HARVARD GAZETTE ARCHIVES
Mystery of how lungs grow is solved
Cells 'feel' the pressure to grow
By William J. Cromie
Harvard News Office
The puzzle of how lungs grow has been solved. Scientists watching the process in mice embryos have found that budding and branching of new air sacs is driven by the mechanical stretching of individual cells.
What's more, they demonstrated that this growth can be adjusted by manipulating mechanical forces involved in the cells' skeleton, a framework of fine tubes and filaments that give the cell its shape and let it move.
By increasing tension in this so-called cytoskeleton, "We've shown that we can speed up lung development, and that we can slow it down by decreasing tension," says Donald Ingber, Judah Folkman Professor of Vascular Biology at Harvard Medical School. Such a capability might be a first step in finding new ways to prevent, minimize, or even correct human diseases and malfunctions of the lungs. For example, it might produce novel treatments to accelerate lung development in premature infants, who often suffer from incomplete lung development.
"Ingber's findings could lead to new approaches to treating bronchopulmonary dysplasia, a serious lung disease that affects 30 to 40 percent of all premature babies," notes Stella Kourembanas, chief of newborn medicine at Children's Hospital Boston, where the research was done. The new understanding could also be helpful in treating "lung hypoplasia, in which lungs are compressed and cannot develop fully," she adds.
Ingber and his colleagues reported the details of their research in the February issue of the journal Developmental Dynamics.
During development, tissues in humans and mice exist in a state of tension wherein all their cells pull on each other. They also pull on a flexible matrix of fibrous proteins and sugars that surrounds and supports every cell. Other cells beneath growing lungs release proteins that unravel and thin down small regions in the tensed matrix. These spots stretch more than the rest of the matrix, causing a thinning that Ingber compares to a run in a nylon stocking. These areas are stretched more than neighboring parts of lung tissue.
If they feel that extra tension, cells will begin to grow. They will bud and branch outwardly, forming new sacs. But decreases in tension stop growth.
These growing lungs need a supply of blood to function. And the researchers have seen an extension of small, nearby blood vessels, or capillaries, growing in tandem with new air sacs. "Capillary development speeds up and slows down with changes in tension that are driven by expansion of the air sacs which they surround," Ingber notes.
He and his team adjusted the tension in developing mouse lungs by inhibiting or simulating the activity of a protein called Rho. This protein triggers a chemical reaction that contracts the cell's skeleton, increasing tension in the cell and in its connections to the surrounding matrix. When that happens, something has to give. The lung tissue buds outward.
Photographs of normal lung development in mice, taken at 12-hour intervals, clearly show each bud ballooning. A bud enlarges until a cleft forms in its tip, pinching the bud into two or three smaller buds. As growth continues, the lung takes on the appearance of an expanding bunch of sacs, not unlike a cluster of small grapes.
But when growing airways get treated with chemicals that inhibit the activity of Rho, lung budding is inhibited, decreasing by more than half in a period of 48 hours. When Rho is energized, growth of both buds and blood capillaries becomes normalized. If such results can be applied to humans, they "could facilitate development of new approaches to prevent, minimize, or correct congenital lung problems, as well as lung diseases in the newborn," Ingber points out.
For him, this demonstration of how lungs grow is an example of a common form of biological architecture Ingber calls "tensegrity." "The term," he explains, "refers to a system that stabilizes itself mechanically because of the way in which tensional and compressive forces are distributed and balanced within a structure like the human body. An explanation of why tensegrity is so ubiquitous in nature may provide new insight into the very forces that drive biological organization - and perhaps into life itself."