Environmental Factor, July 2011, National Institute of Environmental Health Sciences
Duke researcher gives 2011 Rodbell Lecture
By Robin Arnette
Hogan is the George Barth Geller Professor and chair of the Department of Cell Biology at Duke University Medical Center. She also serves as director of the Duke Stem Cell and Regenerative Medicine Program. (Photo courtesy of Jennifer Weinberg)
Lecture host Williams shares interests with Hogan in the area of reproductive biology. (Photo courtesy of Jennifer Weinberg)
NTP postdoctoral fellow Erik Tokar, Ph.D., is a member of the NTP Inorganic Carcinogenesis Branch. (Photo courtesy of Jennifer Weinberg)
Every breath that a terrestrial organism takes is critical to its survival, but the lung is often overlooked in terms of its importance. One researcher, however, who finds beauty in the organ, is Brigid Hogan, Ph.D. Hogan studies lung development in embryonic mice, and hopes her work will lead to a better understanding of birth defects and possibly how environmental factors influence the process of lung development. She discussed her research on June 14 at NIEHS as the 2011 Dr. Martin Rodbell(http://www.niehs.nih.gov/about/highlights/nobel.cfm) Lecture Series speaker.
Hogan(http://www.cellbio.duke.edu/brigid-l-m-hogan/) began her talk by describing the lung as a highly vascularized, branched system of airways. The tree-like organization gets smaller and smaller, ending at the periphery with tiny air sacks called alveoli. She said a layer of epithelial cells line the alveoli, and part of the intricacy of the lung hinges on the many different cell types that line the airway (see text box). She wondered, though, about how did all of these cell types begin. How were they generated, and how were they able to organize properly? These questions formed the basis of her research.
"We determined that in a nine-day old mouse embryo, the lung starts as two little buds which come off on the ventral part of the foregut," Hogan explained. "Thanks to the research contribution of several labs, we now know that signaling pathways in the mesoderm and endoderm drive the expression of the transcription factor Nkx2-1 at the tip of the ventral foregut where the buds form."
The role of signaling pathways in lung development
To determine whether the epithelia cells in the tips of the foregut were able to develop into many different types of cells, one of Hogan's postdocs tracked the cells' descendants. The experiment, called lineage tracing, occurred over a period of several days, and began by marking individual tip cells using a pulse of tamoxifen, a drug that interferes with the activity of estrogen and is used to treat some types of breast cancer. Developmental biologists have co-opted it to switch on special "reporter" genes that can trace all the descendants of a cell in an organ as it develops.
The lineage tracing results showed that the transcription factor Id2 (inhibitor of differentiation) is expressed specifically in these tip cells along with another transcription factor called Sox9. Id2 continues to be expressed in these cells until just before the structure gives rise to the alveoli. These findings have significant human health implications, because premature babies are born at a stage before alveolar cells are generated. Scientists need to know what controls this switch for making the terminal buds and how it can be protected in these babies.
Stem cells in the adult lung
After looking at embryonic tissue, Hogan asked if any of these multipotent cells remained in the adult lung. Another member of her team did a lineage tracing of secretory cells and found that even though they have differentiated characteristics, they could self-renew over a long period of time and help repair small airways after injury. Work with undifferentiated basal cells taken from other parts of the mouse lung demonstrated that these cells function as multipotent stem cells. Basal cells are found throughout the airways of the human lung, and as long-term stem cells, they may be vulnerable to changes induced by toxic and inflammatory agents.
Carmen Williams, M.D., Ph.D.(http://www.niehs.nih.gov/research/atniehs/labs/lrdt/reproductive/index.cfm), an NIEHS researcher with dual appointments in the Laboratory of Reproductive and Developmental Toxicology and the Clinical Research Program, hosted the lecture and spoke afterward about the significance of Hogan's body of work. "Dr. Hogan's use of powerful mouse genetics techniques to perform lineage tracing experiments has enabled her to identify multipotent lung progenitor cells that could lead to new treatment modalities for human lung injury."
Fellow stem cell expert, Guang Hu, Ph.D.(http://www.niehs.nih.gov/research/atniehs/labs/lmc/stemcell/index.cfm), head of the NIEHS Stem Cell Biology Group, also attended the lecture and said, "Her studies help us better understand the lung's response to environmental toxins and have accelerated the development of stem cell-based therapies for lung diseases."
Epithelial cell types in the mouse lung
Trachea and the main stem of bronchi: ciliated, secretory, and basal cells
Bronchioli: ciliated, secretory, and neuroendocrine, but no basal cells
Alveolus: Type 1 and Type 2 cells