Division is a key step in the life of cells and involves complex dynamic interplay between a large number of molecular components. CNRS biologists at the Institut Curie and theoretical physicists of the Max Planck Institute in Germany have devised a theoretical model of cell division of great predictive value.
They have used microtechnology to study individual cell divisions as their environment changes. Based on observations of a great many cells, the researchers have devised a theoretical model that predicts the orientation of cell division. The model, which is reported in the 24 May 2007 issue of Nature, is based on calculation of the forces exerted on the mitotic spindle within the cell, and describes how cells divide normally and what happens when something goes awry. The model shows that certain configurations of the microenvironment induce asymmetric cell division. Once applied to tissues, the model will enable diagnoses to be refined, by describing the abnormal division of diseased cells.
Division is an essential stage in the life of all cells: it is involved in growth of the organism, repair of wounds or infections, and regular renewal of cells. At any given moment, 250 000 million cells are dividing in our bodies. Each of these cells has a very precisely defined location, which is essential to maintaining the shape of tissues and organs. Constraints imposed by other cells—the environment—influence the division and positioning of daughter cells.
Manuel Théry in the CNRS team of Michel Bornens has developed an original approach which he is now pursuing at the Commissariat à l’Energie Atomique in Grenoble(1), to study how a cell’s surroundings affect its division. A method called micropatterning is used to modulate the cell’s environment and observe its response, by imposing a given contour on the cell while giving it different adhesion zones, as if it were surrounded by other cells. This reproduces the spatial information that a cell is likely to receive within its tissue.
The CNRS team of Michel Bornens at the Institut Curie and the theoretical physics group of Frank Jülicher, Director of the Max Planck Institute for the Physics of Complex Systems in Dresden, Germany, have joined forces to use this microtechnology to model cell division. They have measured the orientations of thousands of cell divisions and used their findings to propose a mechanical model of the orientation of the mitotic spindle, an ephemeral cellular structure present only during cell division, based on the activation of motor molecules at the cell surface.
These motors, which are found where the cell contacts its microenvironment, pull on the astral microtubules and orient the spindle. This mechanism aligns the cell’s plane of division with the geometry of its environment.
The researchers have also shown that certain spatial configurations of the cellular microenvironment induce asymmetric orientations of the spindle. Whether or not cell division is symmetric is primordial in the fate of the resulting daughter cells. These results could therefore have interesting applications in the control of the symmetric or asymmetric divisions of stem cells in vitro.
Only microtechnologies such as the micropatterning technique can be used to study the individual “sensitivity” of cells and to derive laws to predict the distribution of cell division orientations, without knowing the details of the molecular mechanisms involved. These laws apply to an embryo or to an organism that is undergoing renewal. In time it may prove possible to describe the mechanics brought into play during development. This may not only result from but also actively regulates the genetics underpinning tissue growth.
It is now possible to quantify precisely a cell’s capacity to respond to its environment, and to identify cells that behave “abnormally”, like cancer cells. Once this model can be applied to tissues, physicians will be able to refine their diagnosis by gathering information on the way division is perturbed in diseased cells.
This work illustrates the value of exchanging skills and know-how, and shows how the bringing together of researchers from different backgrounds, which has long been central to the Institut Curie’s approach, generates a dynamic environment conducive to creativity. In particular, one of the great originalities of the Institut Curie has been to develop collaborations between physicists and biologists. This interface affords another vision of the world of the living cell, and promises much in our understanding of the complexity of living organisms.
Note: (1) Manuel Théry is currently at the Laboratoire Biopuces, in the Institut de Recherches en Technologies et Sciences pour le Vivant (iRTSV) of the Commissariat à l’ Energie Atomique in Grenoble.
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