Organ development in the embryo requires precise coordination and timing of cell growth in three-dimensional space to produce the correct anatomic form and shape. Researchers at Children's Hospital Boston, led by Dr. Donald Ingber, a senior researcher in the Vascular Biology Program, have demonstrated that the process of budding and branching in the developing lung is driven by mechanical forces generated within individual cells. They have also identified a possible biochemical target for intervention. These insights could lead to new ways to prevent, minimize or even correct diseases and anomalies of the lungs, which are common in premature newborns.
Previously, Ingber and colleagues have shown that epithelial tissues – the thin cell layers that line organs and other body structures, including the lung's airways -- take their characteristic three-dimensional forms through differences in cell growth in different spatial locations. This cell growth is influenced by changes in the extracellular matrix, the flexible, egg-carton-like structure that surrounds and supports cells. Cells are physically connected to the matrix via their cytoskeleton, an internal scaffolding of crisscrossing fibers and tubes that generates tensional forces like those in muscle. Through these tensed connections, cells can "feel" mechanical forces that push and pull on the tissue they are in. If they feel a stretch, cells will begin to proliferate; if they feel compressed, they stop growing and may begin to die off. The parts of the tissue with greater cell growth expand more rapidly than the surrounding areas, causing buds and branches to form.
In this new paper, published in the February 2005 issue of Developmental Dynamics, Ingber and colleagues manipulated the mechanical force felt by developing mouse lungs by modulating the activity of a cellular signaling enzyme called Rho. Rho facilitates a chemical reaction that causes contraction of fibers in the cytoskeleton, increasing tension in the cell and in its connections to the matrix. Ingber's team put lungs from embryonic mice in culture and exposed them to various chemical agents that stimulate or inhibit Rho's activity. In normal mice, photographs taken every 12 hours as the lungs grew showed each bud enlarging until a cleft formed in its tip, pinching it into two or three new buds.
When lungs were treated with inhibitors of the Rho pathway, lung bud formation was reduced by more than half when examined 48 hours later. When treated with agents that activate Rho and promote cytoskeletal contraction, budding increased. The agents had similar effects on the growth and development of nearby capillary blood vessels, which must grow in tandem with lung tissue to form a functional organ.
"We've showed that we can slow down lung development and capillary growth by decreasing the level of tension in the cytoskeleton, or speed up development by increasing the tension," says Ingber, the Judah Folkman Professor of Vascular Biology at Harvard Medical School. "This work could lead to novel therapeutic approaches to accelerate lung development in premature infants who often are debilitated by incomplete lung formation."
Dr. Stella Kourembanas, chief of Newborn Medicine at Children's, says that Ingber's findings could lead to new approaches to treating bronchopulmonary dysplasia, a serious lung injury that affects 30 to 40 percent of all premature babies, and lung hypoplasia, in which the lungs are compressed and cannot develop fully, often due to congenital diaphragmatic hernias, which occur in 1 of 2,500 births. Kourembanas is directing an NIH-funded project on the pathology of lung development, of which Ingber is a part.
"Don's work gives us an understanding of how normal lung growth occurs, and gives us tremendous insights into potential intervention pathways," she says.
Ingber is a pioneer in the new, growing field of mechanobiology--the study of how physical forces affect the function and behavior of living cells and tissues and, ultimately, disease. At the turn of the last century, scientists commonly described biological phenomena in terms of mechanics.
"The early developmental biologists watched embryos developing, and saw it as a mechanical process," Ingber says.
This appreciation of mechanics and form fell away as the 20th century progressed. With the advent of molecular biology in the 1970s and 1980s, scientists became focused on finding and mapping individual chemicals and genes as a way of understanding physiology and disease. In this new paper, Ingber and colleagues clearly show that molecular signaling and mechanical forces work hand in hand.
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