New discoveries about role of blood vessels in early lung development

A research team at The Saban Research Institute of Children's Hospital Los Angeles has made critical new discoveries about the role of blood vessels in guiding early lung development, especially in the essential, highly reproducible branching pattern of lung airways.

The study has earned the investigators the cover story in the June issue of the high-impact medical journal, Development. "For a scientist, this is as exciting as being on the cover of Time, Vogue or Vanity Fair is for a politician or showbiz celebrity," said David Warburton, DSc, MD, director of Developmental Biology and Regenerative Medicine at The Saban Research Institute, who headed the research team.

Traditionally, blood vessels have been regarded as an inert network of tubes that supply tissues with nutrients and oxygen, in a process called perfusion. However, The Saban Research Institute team found, in a series of laboratory experiments, that blood vessels also determine the reproducible three-dimensional branching pattern of lung airways.

In a major scientific advance, the investigators also described, for the first time, the fine, three-dimensional structure of the relationship between the developing lining of the lung's airways and the capillaries.

"If these structures are not perfectly aligned, you can't breathe," explains Dr. Warburton. "We see this problem all the time in sick babies in our Newborn and Infant Critical Care Unit at Children's Hospital."

Understanding this critical process of alignment will yield clues that may someday enable these regenerative medicine specialists to engineer lung tissue for newborns with pulmonary hypoplasia (incomplete lung development), as well as for adults with lung failure due to such common diseases as chronic obstructive pulmonary disease and emphysema.

The team employed a breakthrough computer-based three-dimensional reconstruction technique in its studies to view lung tissue and its growth processes at work.

During development, the coordinated branching of the breathing tubes and blood capillary tubes culminates in their co-alignment in the mature lung. The researchers found that when they blocked the signaling mechanism that controls the formation of capillaries, key elements of the alignment process no longer took place.

Specifically, while two-dimensional epithelial branching continued at a nearly normal rate, there was a marked overall reduction in the number of branching events that would normally enter the third dimension. Most importantly, branching processes failed that would normally be needed to rotate the branching process into the third dimension—essential to developing a three-dimensional organ.

The team also identified one reason for the defect in 3-dimensional airway branching—a disturbance in the distribution of specific growth factor signals.

"We've discovered some important things about how the airways talk to the capillaries through growth factors provided by the epithelium," said Dr. Warburton, "but precisely how the capillaries talk to the airways remains an open question. The ultimate objective of this research is to make new lung tissue for people who need it." Next, the research team will seek to understand the molecular mechanisms by which this conversation takes place.

The research is being carried out in collaboration with Dr. Eli Keshet and his team at the Hebrew University of Jerusalem.

Brent Polk, MD, director of The Saban Research Institute said, "The team led by Dr. Warburton is uncovering fundamental mechanisms of the developmental origins of childhood and adult diseases. His group demonstrates the power of interdisciplinary investigators addressing questions that have direct relevance to human health and well being. This approach is representative of our international collaborative strengths at The Saban Research Institute."