Mechanobiology: a frontier science which explores the effects of mechanical pressures on living tissues

What is mechanobiology?

Mechanobiology studies the way physical forces act on and regulate living tissues, either from within or from the outside. Mechanobiology is an integral component of cell differentiation, tissue renewal and homeostasis. The biomechanical interplay between cells fundamentally shapes tissue organisation and organ development.

Mechanobiology is an emerging field of science, sometimes referred to as a new frontier in biology. Mechanical pressure occurs everywhere in the natural world. The surface of an insect's body is covered with mechanosensors which guide locomotion. Plants alter their growth and shape in response to gravity, wind, or touch.

The science of mechanobiology is interdisciplinary, arising from the fields of physiology, cellular and molecular biology, chemistry, structural engineering, biomechanics, and biophysics.

In Neuroprotective Developmental Care (NDC or the Possums programs), the science of mechanobiology is fundamental to our understanding of human breastfeeding and lactation, and to the development of clinical guidelines. I propose that this is one way in which NDC is at the forefront in the field of breastfeeding and lactation medicine internationally, and that it's only a matter of time before understandings of mechanobiology become integrated across all aspects of healthcare.

What kinds of physical forces act upon or within biological systems?

A range of different mechanical forces impact biological systems. These are

• Compression

• Stiffness

• Elasticity

• Membrane tension

• Hydrostatic pressure

• Shear stress

• Deformation.

What is mechanosensing?

Mechanosensing is the process of converting mechanical stimuli into biochemical signals. Living cells not only generate forces, they sense and respond to mechanical forces or physical cues.

In mammals, mechanosensing affects cell function and numerous biological processes, including

• Embryological development and cell differentiation

• Homeostasis

• Tissue repair, and

• Disease progression.

Sensing: mechanobiological pathway #1

The first mechanobiological task of living cells, tissues and organs is to sense mechanical or physical forces, known as mechanosensing.

Mechanosensors (also called mechanoreceptors) are proteins which change in response to physical forces (or mechanical stimulation).

Mechanosensors are located in two places, either

• On the surface of cells, extending through the cell membrane. Cell surface mechanosensors include integrins, cadherins, and ion channels. Integrins, for example, play a pivotal role in cellular mechanosensing by physically connecting proteins found inside the cell (focal adhesion proteins) to the extracellular matrix.

• Inside the cell, including as the cytoskeleton, nucleoskeleton, focal adhesion proteins, and other proteins also organised into molecular complexes specifically responsive to physical signals.

Transduction: mechanobiological pathway #2

After mechanosensors are changed by a mechanical stimulus, mechanosensing transforms into biochemical signals, in a process known as mechanotransduction. Mechanotransduction pathways include mechanosensitive proteins and organelles, which trigger cascades of biochemical signals.

Therefore, any pushing, pulling, or twisting of the extracellular matrix is sensed by cells through two mechanisms.

• The extracellular matrix has a direct physical connection to the nucleus of the cell, starting with transmembrane mechanosensors such as integrins and cadherins which bind to ligands in the extracellular matrix, like collagen. Through this physical connection, any mechanical perturbation of the extracellular matrix can be directly transmitted to the nucleus, consequently affecting cell behavior and function.

• Mechanical inputs to the cell are transduced into biochemical or electrical signals, through mechanotransduction. Through cell membrane-associated mechanosensitive proteins, the cell is able to perceive mechanical stimuli and trigger mechanosignaling cascades.

Mechanoreciprocity: mechanobiological pathway #3

A major response by the cell to mechanical stress is to change its intracellular tension with specific cytoskeletal rearrangements and contraction of actin and myosin (actomyosin) filaments. This is how a cell counter-balances an external force, in a process known as mechanoreciprocity.

Altered gene expression: mechanobiological pathway #4

Cells respond to mechanosensing and mechanotransduction with epigenetic modification of gene expression. The cascade of signals triggered by mechanical transduction determine the fate and behavior of cells by triggering these epigenomic modifications, which regulate gene expression, which further activates key signalling pathways.

How does mechanobiology help us understand the human physiology?

Human tissues are constantly under static and dynamic mechanical loads. Cell mechanosensing and mechanotransduction regulate human biological processes in a myriad ways. Tissues rely on their individual cells to adapt and function in dynamic and physically demanding environments.

As you look through the following list of examples of how mechanobiology shapes human physiology, you'll start to understand why mechanobiology is fundamental to human health and wellbeing, even though this has only been recently recognised and the mechanisms are still being elucidated. You'll also realise, given how profoundly embodied - how profoundly physical- the acts of breastfeeding and milk removal are, why a deep understanding of mechanobiology is fundamental to any effective clinical breastfeeding and lactation intervention.

