing cells in the early embryo is controlled by mechanical forces mediated by microtubules and actin microfilament system. Local variation in physical forces and mechanical cues such as stiffness of the ECM also control the expression of genes that give rise to the embryonic developmental process of
blastulation
Blastulation is the stage in early animal embryonic development that produces the blastula. In mammalian development the blastula develops into the blastocyst with a differentiated inner cell mass and an outer trophectoderm. The blastula (fr ...
. The loss of stiffness-controlled
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...
Cdx
The Cdx gene family, also called caudal genes, are a group of genes found in many animal genomes. Cdx genes contain a homeobox DNA sequence and code for proteins that act as transcription factors. The gene after which the gene family is named (the ...
leads to the ectopic expression of inner cell mass markers in the trophectoderm, and the pluripotent transcription factor,
Oct-4
Oct-4 (octamer-binding transcription factor 4), also known as POU5F1 (POU domain, class 5, transcription factor 1), is a protein that in humans is encoded by the ''POU5F1'' gene. Oct-4 is a homeodomain transcription factor of the POU family. I ...
may be negatively expressed, thereby inducing lineage switching. This cell fate switching is regulated by the mechanosensitive
hippo pathway
The Hippo signaling pathway, also known as the Salvador-Warts-Hippo (SWH) pathway, is a signaling pathway that controls organ size in animals through the regulation of cell proliferation and apoptosis. The pathway takes its name from one of its k ...
Applications
The effectiveness of many of the mechanical therapies already in clinical use shows how important physical forces can be in physiological control. Several examples illustrate this point.
Pulmonary surfactant
Pulmonary surfactant is a surface-active complex of phospholipids and proteins formed by type II alveolar cells. The proteins and lipids that make up the surfactant have both hydrophilic and hydrophobic
In chemistry, hydrophobicity is t ...
promotes lung development in premature infants; modifying the tidal volumes of mechanical ventilators reduces morbidity and death in patients with acute lung injury. Expandable
stents
In medicine, a stent is a metal or plastic tube inserted into the lumen of an anatomic vessel or duct to keep the passageway open, and stenting is the placement of a stent. A wide variety of stents are used for different purposes, from expandab ...
physically prevent coronary artery constriction.
Tissue expanders
Tissue may refer to:
Biology
* Tissue (biology), an ensemble of similar (or dissimilar in structure but same in origin) cells that together carry out a specific function
* ''Triphosa haesitata'', a species of geometer moth ("tissue moth") found in ...
increase the skin area available for reconstructive surgery. Surgical tension application devices are used for bone fracture healing, orthodontics, cosmetic breast expansion and closure of non-healing wounds.
Insights into the mechanical basis of tissue regulation may also lead to development of improved medical devices,
biomaterials
A biomaterial is a substance that has been engineered to interact with biological systems for a medical purpose, either a therapeutic (treat, augment, repair, or replace a tissue function of the body) or a diagnostic one. As a science, biomateria ...
, and engineered tissues for tissue repair and reconstruction.
Known contributors to cellular mechanotransduction are a growing list and include stretch-activated
ion channels
Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of io ...
,
caveolae
In biology, caveolae (Latin for "little caves"; singular, caveola), which are a special type of lipid raft, are small (50–100 nanometer) invaginations of the plasma membrane in the cells of many vertebrates. They are the most abundant surface ...
,
integrins
Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...
,
cadherins
Cadherins (named for "calcium-dependent adhesion") are a type of cell adhesion molecule (CAM) that is important in the formation of adherens junctions to allow cells to adhere to each other . Cadherins are a class of type-1 transmembrane proteins, ...
, growth factor receptors, myosin motors,
cytoskeletal
The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compo ...
filaments,
nuclei, extracellular matrix, and numerous other signaling molecules.
Endogenous
Endogenous substances and processes are those that originate from within a living system such as an organism, tissue, or cell.
In contrast, exogenous substances and processes are those that originate from outside of an organism.
For example, es ...
cell-generated traction forces also contribute significantly to these responses by modulating tensional prestress within cells, tissues, and organs that govern their mechanical stability, as well as mechanical signal transmission from the macroscale to the nanoscale.
See Also
*
Biophysics
Biophysics is an interdisciplinary science that applies approaches and methods traditionally used in physics to study biological phenomena. Biophysics covers all scales of biological organization, from molecular to organismic and populations. ...
References
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Branches of biology
Biological engineering