Abstract
Cell migration on two-dimensional substrates is typically characterized by lamellipodia at the leading edge, mature focal adhesions and spread morphologies. These observations result from adherent cell migration studies on stiff, elastic substrates, because most cells do not migrate on soft, elastic substrates. However, many biological tissues are soft and viscoelastic, exhibiting stress relaxation over time in response to a deformation. Here, we have systematically investigated the impact of substrate stress relaxation on cell migration on soft substrates. We observed that cells migrate minimally on substrates with an elastic modulus of 2 kPa that are elastic or exhibit slow stress relaxation, but migrate robustly on 2-kPa substrates that exhibit fast stress relaxation. Strikingly, migrating cells were not spread out and did not extend lamellipodial protrusions, but were instead rounded, with filopodia protrusions extending at the leading edge, and exhibited small nascent adhesions. Computational models of cell migration based on a motor–clutch framework predict the observed impact of substrate stress relaxation on cell migration and filopodia dynamics. Our findings establish substrate stress relaxation as a key requirement for robust cell migration on soft substrates and uncover a mode of two-dimensional cell migration marked by round morphologies, filopodia protrusions and weak adhesions.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1290-1299 |
| Number of pages | 10 |
| Journal | Nature Materials |
| Volume | 20 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 2021 |
Bibliographical note
Funding Information:We acknowledge R. Stowers (University of California, Santa Barbara) and the Chaudhuri laboratory for helpful discussion, and M. Levenston (Stanford University) for use of mechanical testing equipment. We also acknowledge the Stanford Cell Sciences Imaging Facility for Imaris software access and for technical assistance with Imaris. Figure 5n is a schematic created with BioRender.com. K.A. acknowledges financial support from the Stanford ChEM-H Chemistry/Biology Interface Predoctoral Training Program and the National Institute of General Medical Sciences of the National Institutes of Health under Award Number T32GM120007, and a National Science Foundation (NSF) Graduate Student fellowship. D.G. was funded in part by a National Institutes of Health Fellowship under Award Number GM116328. This work was supported by a National Institutes of Health National Cancer Institute (NIH NCI) grant (U54 CA210190) for D.J.O. and NIH NCI grant R01 CA232256, NIH National Institute of Biomedical Imaging and Bioengineering awards R01EB017753 and R01EB030876, NSF Center for Engineering Mechanobiology grant CMMI-154857, and NSF grants MRSEC/DMR-1720530 and DMS-1953572 to V.B.S., and by an American Cancer Society grant (RSG-16-208-01) and a NIH NCI grant (R37 CA214136) to O.C.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.