The impacts of mechanobiology in some physiological systems seem obvious

• Compressive loads on cartilage and bone during exercise

• Joint movement and muscle contraction

• Generation of blood pressure, including cyclic mechanical stretching of arteries and arterioles in response to cyclic hydrostatic pressure

• Flow-induced shear stress in the vessels of the circulatory and lymphatic systems

• Gut peristalsis

• The somatosensory nervous system

  • Perception of touch, light touch, pressure, vibration, perceived by cutaneous mechanosensors which carry the signals for interpretation in the brain.

  • Perception of pain, perceived by nociceptors and interpreted in the brain.

  • Perception of sound, which is converted into mechanical vibration and interpreted in the brain.

Many other physiological processes are fundamentally shaped by mechanosensing but this can seem less obvious

Cells sense and respond to mechanical cues in embryogenesis. The importance of growth factors and morphogens in the process of growing a single cell into a multi-system organism has long been recognised. But the crucial roles that physical forces and properties play in successful tissue development has only recently begun to be understood.

• Mechanical forces regulate a wide range of cellular activities, including morphogenesis, cell division, protein conformation, migration, polarization, and proliferation.

• Interstitial fluid pressure is regulated at the local tissue level by mechanosensing of pressures, which are affected by factors such as capillary filtration mediated influx, lymph outflow, and the ability of the tissue to expand.

• Mechanosensing and mechanotransduction play vital roles in the cross-talk between stem cells and microenvironments, and how these dynamic interplays are critical in the control of stem cell identity, function and differentiation.

• A multitude of mechanical cues affect the state of macrophages, dictating their function. T-cells, too, are fundamentally mechanosensitive. B-cells rely on mechanical feedback to assess their interaction with antigens. Dendritic cells and other leukocytes, which migrate with their large nucleus facing forward, use their nucleus as a mechanical gauge to assess the pore-size of their microenvironment and to choose the path of least mechanical resistance.

How does mechanobiology help us understand human disease or pathology?

While medicine has typically looked for the genetic and biochemical basis of disease, advances in mechanobiology suggest that changes in cell mechanics, extracellular matrix structure, or mechanotransduction may contribute to the development of many diseases.

All cells are highly sensitive to their physical microenvironment. The field of mechanobiology is leading to advancements in repairing and regenerating damaged tissue, constructing engineered tissues and organs, and providing therapy for diseases. An understanding of mechanobiological mechanisms is helping to generate novel perspectives on the progression and treatment of diseases, and also on the development of new medical devices and biomaterials.

• Mechanical inputs such as flow induced fluid shear stress and contractility play a crucial role in cardiovascular system dysfunctions, including the effects of atherosclerosis and altered mechanical properties of the heart, resulting in cardiac ischaemia or cardiac failure.

• Physical stimuli (tension and pressure) regulate the mechanosensor proteins which affect development and spatiotemporal organization of the nervous system and brain diseases. These mechanosensing pathways become dysfunctional in conditions such as traumatic brain injury, neurodegenerative diseases, or neuroblastoma.

• Cancer was originally believed to be caused solely by genetic mutations affecting cell proliferation, differentiation, survival. But there is now recognition that mechanical factors such as the stiffness, structure and porosity of the local microenvironment can promote tumorigenesis and modulate critical steps during cancer progression.

For example, breast cancer researchers have found that the stiffness of the local microenvironment can modify the behaviour of mammary epithelial cells as they transition from normal alveoli formation to loss of polarity, uncontrolled growth, and invasion. A stiff and fibrous stromal environment promotes invasiveness by upregulating and activating mechanosensitive calcium channels and altering mechanosensitive signaling pathways. It's now widely accepted that women with dense mammary tissue have much higher risk of developing breast cancer.

There is also a strong mechanical basis for many generalised medical disabilities, including

• Lower back pain

• Foot and postural injury

• Joint disease and arthritis

• Osteoporosis

• Irritable bowel syndrome

• Pulmonary fibrosis.

Again, as you consider this discussion on mechanobiology and disease, I hope it becomes obvious to you, as it has been to me, that mechanobiology is a critical component of understanding and clinically responding to the kinds of problems which emerge in breastfeeding and lactation - but has been overlooked until very recently in the research, and completely overlooked clinically until I published elements of this work in Women's Health in 2022.

