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.


 
  • Want to know more about these subjects? Click on the buttons below for more news.

    RIMLSNanomedicine

Related news items


BRAINMODEL: precision medicine for brain disorders

25 October 2021

A team of researchers from Radboudumc, VU Amsterdam and other institutes is going to look for new and better ways to heal developmental disorders in the brain.

read more

How healthy is James Bond? - A flu to a kill No time to die: the pathogens surrounding secret agent 007

21 October 2021

James Bond made a total of 25 films between 1962 and 2021. In all those films, secret agent 007 washed his hands only twice, even though he often stayed in not so hygienic places with considerable health risks. Radboudumc researchers examined all the health risks in the 47 countries Bond visited.

read more

Surprisingly dominant cause underlying type I congenital defect of glycosylation

21 October 2021

Alex Garanto, Melissa Bärenfänger, Mirian Janssen, and Dirk Lefeber published a new study, identifying a surprisingly dominant genetic cause underlying type I congenital defect of glycosylation with neuromusculoskeletal phenotypes.

read more

Sensitive blood-test as a patient-friendly alternative for bone marrow-based cancer monitoring

20 October 2021

Hans Jacobs and Pieter Langerhorst, theme Cancer development and immune defense, and colleagues are one step closer to implementation of personalized diagnostics for bone marrow-based cancer monitoring.

read more

Register for peer coaching for RIMLS PhD candidates

20 October 2021

As a PhD candidate, you are in the lead of your own learning process, but you don’t need to do this alone. Register for the peer-coaching group ‘Stay in the lead – Together’ before 11 November 2021.

read more