584 | Nature | Vol 582 | 25 June 2020
Article
dendritic cells retained a weak locomotive capacity even in smooth
channels (Extended Data Fig. 3a, b, Supplementary Video 7). This is in
line with previous findings that, compared with T cells, dendritic cells
have a higher capacity to transmit forces via unspecific transmem-
brane coupling^8 ,^12 ,^14. These data demonstrate that force transmission
of leukocytes follows a continuum of strategies. They can flexibly use
integrin-mediated adhesion, unspecific transmembrane force coupling
and, if both strategies fail due to the absence of suitable ligands, can
efficiently utilize surface topography to transmit forces.
As a framework to understand topography-based locomotion, we
propose a minimal model (Fig. 3a–c, Supplementary Text) in which
actin is described as a viscous gel that travels from the leading to the
trailing edge of the cell in the absence of any tangential friction force
with the substrate. In serrated but not in smooth channels, this flow
generates local shear stresses and thus a pressure gradient in the actin
gel, which drives locomotion by imposing non-vanishing normal forces
onto the substrate. Here the actin flow generated in the cell can couple
to the environment when its topographical features are smaller than
the flow scale of the actin cortex. To test this prediction, we varied the
period of serrated topography from 6 to 12 to 24 μm. Serrated sectors
were followed by smooth areas as an internal control (Fig. 4a). Wild-type
T cells effectively traversed all (including smooth) channel designs,
while talin-KO cells migrated in 6-μm and 12-μm period patterns but
rarely in the 24-μm patterns (Fig. 4b–d, Extended Data Fig. 4a), in which
the spacing exceeded the average length scale of cortical actin flow in a
cell (Extended Data Fig. 4b). In channels with a successively increased
serration period, continuous single-cell observation showed that, in
qualitative agreement with model predictions, cells slowed from 6 to
12 μm, presented even slower and saltatory movement in the 24-μm
stretches and were unable to enter the smooth channel (Fig. 4c, d,
Supplementary Video 8). The model also predicts a linear depend-
ence of the propulsion force on actin flow speed. Actin flow has two
mechanical components: polymerization pushes filaments from the
front to the back, while actomyosin contraction pulls at the back^12 ,^15 –^17.
Accordingly, inhibition of myosin II slowed down but did not stall cells
under adhesive conditions (Extended Data Fig. 5a–f ). Following dual
inhibition of adhesion and contractility, cells still performed better in
the serrated than in the smooth channels (Extended Data Fig. 5d–f ),
suggesting a direct relation between actin flow speed and locomo-
tive force, as predicted. Next, we quantitatively imaged the actin flow
of talin-KO and EDTA-treated cells in textured channels and found an
increase in the actin retrograde flow relative to the substrate when-
ever the cells slowed between the topographical features (Fig. 4e–g,
Extended Data Fig. 5g, Supplementary Video 9). This suggests that, in
analogy with the molecular clutch formed by transmembrane recep-
tors, topographical features allow the coupling of retrograde actin flow
to a substrate. Finally, we devised an entirely orthogonal approach,
in which we placed primary mouse T lymphocytes on surfaces that
were either passivated or coated with the integrin ligand intracellular
adhesion molecule 1 (ICAM1) and overlaid them with a pad of agarose.
As shown previously^8 , cells migrated on ICAM1, but slipped and did
not migrate on passivated substrate (Extended Data Fig. 6a–g). We
then used passivated surfaces with engraved linear ridges to introduce
anisotropic topography. We found that on these surfaces, migratory
capacity was rescued and that cells predominantly migrated perpen-
dicular but not parallel to the ridges (Extended Data Fig. 6a–g, Sup-
plementary Video 10). Within the same cell, actin showed retrograde
flow in relation to the substrate when the flow was aligned with the
ridges, but not in orientation perpendicular to the ridges (Extended
Data Fig. 7, Supplementary Video 10). Together, these data demonstrate
that the cells slipped in an orientation along the ridges and coupled in
an orientation perpendicular to the ridges.
In our experiments, we demonstrated topography-based force trans-
mission by controlling the topography of the environment, meaning
that we extrinsically imposed shape changes of the cell. To directly link
this to the amoeboid (shape-changing) principle, we tested whether
cells can autonomously generate appropriate deformations. Morpho-
metric analysis of T cells showed that they have the intrinsic capacity
to produce rearwards-propagating deformation waves (Extended Data
Fig. 8a–e and previously published studies^18 –^23 ) and that the travelling
speed of these waves scaled with the speed of actin flow. Such deforma-
tion waves could intercalate with any textured environment and propel
a cell as conjectured by Abercrombie^2.
Altogether, our findings demonstrate that cells can transmit forces
by coupling the retrograde flow of actin to a geometrically irregular
environment, and that this can happen in the complete absence of any
transmembrane receptors that link the cytoskeleton to the substrate.
Notably, force transmission by specific adhesion receptors, by unspecific
friction and by shape change are not mutually exclusive mechanisms.
Rather, they are variants of the same fundamental principle of couplingO < LO ∞Cell cortexForceO = 2π/kCon ning
wallF-actin owv 0v 0Lcaby
xy
xw(x)
U = 0U > 0h+(x)
h–(x)CytoplasmFig. 3 | Physical model of adhesion-free cell migration in a complex
environment. a, Scheme of the model: the channel has a varying wavy
cross-section w(x) and period λ = 2π/k. The cell contains cortical F-actin that
presents a retrograde f low of length L, an average speed v 0 and is modelled as a
viscous f luid layer of thickness h(x). b, Scheme of a modelled cell in a smooth
channel with an adhesion-free coupling of the actin cytoskeleton with the
environment. The cell is polarized and has a high retrograde actin f low (black
arrows) but cannot move forwards. c, Scheme of the modelled non-adhesive
cell in a serrated channel. Cell propulsion is created by the shear stress in the
actin cortex, which is caused by the bending of f low lines (black arrows) by the
environmental topography. This induces a pressure gradient in the cortical
F-actin mesh and thus non-vanishing normal forces onto the substrate. U, cell
speed.