Heidelberg University (Germany) researchers decode molecular mechanism of collective cell migration important for wound healing.
For wounds to close, cells need to
move collectively in one direction in a coordinated fashion. Until now
the central molecular mechanism that allows cells to coordinate these
movements over larger distances has been unclear. Now researchers from
Heidelberg University and the Max Planck Institute for Intelligent
Systems in Stuttgart have succeeded in decoding it. Collective cell
migration is not only important in wound healing, but also in the
development of the embryo and even of cancer. The results of their
research, published in the journal “Nature Cell Biology”, have
tremendous implications for all three of these areas.
“The collective migration of cells and biological systems is one of
the most important natural phenomena and occurs in nature at different
levels and length scales. We have now identified the key molecular
player and the related mechanism that controls the collective migration
of epithelial cells, that is the covering layer of skin cells,” explains
Prof. Dr. Joachim Spatz of the Institute for Physical Chemistry at
Heidelberg University and the Max Planck Institute for Intelligent
Systems. In their investigation, the researchers introduce a complete
molecular mechanism that focuses on the protein called Merlin. The
results link intercellular mechanical forces to collective cell
movements and also demonstrate how local interactions give rise to
collective dynamics at the multicellular level. “They create an analogy
with what we already know about collective movements observable in both
the biological and physical world,” explains Prof. Spatz.
The researcher compares the process of cell migration to running a
marathon. “At the level of the organism, an individual in a collective
consciously tries to align its movements with those of its neighbours,
which involves orchestrated sensing and action.” Within a cellular
collective, these two processes are linked via signal transduction
pathways. There is a lead cell in the collective, similar to the leader
in a marathon. It is mechanically connected to its follower cells by
cell-to-cell contacts. The forward motion of the lead cell puts
mechanical tension on the follower cells, according to Spatz. The merlin
protein senses this mechanical tension and initiates spatially
polarised following movement. This transmits the mechanical tension
among the follower cells from one cell to the next. The follower cells
respond by forming ‘leg-like’ protrusions directed at the lead cell in
order to move forward.
“Until now it has been unclear what molecular link connects these two
events, sensing and action,” says Joachim Spatz. “Our study now shows
how the mechanosensitive Merlin protein converts cellular forces to
collective cell motions by acting as a mechanochemical transducer.
What’s truly astonishing is that Merlin is the only protein in the
responsible signal network that conveys this property to cellular
collectives – that there are no replacement mechanisms. If Merlin fails,
the cells lose their ability to move collectively and trigger the
related medically relevant, pathophysiological properties in the
organism”.
The major player in the study, Merlin, is also a known tumour
suppressor that is responsible for several types of cancer. Merlin is
also a regulator of the Hippo pathway, an important signal pathway in
biology that controls cell proliferation and organ size. It has been
preserved in evolution since the emergence of primitive multicellular
organisms. “It’s exciting to see a connection between these seemingly
disparate fields, linked by a Merlin-mediated signalling mechanism,”
says the researcher.
Researchers from the Hamamatsu Tissue Imaging and Analysis (TIGA)
Center at the BioQuant Centre of Ruperto Carola and the National Center
for Tumor Diseases (NCT) Heidelberg also participated in the study.
Original publication:
T. Das, K. Safferling, S. Rausch, N. Grabe, H. Boehm, J. Spatz: A
molecular mechanotransduction pathway regulates collective migration of
epithelial cells. Nature Cell Biology (published online 23 February
2015), doi: 10.1038/ncb3115
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