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Mechanosensation and Mechanotransduction: Our Connection to the Outside World

Posted in Biological Networks, Gene Regulation and Evolution, Bone Disease and Musculoskeletal Disease, Cell Biology, Signaling & Cell Circuits, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Human Sensation and Cellular Transduction: Physiology and Therapeutics, Uncategorized, tagged actin, biomechanics, Biophysics, Cellular differentiation, cellular mechanics, Cytoskeleton, forces, hydrostatic pressure, Julius Wolff, mechanical, mechanosensation, mechanotransduction, osteocytes, primary osteocyte, shear stress, Signal transduction, signalling, Vatsa, wollf's law on February 20, 2013| 2 Comments »

Author: Aviral Vatsa PhD MBBS

This is the first post in a series of posts on mechanosensation and mechanotransduction and their role in physiology and disease.

Future posts in this category will focus on various aspects of role of mechanosensation and mechanotransduction in human physiology. These aspects will include among others: gene modulation, cellular mechanosensation, tissue regeneration, stem cell differentiation, cancer, disease models, nanomodulation, material science and therapeutics etc.

Based on Zhang et al [1]

Multicellular organisms such as humans require intricate orchestration of signals between cells to achieve global morphogenesis and organ function and thus maintain haemostasis. Three major ‘signalling modalities’ work in unison intracellularly and/or exrtacellularly to regulate harmonious functioning of the physiological milieu. These ‘modalities’ namely biochemical molecules, electrical currents or fields and mechanical forces (external or internal) cohesively direct the downstream regulation of physiological processes.

Traditionally most of the biological studies have focused on biochemical or electrical signalling events and relatively lesser resources have been dedicated towards exploring the role of mechanical forces in human health and disease. Despite early theories proposed by scientists such as Julius Wolff (Wolff’s law [2]) in the late nineteenth century “ that bone in a healthy person or animal will adapt to the loads under which it is placed”, relatively little has been studied about the role of external mechanical forces in maintaining haemostasis. However, recent important developments such as

identification of external force dependent regulation of signalling pathways [3]
determination of mechanosensing elements of cellular cytoskeleton [4]
manipulation of single molecules [5]

have reinstated the importance of external mechanical forces in physiology. As a result more recent investigations have demonstrated that external mechanical forces are major coordinators of development and haemostasis of organisms [6], [7] [8].

‘Mechanotransduction’ has been traditionally defined as the conversion of mechanical stimulus into chemical cues for the cells and thus altering downstream signalling e.g conformational changes in ion channels might lead to initiation of downstream signalling. However, with the accumulation of new knowledge pertaining to the effects of external mechanical loads on extracellular matrix or a cell or on subcellular structures, it is being widely accepted that mechanotransduction is more than merely a physical switch. Rather it entails the whole spectrum of cell-cell , cell-ECM, and intracellular interactions that can directly or indirectly modulate the functioning of cellular mechanisms involved in haemostasis. This modulation can function at various levels such as organism level, tissue level, cellular level and subcellular level.

Forces in cells and organisms

From biological point of view mechanical forces can be grouped into three categories

intracellular forces
intercellular forces
inter-tissue forces

In the eukaryotic cells these forces are generally generated by the the contractile cytoskeletal machinery of the cell that is comprised of

microfilaments : Diameter-6 nm; example- actin
intermediate filaments: Diameter-10 nm; example- vimentin, keratin
microtubules: Diameter-23 nm; example- alpha and beta tubulin

Actin labeling in single Osteocyte in situ in mouse bone. Source: Aviral Vatsa

Actin (cytoskeleton) staining of single osteocyte in situ in mouse calvaria (source: Aviral Vatsa)

There are a range of forces generated in the biological milieu (adopted from Mammoto et al [8]):

Hydrostatic pressure: mechanical force applied by fluids or gases (e.g. blood or air) that perfuse or infuse living organs (e.g. blood vessels or lung).
Shear stress: frictional force of fluid flow on the surface of cells. The shear stress generated by the heart pumping blood through the systemic circulation has a key role in the determination of the cell fate of cardiomyocytes, endothelial cells and hematopoietic cells.
Compressive force: pushing force that shortens the material in the direction of the applied force. Tensional force: pulling force that lengthens materials in the direction of the applied force.
Cell traction force: is exerted on the adhesion to the ECM and other cells as a result of the shortening of the contractile cytoskeletal actomyosin filaments, which transmit tensional forces across cell surface adhesion receptors (e.g. integrins, cadherins).
Cell prestress: stabilizing isometric tension in the cell that is generated by the establishment of a mechanical force balance within the cytoskeleton through a tensegrity mechanism. Pulling forces generated within contractile microfilaments are resisted by external tethers of the cell (e.g. to the ECM or neighboring cells) and by internal load-bearing structures that resist compression (e.g. microtubules, filipodia). Prestress controls signal transduction and regulates cell fate.

It is the interplay of these forces generated by the cellular cytoskeleton and the ECM that regulate physiological functions. Disruption in mechanotransduction has been implicated in a variety of diseases such as hypertension, muscular dystrophies, cardiomyopathies, loss of hearing, cancer progression and metastasis. Ongoing attempts at unravelling the finer details of mechanosensation hold promising potential for new therapeutic approaches.

References

[1] H. Zhang and M. Labouesse, “Signalling through mechanical inputs – a coordinated process,” Journal of Cell Science, vol. 125, no. 17, pp. 4172–4172, Oct. 2012.

[2] R. A. Brand, “Biographical Sketch: Julius Wolff, 1836–1902,” Clin Orthop Relat Res, vol. 468, no. 4, pp. 1047–1049, Apr. 2010.

[3] A. J. Hudspeth, “The cellular basis of hearing: the biophysics of hair cells,” Science, vol. 230, no. 4727, pp. 745–752, Nov. 1985.

[4] N. Wang, J. P. Butler, and D. E. Ingber, “Mechanotransduction across the cell surface and through the cytoskeleton,” Science, vol. 260, no. 5111, pp. 1124–1127, May 1993.

[5] J. T. Finer, R. M. Simmons, and J. A. Spudich, “Single myosin molecule mechanics: piconewton forces and nanometre steps,” , Published online: 10 March 1994; | doi:10.1038/368113a0, vol. 368, no. 6467, pp. 113–119, Mar. 1994.

[6] P. A. Janmey and R. T. Miller, “Mechanisms of mechanical signaling in development and disease,” J Cell Sci, vol. 124, no. 1, pp. 9–18, Jan. 2011.

[7] R. Keller, L. A. Davidson, and D. R. Shook, “How we are shaped: The biomechanics of gastrulation,” Differentiation, vol. 71, no. 3, pp. 171–205, Apr. 2003.

[8] T. Mammoto and D. E. Ingber, “Mechanical control of tissue and organ development,” Development, vol. 137, no. 9, pp. 1407–1420, May 2010.