The soft framework of the cellular machine

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Original entry: Nefeli Georgoulia, APPHY 226, Spring 2009

The soft framework of the cellular machine

This publication is not directly relevant to capillarity and wetting. Nevertheless, it is fascinating since it provides a review of past and present research in the field of cell micro-rheology <math>^1</math>. The cell owes its shape and mechanical properties to an assortment of filamentous structures which comprise the cytoskeleton. These are: microtubules (MT), microfilaments (MF) and intermediate filaments (IF). Rheological measurement of these structures have attracted scientific attention, especially because in vitro reconstituted filamentous networks of all three sorts display viscoelastic behavior. Small deformations elicit an elastic response in these networks, whereas at large deformations they become viscous. This observation correlates with cellular function very well: cells can respond to small mechanical stimuli by elastic deformation, all the while retaining the ability to be very stiff when faced with a large mechanical stimulus (and resist destruction). This behavior is referred to as strain-stiffening. This theory has largely been based on rheological measurements performed on in vitro protein networks, while the intent to test the theory on the cytoskeleton of live cells has yet to overcome a few obstacles. One is that in vivo all three filaments are intertwined in a tight and crowded cytoskeletal structure. Another obstacle is the molecular noise and movement of a living cell, which interferes with measurements.

However, Sivaramakrishnan et al.<math>^2</math> have overcome these in their studies of alveolar epithelial cells, by chemically dissolving the cell membrane, cytoplasmic content, microtubules and microfilaments, all the while maintaining an intact structure of keratin intermediate filaments. They then proceed to perform multiparticle tracking microrheology by injecting small fluorescent PEG-coated probe particles in the remaining networks. The results shed significant light into the cellular machinery. As demonstrated in the image the cells, which constitute the interior lining of lungs, display a shrinking of the keratin-network mesh size as one moves from the membrane toward the nucleus (fig.B). The authors identify three zones according to keratin filament concentration, and track the thermal motion of beads in them with microscopy. From the bead's random walk (fig.A), the mean square displacement is extracted (fig.C) and from that the elastic modulus is calculated (fig.D). The elastic modulus <math>G'</math> decreases from zone 1 to zone 3 (fig.E), indicating that near the nucleus (zone 1), these cells have thick, entangled keratin networks to ensure prompt elastic response to movement of the nucleus. Near the cell periphery, the networks are more dilute and less elastic to accommodate cellular plasticity and facilitate cell motility. The viscous regime could not be probed with this experimental method, mostly because the thermal motion of beads can not induce large enough deformations to induce the cellular strain-stiffening. A lot is waiting to be discovered in this field of study!

Keratin.jpg

  • <math>^1</math>D. A. Weitz & P. A. Janmey,'The soft framework of the cellular machine', PNAS 2008, 105, 1105–1106
  • <math>^2</math>Sivaraj Sivaramakrishnan, James V. DeGiulio, Laszlo Lorand, Robert D. Goldman & Karen M. Ridge, 'Micromechanical properties of keratin intermediate filament networks', PNAS 2008, 105, 889–894


Don's Comments: It would be helpful to people without rheological backgrounds to provide some basic information on rheology,
such as explaining the physical/material properties that G' and G' ' represent. This general information could also go on
the "Stubs" page.
Why is this interesting to you? Could we reproduce these cellular networks artificially to have similar rheological response? --Lidiya 02:25, 18 February 2009 (UTC)

Tony's Comments: Wow, that is really cool that there has been some in vivo microrheology. I read recently cancerous cells are a far more "soft" than their healthy counterparts (Cross et al. Nanomechanical analysis of cells from cancer patients. Nature Nanotechnology 2007 Vol.2 (p.780)) as this allows them to easily filter through the body's vascular and lymph system. However these studies have all been done by essentially poking cells with an AFM and reporting the ease with which they are deformed. It would be really interesting to see someone do some in vivo microrheology of cancerous vs. non-cancerous cells. Also, I presume that the particles were not forced except by the cytoskeleton? If this was the case (passive microrheology) then its actually pretty tricky to figure out what the properties of the cytoskeleton are since the cell is not at thermodynamic equlilibrium - which the typical passive microrheology analysis relies upon. A recent paper presented some "active microrheology" (in vitro) where they managed to separate out the effects of the passive and motor induced response of these networks (MacKintosh et al. Active and Passive Microrheology in Equilibrium and Nonequilibrium Systems. Macromolecules 2008, 41 (19) 7192).