Drive mechanism for alveoli formation revealed

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Many organ systems found in animals exhibit very complex structures, which are essential for their various functions. How such structures develop during embryonic development is a central question in biology. Physicists led by Erwin Frey (professor of statistical and biological physics at LMU Munich) and Andreas Bausch (professor of cell biophysics at Technical University of Munich) studied this fundamental problem using mini-organs called organoids as an experimental system. The team focused on the spherical “alveoli” in which the ducts of the lactating mammary gland terminate. The study demonstrated in detail that these alveoli form according to the same principles as droplets in a jet of water coming out of a pipe.

The experimental work was performed in Bausch’s lab and used mammary gland organoids grown in culture from excised human tissue. Organoids are three-dimensional model systems that exhibit many physiologically relevant properties of the organ from which they originate. Thus, the organoids of the mammary gland form ducts that branch out into groups of smaller tubular structures, each terminating in a spherical sac or alveolus. This architecture is typical of the lactating human mammary gland, but it is also found in many other organs including the lung. Bausch and his group were able for the first time to follow the growth dynamics of mini-organs over several days by time-lapse microscopy. In addition, they investigated the micromechanical response of developing tissue to localized laser-induced cell ablation.

Using this strategy, the researchers were able to link the formation of spherical alveoli to a change in the direction of cell movement in developing tissue. The cells in each tubule are constantly in motion, pulling on their immediate neighbors. At first, they collectively migrate back and forth along the walls of the tubules. “But at some point, the cells at the end of the tubules start to follow a spinning path. This change in behavior, coupled with interactions between neighboring cells, then propagates backwards until all cells near the end of a branch begin to collectively spin, ”explains group member Andriy Goychuk. research by Erwin Frey and co-author of the publication. His colleagues Pablo Fernandez and Benedikt Buchmann from Andreas Bausch’s group, who performed the ablation experiments, explain what happens as follows. “The cells no longer exert the same force in all directions, which leads to an alteration in their trajectories. While the cells which alternate forward and backward movement exert more force towards the axis of the tube than around its circumference, this is no longer the case for the cells which follow a rotational stroke. Due to the greater tensile stress along the circumference, the tip of each tube develops into a spherical protrusion.

According to the authors, the mode of formation of spherical protuberances is analogous to the mechanism responsible for the formation of drops in a water jet. Like the cells of the developing organoid, the surface of the water jet is under tension. All objects subjected to a tensile force try to minimize their surface. Since the area of ​​a sphere is smaller than that of a cylinder, the water jet breaks down into discrete droplets – and in the tissue of the mammary gland, the rotation of the main cells changes the balance of forces in the tubular branches in such a way that they become unstable, as in the case of the water jet, and form spherical protuberances. “This theoretical model provides an important framework for the analysis of more complex geometric transformations in biological tissues – such as those that occur during the development of the salivary glands, pancreas, kidney and lung,” explains Frey.

Reference: Fernández PA, Buchmann B, Goychuk A, et al. Surface tension induced budding causes alveologenesis in organoids of the human mammary gland. Nat. Physical. 2021; 17, 1130-1136. doi: 10.1038 / s41567-021-01336-7

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