An Introducttion to Mechanobiology

7/31/2019 An Introducttion to Mechanobiology

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An Introduction to Mechanobiology

S. D. Dubal and Y. L. Vyas

Department of Anatomy,

College of Veterinary Sci.& A.H.,

Anand Agricultural University, Anand - 388 001 (Guj) India

If someone asks why we are? It is impossible to give the answer. However, if it is

asked what and how we are, there are fair chances of the answer. It may happen that the

answer may be of religious philosophical, socio-economical or what is now a day said

scientific. Yes, where the religious philosophy ends, the science comes to settle the

questions.

No human being can have his/her past more than 150 years. It is also difficult to

remember the whole past. The ignorance is dangerous but it is the force behind all

creativities and innovations to open the gate of knowledge. When we think about how

much time lapsed since the appearance of first living organism, our past time span is

nothing. At least it is physically plausible to understand the life (the living organism).

There are several types of living organisms and lot of variations in the forms and (hence)

habitats exit. Nevertheless all the organisms are constructed on same materials and

principles.

The answer of question ' what are the organisms' is thus simple. The organisms

are nothing but chemicals. The chemicals are such that they emerge through hierarchical

self-assembly of nanoscale components. This assembly is highly unstable and is always

in surge of stability. The stability is achieved under the action of various forces that are

mechanical or converted into mechanical forces. Without mechanical forces the life is not

possible.

The molecules that are assembled were not synthesized in one day. There had

been synthesis of different molecules. Amongst all molecules synthesized, a few were

had the ability to self-assemble and, which could remodel to form flexible structures

under the influence of highly flexible clay minerals (and hence they can catalyze

chemical reactions with greater efficiency, including reactions that produced the first

organic polymers).

This took millions of years to have such molecules. The assembly which could

remain persisted gave the birth of the living organisms. This was the beginning of

survival of fittest. The surge for stability is still continuing. Without a cellular structure as

the basis of life, there is no basis for cell growth and division and therefore evolution anddiversification would likely have been impossible. Living cells are the ultimate

intelligent materials. They are mechanically strong and resilient; exhibit integrated

multifunctional chemical/mechanical/electrical/optical and information-processing

capabilities; grow, move and self-heal; learn, adapt, and self-organize (Inber, 2000).

As a first priority, they required mechanisms that would protect their delicate

scaffold from potentially damaging stimuli. However, to interact with their changing

environment (e.g., during feeding, escaping, or mating), they needed mechanosensitivity.

On the basis of mechanical properties of the surroundings, the cell performs the

physical and chemical activities so that it can remodel. The continuous process of

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remodeling leads to survival of the cell (organism).This is the evolution. During the

evolution, the cell developed its own scaffold that bridged the extracellular materials

(matrix - ECM) and central body that has the ability to control the synthesis o f desired

molecules as per the mechanical stimuli. Thus the whole assembly is dependent upon the

recognition of the external mechanical stimuli. In other word, the mechanical stimuli are

necessary for the livingness of the cell. The following pages concern the present day

multicellular organisms.

Cytoskeleton: The simple understanding about the structure of a cell is that it is

composed of cell membrane and nucleus (bound by nuclear membrane). Between them

lies the cytoplasm, which is in the form of interchangeable sol- gel phase and the

organelles and several inclusions form the cytoplasm. Due to the use of point-loading,

cells have a structural framework to transmit forces from one place to another inside their

cytoplasm. This structure, known as the cytoskeleton (CSK), is a highly interconnected

three dimensional network composed of three major biopolymer systems, microfilaments,

microtubules, and intermediate filaments along with their associated proteins.

Microfilaments contain polymerized actin. Actin filaments are continuously under

tension that is continuously transmitted throughout the entire interconnected actin lattice

and thus, the whole cell.

Microtubules are hollow tubular polymers composed of different tubulin

monomer isotypes and resist compression. Growing microtubule buckles under

compression. The buckling occurs when the microtubule elongates and pushes against

other components of the cells skeleton.

Intermediate filaments like actin filaments, they function in the maintenance of

cell-shape by bearing tension. Intermediate filaments organize the internal 3D structure of

the cell, anchoring organelles and serving as structural components (e.g., vimentin,

desmin, cytokeratin).

Natu ra l Design Principles: Cytoskeleton is based on the following Natural Design

Principles (Ingber, 2000):

1. Minimize energy expenditure.

2. Obey spatial constraints.

3. Develop emergent properties through architecture.

4. Establish a mechanical equilibrium.

5. Use discrete networks.

6. Maximize tensile materials.

7. Stabilize through triangulation or prestress.8. Use structural hierarchies.

9. Develop self-renewing functional webs through emergence of autocatalytic sets.

10. Enhance functional efficiency through solid-state biochemistry.

Tensegrity: All of the basic design principles listed above are embodied in one

architectural system that is known as tensegrity. Tensegrity is a prestressed structure,

having architectural system, in which, structures stabilize themselves by balancing the

counteracting forces of compression and tension. It gives shape and strength to both

natural and artificial forms ((Ingber, 2008). The necessary and sufficient conditions, for

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On the other hand, Mechanobiology wants to predict growth and differentiation

of tissue and cells in quantitative terms, based on a given force exerted on a given tissue

matrix populated by cells (van der Meulen and Huiskes 2002). Thus,

Mechanobiology is mainly concerned with the study of the influence of mechanical

forces on cells and tissues and their clinical or therapeutical applications. Naturally,

mechanobiological research is based on interdisciplinary approaches.

