Home | Pregnancy Timeline | News Alerts |News Archive Mar 10, 2015

Myosin (red) swarms to the site where a cell is probed.   Image Credit: Win Pin Ng and Sungmin Son, Johns Hopkins University School of Medicine

Mechanical stress is key in cell to cell fusion

The process of cell fusion was thought to be simple and straight forward, but turns out to be complicated. It is a two way street where one cell protrudes into another, while the invaded cell pushes back. Resistance is critical to the fusion process. Without it, the cell being invaded is simply pushed away ending fusion.

Researchers have found that in fusion, a receiving cell plays its part by producing a key structural protein in response to pressure on it's cell wall. The study helps us better understand the fusion process which we see again and again in muscle formation, cell regeneration, fertilization, as well as in our immune response system.

The work appeared March 9 in the journal Developmental Cell.

"We knew that in cell fusion, one cell attacks its fusion partner, but we didn't know how the other cell responded," says Elizabeth Chen, PhD , an associate professor of molecular biology and genetics at the Johns Hopkins University School of Medicine. "Now we know that the other cell is putting up resistance."

The merging of two cells is crucial at conception and throughout the development and physiology of complex organisms. It was long thought to be a symmetrical process with both cells equally involved. But two years ago, Chen's research revealed fusion is initiated by fingerlike protrusions extended into a second cell.

For this study, Chen's group and collaborators focused on the receiving cell. Using fruit fly embryos and lab-grown cells induced to fuse, researchers observed that when "attacking cells" drilled through the cell membrane of another cell, the cell "uner attack" quickly fortified it's own cellular skeleton, creating resistance.

"We think that by stiffening its skeleton, the receiving cell avoids being pushed away from the attacking cell. The interplay of the two cells pushing against one another brings both cell membranes into close proximity so that fusion can proceed."

Elizabeth Chen, PhD , associate professor, Molecular Biology and Genetics, Johns Hopkins University School of Medicine.

But how are cell building blocks, such as the protein myosin II, being summoned to respond? In order to find out, Chen's group turned off cell surface proteins in fly embryos' receiving the protrusions of "attacking" cells, proteins known to relay chemical signals.

"In most cells, we saw myosin still swarm to the fusion site, despite chemical signaling having been disabled."

Elizabeth Chen, PhD

In other words, myosin can still "sense and respond" to pressure on the outside of the cell wall even after being disabled. Myosin's "mechanosensory" response was also seen when Chen's collaborators used either a tiny pipette to apply a pulling force or a tiny probe to apply a pushing force to lab-grown cells. But how?

So, there is much still to learn about the process of cell fusion. Chen's group plans to continue examining how pressure on the cell membrane activates specific skeletal proteins to respond and thus facilitate cell fusion — a process critical to life beginning and regenerating.

Abstract
Highlights
•Invasive protrusions trigger a mechanosensory response in a cell-fusion partner
•Mechanosensory function of MyoII directs its accumulation at the fusogenic synapse
•MyoII increases cortical tension and promotes fusion pore formation
•Mechanical tension at the fusogenic synapse drives cell membrane fusion

Summary
Membrane fusion is an energy-consuming process that requires tight juxtaposition of two lipid bilayers. Little is known about how cells overcome energy barriers to bring their membranes together for fusion. Previously, we have shown that cell-cell fusion is an asymmetric process in which an “attacking” cell drills finger-like protrusions into the “receiving” cell to promote cell fusion. Here, we show that the receiving cell mounts a Myosin II (MyoII)-mediated mechanosensory response to its invasive fusion partner. MyoII acts as a mechanosensor, which directs its force-induced recruitment to the fusion site, and the mechanosensory response of MyoII is amplified by chemical signaling initiated by cell adhesion molecules. The accumulated MyoII, in turn, increases cortical tension and promotes fusion pore formation. We propose that the protrusive and resisting forces from fusion partners put the fusogenic synapse under high mechanical tension, which helps to overcome energy barriers for membrane apposition and drives cell membrane fusion.

Other authors on the paper are Ji Hoon Kim, Yixin Ren, Shuo Li, Yee-Seir Kee, Shiliang Zhang and Douglas N. Robinson of The Johns Hopkins University; Win Pin Ng, Sungmin Son and Daniel A. Fletcher of the University of California, Berkeley; and Guofeng Zhang of the National Institute of Biomedical Imaging and Bioengineering.

Return to top of page

Cell skeleton can affect cell proliferation

It appears that a cell's skeleton can trigger multiplication of more cells through proteins that control its otherwise rigid cell wall. This process uses genes that promote cancer - oncogenes - also become activated and can lead to tumor formation.

A research team from Instituto Gulbenkian de Ciencia (IGC; Portugal), led by Florence Janody, in collaboration with Nicolas Tapon from London Research Institute (LRI; UK), discovered that the cell's skeleton can trigger the multiplication of cells through the action of proteins that control cellular rigidity. During this process genes that promote cancer - oncogenes - become activated, leading to tumor formation in living organisms. This study was published in the latest edition of the scientific journal Current Biology*.

The cell's skeleton - the cytoskeleton - is composed of a mesh of filaments made of protein. Similar to our skeleton that supports our body and helps us in several daily functions, the cytoskeleton confers the shape of the cell, helps cells moving, and also works as a road that proteins use to move inside the cell and perform their job. For long, scientists have been studying the different roles of the cytoskeleton, but only recent studies done in cultured cells suggested that mechanical forces could impact on how the cytoskeleton is organized and could result in the proliferation of cells. Florence Janody and her team took a step forward and have now shown that proteins of the cytoskeleton, which control mechanical forces, can induce the activation of factors that promote tumor growth in a living organism: the fruit fly (Drosophila melanogaster, in its scientific name). Janody's team observed that when the dynamics of the cell's skeleton changes, this leads to different rearrangements in the mesh of filaments, which can have direct consequences on cell proliferation and tissue overgrowth: if the cytoskeleton becomes less elastic, the cells proliferate faster.

Using both genetic and molecular approaches, the research team identified a protein important for this process, named Zyxin. This protein controls the "correct" assembly of the cytoskeleton to allow cell's normal function. If Zyxin does not work properly, it compromises the cytoskeleton organization, unleashing the function of other proteins that ultimately lead to uncontrolled cell proliferation and tumor development.

Florence Janody says: "The cell's skeleton has been discovered more that 150 years ago, as the cellular structure allowing muscles to create forces. We came to realize only recently that mechanical forces generated by the cell's skeleton dictate the behavior of all cells of the body. The next challenge will be to identify the large diversity of mesh of skeleton filaments built in the cells and characterize their mechanical properties".

Pedro Gaspar, researcher in Florence Janody's laboratory and first author in this study, adds: "We hope that our findings will shed new light to understand how mechanical forces are relayed through the cell skeleton and how they impact on cell proliferation. In the future, we hope these perspectives may inspire new bioengineering approaches in tumor therapy and regenerative medicine."

Since the proteins identified in fruit flies to be involved in this mechanism also exist in other organisms, including humans, it is expected that similar mechanisms also occur in human cells.

###

This study was carried out at Instituto Gulbenkian de Ciencia (Oeiras, Portugal), funded by Fundacao para a Ciencia e a Tecnologia (FCT), and at London Research Institute, Cancer Research UK (London, UK), funded by Cancer Research UK (CRUK).

Return to top of page