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Dec 11, 2013

Tracking Push-Me Pull-You Cells in Developing Embryos

  • Although the tractive forces exerted by cells roaming petri dishes have been measured, hardly anything is known about the forces generated by cells as they assemble three-dimensional tissues and shape embryonic organs. A new technique, however, is characterizing the forces generated by cells in aggregates of living tissue. Besides promising to explicate the role of cell-generated mechanical forces in embryonic development, this technique may advance knowledge regarding other processes including birth defects, tumor growth and metastasis, and diseases in which imbalanced cellular forces play a role.

    The technique was described in an article published December 8 in Nature Methods, in an article entitled “Quantifying cell-generated mechanical forces within living embryonic tissues.” In this article, the authors presented “a method to quantify cell-generated mechanical stresses exerted locally within living embryonic tissues, using fluorescent, cell-sized oil microdroplets with defined mechanical properties and coated with adhesion receptor ligands.”

    “After a droplet is introduced between cells in a tissue,” the authors continued, “local stresses are determined from droplet shape deformations, measured using fluorescence microscopy and computerized image analysis.”

    The technique described in the paper was developed initially in the Wyss Institute at Harvard University by Otger Campàs, Ph.D., and Donald E. Ingber, M.D., Ph.D., both of whom are listed among the paper’s authors. Now an assistant professor who holds the Mellichamp Chair in Systems Biology at UC-Santa Barbara, Dr. Campàs leads a lab that is exploring the technique’s possibilities.

    “There is a lot of interest in understanding how genetics and mechanics interplay to shape embryonic tissues,” said Dr. Campàs. “I believe this technique will help many scientists explore the role that mechanical forces play in morphogenesis and, more generally, in biology.”

    Highlighting the differences between cellular forces generated in an embryo and those generated in a petri dish, Dr. Ingber, director of the Wyss Institute, added, “It has not been possible to demonstrate a direct causal relationship between mechanics and behavior in vivo because we previously had no way to directly quantify force levels at specific locations in 3D living tissues.”

    The paper’s authors reported that after applying their oil-drop method, they were able to quantify the anisotropic stresses generated by mammary epithelial cells cultured within 3D aggregates. In addition, they confirmed that these stresses “are dependent on myosin II activity and are more than twofold larger than stresses generated by cells of embryonic tooth mesenchyme, either within cultured aggregates or in developing whole mouse mandibles.”

    In evaluating the significance of these findings, the authors looked forward to bringing mechanobiology to a new level. “The technique,” they wrote, “is well suited for any study that requires quantification of stresses generated by individual living cells or groups of cells in culture, embryonic tissues or adult organs. This technique should therefore enable quantitative analysis of the role of cellular forces in embryonic development and potentially in disease processes as well.”

    According to Dr. Ingber, examples of disease processes that could be studied include “hyper contractility in airway smooth muscle cells in asthma; vascular smooth muscle cells in hypertension; intestinal smooth muscle in irritable bowel disease; skin connective tissue cells in contractures and scars, etc. as well as low contractility in heart muscle cells in heart failure, and so on.” Investigating the forces behind tissue stiffness and contractility may also aid the diagnosis of tissue abnormalities.



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