Abstract
The mechanical properties of cells change with their differentiation, chronological age, and malignant progression. Consequently, these properties may be useful label-free biomarkers of various functional or clinically relevant cell states. Here, we demonstrate mechano-node-pore sensing (mechano-NPS), a multi-parametric single-cell-analysis method that utilizes a four-terminal measurement of the current across a microfluidic channel to quantify simultaneously cell diameter, resistance to compressive deformation, transverse deformation under constant strain, and recovery time after deformation. We define a new parameter, the whole-cell deformability index (wCDI), which provides a quantitative mechanical metric of the resistance to compressive deformation that can be used to discriminate among different cell types. The wCDI and the transverse deformation under constant strain show malignant MCF-7 and A549 cell lines are mechanically distinct from non-malignant, MCF-10A and BEAS-2B cell lines, and distinguishes between cells treated or untreated with cytoskeleton-perturbing small molecules. We categorize cell recovery time, ΔTr, as instantaneous (ΔTr~0 ms), transient (ΔTr⩽40 ms), or prolonged (ΔTr>40 ms), and show that the composition of recovery types, which is a consequence of changes in cytoskeletal organization, correlates with cellular transformation. Through the wCDI and cell-recovery time, mechano-NPS discriminates between sub-lineages of normal primary human mammary epithelial cells with accuracy comparable to flow cytometry, but without antibody labeling. Mechano-NPS identifies mechanical phenotypes that distinguishes lineage, chronological age, and stage of malignant progression in human epithelial cells.
Highlights
Cells derive their mechanical properties from the structure and dynamics of their intracellular components, including the cytoskeleton, cell membrane, nucleus, and other organelles—all of which, in turn, emerge from cell type-specific genetic, epigenetic, and biochemical processes
We investigated whether mechano-node-pore sensing (NPS) could distinguish between immortal malignant and non-malignant states in two different epithelial tissue types based on their mechanical properties alone
We previously reported a method for producing post-stasis and immortal human mammary epithelial cells (HMECs) cell lines in the absence of gross, and confounding, genomic errors[81]
Summary
Cells derive their mechanical properties from the structure and dynamics of their intracellular components, including the cytoskeleton, cell membrane, nucleus, and other organelles—all of which, in turn, emerge from cell type-specific genetic, epigenetic, and biochemical processes. Atomic-force microscopy (AFM)[15,16,17] and micropipette aspiration[18,19] are the gold standard for performing mechanical measurements on cells These methods provide controlled loading conditions (for example, stress relaxation and creep indentation) and quantify such cellular properties as elastic modulus and cortical tension. Optical tweezers[23,24] and microplate rheometery25—two other wellestablished methods to measure cellular mechanical properties — suffer from low throughput Given these drawbacks, a number of microfluidic platforms have been developed, including hydrodynamic stretching cytometry[26,27,28], suspended microchannel resonators (SMR)[29], and real-time deformability cytometry (RT-DC)[30], to name only a few. Populations of cells are Received: July 2017; revised: September 2017; accepted: 16 October 2017 a PDMS mold
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