Cell contact guidance via sensing anisotropy of network mechanical resistance

Greeshma Thrivikraman Nair, Alicja Jagiełło, Victor K. Lai, Sandra L. Johnson, Mark Keating, Alexander Nelson, Billianne Schultz, Connie M. Wang, Alex J. Levine, Elliot L. Botvinick, Robert T. Tranquillo

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


Despite the ubiquitous importance of cell contact guidance, the signal-inducing contact guidance of mammalian cells in an aligned fibril network has defied elucidation. This is due to multiple interdependent signals that an aligned fibril network presents to cells, including, at least, anisotropy of adhesion, porosity, and mechanical resistance. By forming aligned fibrin gels with the same alignment strength, but cross-linked to different extents, the anisotropic mechanical resistance hypothesis of contact guidance was tested for human dermal fibroblasts. The cross-linking was shown to increase the mechanical resistance anisotropy, without detectable change in network microstructure and without change in cell adhesion to the cross-linked fibrin gel. This methodology thus isolated anisotropic mechanical resistance as a variable for fixed anisotropy of adhesion and porosity. The mechanical resistance anisotropy | Y*| -1 - | X*| -1 increased over fourfold in terms of the Fourier magnitudes of microbead displacement | X*| and | Y*| at the drive frequency with respect to alignment direction Y obtained by optical forces in active microrheology. Cells were found to exhibit stronger contact guidance in the cross-linked gels possessing greater mechanical resistance anisotropy: the cell anisotropy index based on the tensor of cell orientation, which has a range 0 to 1, increased by 18% with the fourfold increase in mechanical resistance anisotropy. We also show that modulation of adhesion via function-blocking antibodies can modulate the guidance response, suggesting a concomitant role of cell adhesion. These results indicate that fibroblasts can exhibit contact guidance in aligned fibril networks by sensing anisotropy of network mechanical resistance.

Original languageEnglish (US)
Article numbere2024942118
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number29
StatePublished - Jul 20 2021

Bibliographical note

Funding Information:
microscope and associated image analysis software (NIS-Elements Confocal, NIS-Elements Confocal Advanced Research). Funding support for this work was provided by NSF/Chemical, Bioengineering, Environmental, and Transport

Funding Information:
Systems (CBET) Grant 1606008 (to R.T.T.), NIH Grant R01-EB005813, NSF Grant 1763272, University of California Office of the President Grant MRI-17-454791, and NIH Grant R01-HL085339 (to E.L.B.).

Publisher Copyright:
© 2021 National Academy of Sciences. All rights reserved.


  • Contact guidance | aligned fibril networks | mechanical resistance anisotropy | fibroblasts


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