20 November 2019

Koen van den Dries and Alessandra Cambi, Dept. of Cell Biology, theme Nanomedicine, revealed how the nanoscale architecture of podosomes enables dendritic cells to protrude and sense their extracellular environment. They have published their results in Nature Communications.

On the photo: From left to right: Koen van den Dries, Alessandra Cambi and research technician Ben Joosten. 

Cells of the immune system such as antigen-presenting dendritic cells migrate long distances through the body, thereby crossing many tissue boundaries or basement membranes. This specialized migration process is controlled by micron-sized cytoskeletal structures called podosomes. An adequate structural framework, however, for how podosomes contribute to this process was still missing. In collaboration with biophysicists from the NKI, the ErasmusMC and McGill University, and benefiting of the Radboud Technology Center MIC, Van den Dries and colleagues have used a variety of super-resolution microscopy techniques to simultaneously image multiple podosome components in human dendritic cells on substrates with different mechanical properties.

They found that, at the nanoscale level, individual podosomes contain several functionally distinct substructures defined by different actin organizations: the very central branched actin substructure polymerizing towards the substrate is encased by filamentous actin, thus generating mechanical forces that allow the cells to protrude. They further identified another substructure composed by actin filaments that, like ropes, link each podosomes to the integrins in the cell membrane and sense differences in tissue stiffness. A fourth type of actin filaments, crosslinked by nonmuscle myosin, connects neighboring podosomes leading to force redistribution. Finally, when exposed to a stiff environment, podosomes mediate long-range substrate exploration, associated with degradative behavior, whereas on soft material, podosomes display only short-range connectivity and a protrusive, non-degradative state.

At the crossroad between cell biology and biophysics, the results from this study redefine the podosome nanoscale architecture and reveal that protrusion and tissue stiffness sensing is controlled by distinct podosome substructures, something which has important implication for how understanding how cells detect weak spots in basement membranes to cross tissue boundaries.

In a broader context, understanding how leukocytes remodel their cytoskeleton while migrating and probing the environment is relevant for several reasons: 1) leukocytes in the tissues deal with patho-physiological changes in tissue stiffness (e.g.: fibrosis, cancer stroma) that influence their function in ways that are still poorly defined; 2) leukocytes are the first cells interacting with biomaterials used for implants, which is known to in turn affect tissue regeneration; 3) many other cell types make podosomes, including osteoclasts in the bone and endothelial cells for vessel sprouting, and cancer cells make podosome-like protrusions called invadopodia that aid cancer dissemination.

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