There are numerous examples that show the effect of force on various biological

processes. Mechanical forces (for example, muscle contraction) are essential for healthy

embryonic skeletal development. In the absence of muscle contraction in mouse, there is

loss of shoulder and elbow joints (Kahn et al., 2009); there is cartilaginous fusion of the

femur and tibia in stifle joint of chick (Roddy et al., 2011). Further more, treatment with

agents (e.g., Y27632, cytochalasin D; 2,3-butanedione 2-monoxime (BDM) and ML9)

that disrupt or suppress cytoskeletal tension generation by various mechanisms, inhibit

lung morphogenesis in mouse (Ingber, 2006).

Mechanical strain on bone marrow stromal cells induces proliferation and

differentiation into osteoblast-like cells. Static control and short time strained cells

display no mineralization at all. After long time straining, cells showed significant

mineralization (Griensven et al., 2005)

The structure and function of tendon and ligament are sensitive to alterations in

mechanical loading. Immobilization results in decreased tendon size and strength. This

strength slightly return after tendons are exercised (Lujan, 2010). Mechanical loading

also affects the postnatal development of the supraspinatus tendon-to-bone attachment

(enthesis) (Thomopoulos et al., 2010). The collagen fiber distribution is less organized in

unloaded tendon in comparison to the loaded tendon. Ultimate stress is significantly

lower in the unloaded tendon in comparison to the loaded tendon.

Bone adapts during skeletal growth and development by continuously adjusting

skeletal mass and architecture to changing mechanical environments. The changes may

be summarized into three fundamental rules that govern bone adaptation (Turner, 1998):

1. It is driven by dynamic, rather than static, loading.

2. Only a short duration of mechanical loading is necessary to initiate an

adaptive response.

3. Bone cells are less responsive to routine mechanical loading signals.

Living cells that continually remodel bone are able to sense changes in

mechanical stresses in their local environment and that they respond by depositing newextra-cellular matrix ECM where it is needed and removing it from where it is not

(W olff s Law). Mechanical force (load) affects the organization of the network of

trabeculae bone (Chen and Ingber, 1999). Trabeculae bones are arranged along the line of

action of force and provide maximum strength. It is one of the most beautiful examples of

the importance o f cellular mechanotransduction for regulation of tissue morphogenesis.

Mechanical loading is a critical factor in proper differentiation of stem cells into

cartilage cells (chondrocytes) that synthesis load-bearing tissue. Dynamic loads are more

advantageous than static loads. Similarly, blood vessels, when exposed to pulsating loads,

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the smooth muscle cells align uniformly at a 65 angle to the applied force. Cyclic

stretching induces the production of collagen and proteoglycans (Lujan, 2010 )

In immobilized stifle joints, expression of the COL2A1 and TNC mRNA genes are

adversely affected. There is absence of the inter-articular ligaments, the chondrogenous

layers, the joint capsule, patella region and menisci (Roddy et al., 2011). Further more,

cyclic strain induces actin reorganization, nuclear translocation of MAL/MRTF-A and

tenascin-C expression in fibroblasts (Chiquet et al., 2009).

The mechanosensitive responces of stem cell for differentiation depend on the

biomechanical properties of ECM (Engler et al., 2006). Mesenchymal Stem Cells

(MSCs) are platted onto collagen-coated gels of varying stiffness. On soft, collagen-

coated gels that mimic brain elasticity (0.1-1 kPa), the vast majority of MSCs adhere,

spread, and exhibit an increasingly branched, filopodia-rich morphology. MSCs on 10

fold stiffer matrices that mimic striated muscle elasticity (8-17 kPa) lead to spindle

shaped cells similar in shape to myoblasts. Stiffer matrices (25-40kPa) that mimic the

crosslinked collagen of osteoids yield polygonal MSCs similar in morphology to

osteoblasts.

Mechanotransduction: The mechanical stimuli are converted into a physiological

phenomenon by the following processes:

1. Mechanical coupling: The transformation of the applied force into a force which

is detectable by the cells or the induction of a physical phenomenon.

2. Mechanotransduction: the process by which cells sense and respond to

mechanical signals and is mediated by extracelluar matrix (ECM), transmembrane

integrin receptors, cytoskeletal structures (CSK) and associated signaling

molecules.

3. Signal transduction: The conversion of the mechanical signal into intracellular

physiological signals.

4. Cellular response: Regulation of a gene, release of autocrine or paracrine factors,

expression specific receptors.

