Foreword: You might not know that, while pursuing biology as my major field of study, I am also a physics enthusiast. Over the past year, I have been exploring cell mechanobiology, the intersection of these two disciplines. I was surprised to find new technologies, new experimental approaches, and new perspectives on biology research taking root in physics principles; furthermore, it moved me that these unconventional practices are showing so much promise to medicine and healthcare. Hence, I would like to begin this thriving year of 2025 with a journal on this thriving field of mechanobiology. I will publish them in two separate blogs; this is the first half.
Over the past decade, the field of cell mechanobiology has gained much attention. It was increasingly recognized that without a thorough understanding of cell mechanics, so many unknowns remain about cell behavior that they impeded breakthroughs in research and application.
The field of cell mechanobiology introduces transformative perspectives on the cell. First, it is not merely the “laboratory” of biochemical reactions but also a dynamic, three-dimensional body; it interacts with its external environment while changing its structure and properties adaptively. More specifically, an adherent cell performs diverse behaviors on its substrate, which include spreading, migration, proliferation, alignment with other cells, etc. In addition, many behaviors share a mechanical driver: for instance, cell spreading and migration both gain thrust from the cytoskeleton, particularly the actin stress fibers. Therefore, while our study focuses on cell spreading with spatial confinement, our model and predictions for cell spreading may apply to cell migration and other analogous behaviors.
Topics in cell mechanobiology usually involve two intracellular structures: the nucleus and the cytoskeleton. Both participate in mechanotransduction, as they sense mechanical stimuli and respond by changing their structures, morphologies, and spatial organizations [1]. While these changes alter other cellular pathways and create ripple effects, they are also within limits for the cell to maintain its mechanical integrity and functionality. In recent years, the nucleus and the cytoskeleton were further viewed as a single mechanical unit to recognize their structural connections [1]. Diverse perspectives of the organelles are integral to our understanding of cell spreading.
The nucleus, about 6-10 μm in diameter, is the largest and stiffest organelle of the cell. It rises from the cell body when the cell is attached to a flat substrate; the result is a clear distinction between the high nuclear region and the low lamellipodial region. The nucleus is approximately 5-10 times stiffer than its surrounding cytoskeleton [2]. Nonetheless, it is noteworthy that the nucleus can modulate its stiffness to resist mechanically applied tension via the phosphorylation of emerin in the inner nuclear membrane. The dense nuclear lamina lines the interior of the nuclear envelope and dampens external forces. Nuclear deformation is either a recoverable response to transient decreases of extracellular osmotic pressure, or an unhealthy condition in an unbalanced mechanical environment.
The impacts of mechanical stress on the cell are much more amplified in the cell cytoskeleton than in the nucleus. Comprised of microtubules, actin filaments, and intermediate filaments, the cytoskeleton is a dynamic skeletal system that structures and supports the cell. Microtubules (approx. 25 nm in diameter) radiate from the centrosome near the nucleus; actin filaments (approx. 7 nm) form long stress fibers across the cell and a thin actin cortex underlying the plasma membrane; intermediate filaments (approx. 10 nm) constitutes the nuclear lamina and anchors organelles [4].
References
[1] Kalukula, A. D. Stephens, J. Lammerding, and S. Gabriele, “Mechanics and functional consequences of nuclear deformations,” Nature Reviews Molecular Cell Biology, vol. 23, no. 9, pp. 583–602, May 2022, doi: 10.1038/s41580-022-00480-z.
[2] Lammerding, “Mechanics of the Nucleus,” Comprehensive Physiology, vol. 1, no. 2, pp. 783–807, Apr. 2011, doi: 10.1002/cphy.c100038.
[3] B. Enyedi and P. Niethammer, “A Case for the Nuclear Membrane as a Mechanotransducer,” Cellular and Molecular Bioengineering, vol. 9, no. 2, pp. 247–251, Jan. 2016, doi: 10.1007/s12195-016-0430-2.
[4] M. Cooper, “Intermediate Filaments,” The Cell - NCBI Bookshelf, 2000. https://www.ncbi.nlm.nih.gov/books/NBK9834/.