DNA Nanotechnology as an Emerging Tool to Study Mechanotransduction in Living Systems

Pui‐Yan, Victor; Salaita, Khalid

doi:10.1002/smll.201900961

Cited by 70 publications

(48 citation statements)

References 123 publications

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“…We previously developed molecular tension-based fluorescence microscopy (MTFM) to address the challenge of realtime mapping of the pN forces exerted by live cells (1). MTFM probes are anchored to a surface and composed of a spring-like element flanked by a fluorophore and quencher and presenting a biological ligand for receptor recognition (2,3). The key design requirement for MTFM probes is to maximize fluorophore quenching when the probe is at rest and to conversely minimize quenching when the probe experiences pN force.…”

mentioning

confidence: 99%

DNA probes that store mechanical information reveal transient piconewton forces applied by T cells

Kellner

Pui‐Yan

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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107

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The advent of molecular tension probes for real-time mapping of piconewton forces in living systems has had a major impact on mechanobiology. For example, DNA-based tension probes have revealed roles for mechanics in platelet, B cell, T cell, and fibroblast function. Nonetheless, imaging short-lived forces transmitted by low-abundance receptors remains a challenge. This is a particular problem for mechanoimmunology where ligand–receptor bindings are short lived, and a few antigens are sufficient for cell triggering. Herein, we present a mechanoselection strategy that uses locking oligonucleotides to preferentially and irreversibly bind DNA probes that are mechanically strained over probes at rest. Thus, infrequent and short-lived mechanical events are tagged. This strategy allows for integration and storage of mechanical information into a map of molecular tension history. Upon addition of unlocking oligonucleotides that drive toehold-mediated strand displacement, the probes reset to the real-time state, thereby erasing stored mechanical information. As a proof of concept, we applied this strategy to study OT-1 T cells, revealing that the T cell receptor (TCR) mechanically samples antigens carrying single amino acid mutations. Such events are not detectable using conventional tension probes. Each mutant peptide ligand displayed a different level of mechanical sampling and spatial scanning by the TCR that strongly correlated with its functional potency. Finally, we show evidence that T cells transmit pN forces through the programmed cell death receptor-1 (PD1), a major target in cancer immunotherapy. We anticipate that mechanical information storage will be broadly useful in studying the mechanobiology of the immune system.

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mentioning

confidence: 99%

DNA probes that store mechanical information reveal transient piconewton forces applied by T cells

Kellner

Pui‐Yan

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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107

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“…MTP is similar to TGT in that both use the same property of a DNA duplex, which can be ruptured by a defined force. Unlike TGT, which prevents excessive force to exert on the receptor-ligand bond upon DNA rupture, MTP reports the number of receptor-ligand bonds with an above threshold force exerting on them, which unzips a DNA hairpin to separate a quencher from a fluorophore to allow fluorescence to be imaged [65]. A consequence of the different dynamic bond types is that they greatly amplify the differential bond lifetimes between the positive and negative selection ligands under 10-15 pN force.…”

Section: Force Enhances the Discriminative Power Of Positive And Negamentioning

confidence: 99%

Mechanotransduction in T Cell Development, Differentiation and Function

Rushdi

Yuan

et al. 2020

Cells

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Cells in the body are actively engaging with their environments that include both biochemical and biophysical aspects. The process by which cells convert mechanical stimuli from their environment to intracellular biochemical signals is known as mechanotransduction. Exemplifying the reliance on mechanotransduction for their development, differentiation and function are T cells, which are central to adaptive immune responses. T cell mechanoimmunology is an emerging field that studies how T cells sense, respond and adapt to the mechanical cues that they encounter throughout their life cycle. Here we review different stages of the T cell’s life cycle where existing studies have shown important effects of mechanical force or matrix stiffness on a T cell as sensed through its surface molecules, including modulating receptor–ligand interactions, inducing protein conformational changes, triggering signal transduction, amplifying antigen discrimination and ensuring directed targeted cell killing. We suggest that including mechanical considerations in the immunological studies of T cells would inform a more holistic understanding of their development, differentiation and function.

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“…Forces in the order of pico-Newtons, applied by integrins on ligands, have also been assessed by DNA mechanotechnology (Brockman et al, 2018;Glazier et al, 2019;. However, significant challenges regarding the integrity of the DNA probes in cell culture conditions and the type of receptor-ligand interactions that can be probed remain (Ma and Salaita, 2019;Yasunaga et al, 2019).…”

Section: Conclusion and Outlooksmentioning

confidence: 99%

Mechanical Characterization for Cellular Mechanobiology: Current Trends and Future Prospects

Narasimhan

Ting

Kollmetz

et al. 2020

Front. Bioeng. Biotechnol.

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DNA Nanotechnology as an Emerging Tool to Study Mechanotransduction in Living Systems

Cited by 70 publications

References 123 publications

DNA probes that store mechanical information reveal transient piconewton forces applied by T cells

DNA probes that store mechanical information reveal transient piconewton forces applied by T cells

Mechanotransduction in T Cell Development, Differentiation and Function

Mechanical Characterization for Cellular Mechanobiology: Current Trends and Future Prospects

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