The big picture: quantum physics, gravitational science, and evolution

Please bear with me here for a minute!

The biggest picture, and frankly, the fundamental context for any scientific endeavour in human health and wellbeing, starts with the universe in which we live, that unthinkable, ever-expanding, primordial womb of creativity composed of two trillion galaxies (each of which contains about 100 billion stars). Each particle which makes up our body was created 13.8 billion years ago in the incomprehensible primordial flaring forth of our universe, more latterly recycled and given to us by the explosion of stars.

One of the stunning mysteries of the universe in which we live, revealed to us by the brilliant quantum physicists and mathematical cosmologists of the 20th century and now by the extraordinary cosmogenesis story emerging from these sciences in the 21st century, is the discovery that everything in the universe acts gravitationally on everything else, from the most microscopic through to the most macroscopic of entities.

Gravitational mathematics teaches us the laws of physical forces and mechanical pressures which continue to determine the constraints within which the universe, the Earth's geophysical forms, and life on Earth has evolved. As a result, mechanical forces act upon and shape the evolution of every single entity and every single living cell.

Yet until the last few years, the foundational effect of gravitational and mechanical forces on the unfolding of Earth's complex biological ecosystems has been largely overlooked. Although mechanical pressures shape the way genes are expressed and the way biological tissues develop, mechanobiology has not featured much at all to date in the study of health and disease. Nor have the effects of mechanobiology been considered in the breastfeeding mother and infant, at least not until very recently, despite the elemental impact of mechanical forces on breastfeeding and lactation. Neuroprotective Developmental Care places mechanobiological principles in their proper place, at the very foundation of our models and our clinical interventions for breastfeeding and lactation related problems.

Selected references

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Basree M, Shinde N, Koivisto C. Abrupt involution induces inflammation, estrogenic signaling, and hyperplasia linking lack of breastfeeding with increased risk of breast cancer. Breast Cancer Research. 2019;21(80):https://doi.org/10.1186/s31058-019-1163-7

Butcher DT, Alliston T, Weaver VM. A tense situation: forcing tumour progression. Nature Review Cancer. 2009;9:108-122.

Douglas P. Re-thinking benign inflammation of the lactating breast: a mechanobiological model. Women's Health. 2022;18:17455065221075907.

Douglas PS. Re-thinking benign inflammation of the lactating breast: classification, prevention, and management. Women's Health. 2022;18:17455057221091349.

Douglas PS. Re-thinking lactation-related nipple pain and damage. Women's Health. 2022;18:17455057221087865.

Fetherstone C. Mastitis in lactating women: physiology or pathology? Breastfeeding Review. 2001;9:5-12.

Ingman WV, Glynn DJ, Hutchinson MR. Inflammatory mediators in mastitis and lactation insufficiency. Journal of Mammary Gland Biology and Neoplasia. 2014;19:161-7.

Jindal S, Narasimhan J, Vorges VF, Schedin P. Characterization of weaning-induced breast involution in women: implications for young women's breast cancer. Breast Cancer. 2020;6(55):https://doi.org/10.1038/s41523-020-00196-3.

Kim T-J. Mechanobiology: a new frontier in biology. Biology. 2021;10(570):https://doi.org/10.3390/biology10070570.

Kobayashi K, Han L, Lu S-N, Ninomiya K, Isobe N, Nishimura T. Effects of hydrostatic ompression on milk production-related signaling pathways in mouse mammary epithelial cells. Experimental Cell Research. 2023;432:113762.

Muncie JM, Weaver VM. The physical and biochemical properties of the extracellular matrix regulate cell fate. Current Topics in Develomental Biology. 2018;130:1-37.

Noam Zuela-Sopilniak, Lammerding J. Can’t handle the stress? Mechanobiology and disease. Trends in Molecular Medicine. 2022;28(9):710-725.

Stewart TA, Hughes K, Stevenson AJ, Marino N, Ju AL, Morehead M, et al. Mammary mechanobiology - investigating roles for mechanically activated ion channels in lactation and involution. Journal of Cell Science. 2021;134:doi:10.124/jcs.248849.

Weaver SR, Hernandez LL. Autocrine-paracrine regulation of the mammary gland. Journal of Dairy Science. 2016;99:842-53.

Zaragoza R, Garcia-Trevijano ER, Lluch A, Ribas G, Vina JR. Involvement of different networks in the mammary gland involution after the pregnancy/lactation cycle: implications in breast cancer. International Union of Biochemistry and Molecular Biology. 2015;67(4):227-38.