Mechanotransduction and Integrins:

Cells are linked together by extracellular matrix (ECM) scaffolds. Cell-matrix

adhesion (the interaction between cells and the components of ECM) contacts act as sites

of mechanosensation. Cells adhere to the ECMs (mainly composed of laminin, collagen,

fibronectin, elastin, glycoproteins and proteoglycans) via binding of specific cell surface

receptors, known as integrins. Integrins molecules are present on the surface o f the cell

membrane and form a multi-molecular bridge between the ECMs and internal

cytoskeleton of the cell. Many of the actin filaments closely associate with myosinfilaments, which slide along each other, shorten and thereby, generate mechanical tension

that is distributed to all elements of the cell, as well as to the external ECM, via their

integrin contact points. Moreover, forces transmitted over these integrins are converted

into changes in the form of intracellular biochemistry and gene expression. The cell-

matrix adhesions regulate the shape and activity of the cell (cell migration, growth, and

differentiation); determine 3-D organization of tissues and organs during embryonic

development and play a role in cancer formation (Geiger et al., 2001 and 2009; Ingber,

2008).

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Integrins: It is the most important receptor that attaches cells to their extracellular

microenvironment. The interaction is likely: ECM-Integrins-Linkers (adaptors)-

cytoskeleton-Nuclear membrane- Gene expressions.

Structu re o f the Integrin:

Extracellular domain: is composed of dimer of alpha (17 types) and beta (8 types)

subunits linked non-covalently. The alpha subunit has 7-bladed b propeller and I-domain;

beta subunit has I-domain only. There is RGD binding site on I-domain of beta unit. Ca2+

are required to maintain structure.

Intracellular domain: It binds to linkers like Vinculin and Talin--linkers to actin. Also

binds Plectin which links to keratin intermediate filaments. ECM-integrin interaction

activates FAK. Integrins coordinate regulation of exogenous tension (matrix rigidity) and

endogenous tension (contractility). The results are:

A: Cells and matrix mutually interact to regulate tension.

B: Tension in the cell microenvironment is distributed by integrin receptors that signal bi

directionally between extracellular and intracellular compartments. Tension levels may

alter outside-in and inside-out integrin signaling. Integrin engagement with extracellular

matrix (ECM) regulates endogenous cellular tension by triggering actin cytoskeletal

organization and acto-myosin contractility. Endogenous tension levels can indirectly or

directly control exogenous tension (matrix rigidity).

M echanotransduction Response:

The network including integrin and the cytoskeleton is activated by mechanical

stress and causes binding of cytoskeletal elements such as talin, paxcillin (PAX), vinculin

(VIN), or focal adhesion kinase (FAK), eventually leading to transcription factor

activation. The GTPase Rho causes realignment of actin stress fibers during FSS and is

associated with induction of gene expression .

Diseases of Mechanotransduction: Not all but most of diseases of heart, GIT, kidneys,

eyes, organs of nervous system, skin, lung, diabetes, pediatric and cancers are rooted into

the mechanotransduction. The obvious causes lie at the level of ECM, Integrins, Lnkers

CSK and Nucleus (including nuclear membrane). New drugs are targeted at these entry

levels to cure the tedious and fatal diseases.

Applications of Mechanobiology: There are several applications for the treatment of

diseases. The following are a few examples:

1. Fracture fixation now emphasizes micromotion to accelerate new bone formation.

There is improved callus formation when micromotion occurs at fracture (Lujan, 2010).

2. Future techniques to reduce bone resorption.

i. Distraction osteogenesis (limb lengthening)

ii. Osteoporosis: Mechanical loading of bones is taking a central role in treatment

and prevention of this disease.

3. Cross-fiber massage performed on ligament after injury, improves fiber orientation and

strength (Lujan, 2010).

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4. Skin wound healing: Skin wound healing takes a long time when there is no fluid

pouring on the wound. The laminar fluid flow enhances the wound healing, while the

turbulence fluid flow takes longer time than the laminar fluid flow (but the time is shorter

than the time taken by the no fluid flow therapy).

5. Most o f the physiotherapies are based on the proper knowledge of mechanobiology.

6. Diagnosis of Cancer cell Metastasis: Simulation studies indicate that the most

important factor in the metastasis of cancer cells is the cell-matrix adhesions. An altered

ECM enhances the metastasis of cancer cells. Reestablishment of biomechanical

properties of ECM prevents the metastasis (Chaplain et al., 2011).

7. The knowledge of mechanobiology is assisting efforts in tissue engineering.

Bioreactors are being used to apply loading regimes during tissue culture to engineer

functional constructs that can withstand large and recurring forces. In future there will be

developing of multiscale models for the cancerous cell metastasis. The molecules those

mediate mechanotransduction including ECM molecules may represent future targets for

therapeutic innervations (Makale, 2007).

8. Therapeutic strategies of left ventricle of heart should include either a complete and

continuous reduction of load or normalization of left ventricular mass by interventions

aimed at specific targets involved in mechanotransduction (Tavi et al., 2001).

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An Introducttion to Mechanobiology

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