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Review
. 2022 Jan 31;45(1):26-32.
doi: 10.14348/molcells.2022.2049.

Molecular Tension Probes to Quantify Cell-Generated Mechanical Forces

Kyung Yup Baek  1   2 , Seohyun Kim  1   2 , Hye Ran Koh  1
Affiliations
Review

Molecular Tension Probes to Quantify Cell-Generated Mechanical Forces

Kyung Yup Baek et al. Mol Cells. .

Abstract

Living cells generate, sense, and respond to mechanical forces through their interaction with neighboring cells or extracellular matrix, thereby regulating diverse cellular processes such as growth, motility, differentiation, and immune responses. Dysregulation of mechanosensitive signaling pathways is found associated with the development and progression of various diseases such as cancer. Yet, little is known about the mechanisms behind mechano-regulation, largely due to the limited availability of tools to study it at the molecular level. The recent development of molecular tension probes allows measurement of cellular forces exerted by single ligandreceptor interaction, which has helped in revealing the hitherto unknown mechanistic details of various mechanosensitive processes in living cells. Here, we provide an introductory overview of two methods based on molecular tension probes, tension gauge tether (TGT), and molecular tension fluorescence microscopy (MTFM). TGT utilizes the irreversible rupture of double-stranded DNA tether upon application of force in the piconewton (pN) range, whereas MTFM utilizes the reversible extension of molecular springs such as polymer or single-stranded DNA hairpin under applied pN forces. Specifically, the underlying principle of how molecular tension probes measure cell-generated mechanical forces and their applications to mechanosensitive biological processes are described.

Keywords: cellular forces; mechanobiology; molecular spring; molecular tension fluorescence microscopy; tension gauge tether; tension probes.

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Conflict of interest statement

CONFLICT OF INTEREST

The authors have no potential conflicts of interest to disclose.

Figures

Fig. 1
Fig. 1. Schematic of force-dependent cellular pathways.
Cell senses mechanical forces generated by ligand–receptor interaction (direct) or by deformation of ECM (indirect) and responds to them either via gene transcription, adaptor recruitment, actin polymerization, or ion channel gating.
Fig. 2
Fig. 2. Schematics of TGT and MTFM to quantify cellular forces at the pN level.
(A) Schematic of TGT assay. The cellular force larger than the rupture force of the dsDNA tether activates the mechanosensitive receptor. (B) The rupture force of dsDNA depends on the force application geometry, which is the lowest at the unzipping geometry and the highest at the shearing geometry. (C) Signal of cell activation increases with increasing rupture force of dsDNA tether, exhibiting the threshold force required for cell activation marked by a dotted line. (D) Schematics of MTFM using PEG (top) and DNA hairpin (bottom) as a tension probe. A molecular tension probe is conjugated with a ligand of interest, a fluorophore, and a quencher. (E) DNA hairpin exhibit a more abrupt change of fluorescent intensity compared with PEG at the threshold force in response to external forces, and the percentage of GC content and the length of the DNA hairpin stem modulate the intensity of threshold force.
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