Modeling cell-substrate de-adhesion dynamics under fluid shear

Abstract

Changes in cell-substrate adhesion are believed to signal the onset of cancer metastasis, but such changes must be quantified against background levels of intrinsic heterogeneity between cells. Variations in cell-substrate adhesion strengths can be probed through biophysical measurements of cell detachment from substrates upon the application of an external force. Here, we investigate, theoretically and experimentally, the detachment of cells adhered to substrates when these cells are subjected to fluid shear. We present a theoretical framework within which we calculate the fraction of detached cells as a function of shear stress for fast ramps as well as the decay in this fraction at fixed shear stress as a function of time. Using HEK and 3T3 fibroblast cells as experimental model systems, we extract characteristic force scales for cell adhesion as well as characteristic detachment times. We estimate force-scales of ∼500 pN associated to a single focal contact, and characteristic time-scales of [Formula: see text] s representing cell-spread-area dependent mean first passage times to the detached state at intermediate values of the shear stress. Variations in adhesion across cell types are especially prominent when cell detachment is probed by applying a time-varying shear stress. These methods can be applied to characterizing changes in cell adhesion in a variety of contexts, including metastasis.

Biophysics of Cell-Substrate Interactions Under Shear

“…We now discuss models for cell adhesion and describe a recently proposed simple model for how the number of adhered cells vary with the flow (Maan et al, 2018). Such adhesion is primarily mediated by the integrin family of proteins as discussed in earlier sections.…”

“…They also have varying spread area and their FAs distributions may be further altered under applied stresses. Fluid shear-based deadhesion experiments to quantify the critical shear stress for cell detachment offer a distinct advantage in measuring the attachment strength of cells to substrates (Holle and Engler, 2011; Maan et al, 2018).…”

Correlation of in vitro cell adhesion, local shear flow and cell density

“…The mechanical event of cell adhesion and detachment is also a thermodynamic process. To apply a minimal model as in other earlier publications 7,21,22 following the pioneering works of Bell, 23 we consider the cell adhesion molecules either in adherent (A) or unbound (B) state. An according Gibbs potential can be approximated by a potential with two minima as illustrated in Fig.…”

“…25 However, many studies investigate cell detachment for surface coverage in the range of 50%. 7 We here performed detachment experiments as described above but varying the cell density, while all other parameters are kept constant. Fig.…”

“…To ensure the osseointegration of medical implants, it is of particular interest to quantify the strength of cell adhesion to substrates under ow. Research in that direction today can be categorized by four techniques, namely centrifugation, spinning disk devices, ow chambers and microuidics as summarized by Khalili et al 4 It began with a rotating disk in a uid above a substrate with adhered cells, [5][6][7] and rotating centrifugal systems. 8 Changing the concept from rotating systems, ow chambers providing a linear variation of shear stress 9 were established.…”