Our lungs have a complex three-dimensional structure which facilitates respiration and host defence. Building this structure requires that lung embryonic progenitor cells produce the correct types and numbers of cells in the correct sequence. How is this controlled? And how is the final structure maintained in the adult? Our lab investigates the cellular and molecular mechanisms which control stem and progenitor cell fate decisions in the developing and adult lungs. Key unanswered questions include: which cells are the stem and progenitor populations? And what mechanisms control the decision of lung progenitors to self-renew or to differentiate? Our approach is to use the power of mouse genetics to understand the control of lung progenitor cell behaviour at the single cell level. This allows individual cells to be analyzed quantitatively in vivo, or by live imaging in organ culture systems.

Low magnification view of the embryonic mouse lung showing the branching airways (blue) and differentiating bronchiolar cells (red and green).

We have previously shown that in the embryonic lung there is a population of Id2+ multipotent epithelial progenitor cells located at the distal tips of the budding epithelium. The developmental potential, or competence, of these cells changes during embryogenesis. At the same time the cells undergo a change in gene expression pattern. Currently we are testing the function of some of these genes, which are hypothesized to regulate the sequence of descendents produced by the progenitors.

The identity of the epithelial stem and progenitor cells in the postnatal lung remains controversial. Our previous work has shown that each anatomical region (trachea, bronchioles, alveoli) has its own progenitor cell population and that the behaviour of these progenitors can change in response to local conditions. Our current postnatal work focuses on:

• Better characterizing the adult lung progenitor cells. This includes testing whether progenitor cell behaviour is widespread or there are stem cells.

• Understanding the genetic regulation of the progenitors under several different physiologically-relevant conditions. In particular, we are focusing on genes that are hypothesized to control the decision to self-renew or differentiate.

Wholemount early stage embryonic lungs stained for Id2 mRNA (purple), which is located at the distal tips of the budding epithelium. The lungs form by progressive branching of an epithelial tube, which is surrounded by loosely packed mesenchymal cells.

Higher magnification view of a section of the late-stage embryonic lung. Id2+ progenitor cells (green) are located at the tips of the branching airways (red).

Plain English:
Our ability to breathe at birth requires that during embryonic development our lungs make many types of specialized cells, arranged in a specific structure. This structure must then be maintained throughout life, even when the air that we breathe is contaminated by pollutants and toxins. Building and maintaining the lung involves progenitor cells. These cells divide to generate the different specialized cell types. Their divisions must be tightly controlled to ensure that our lungs always have the correct numbers and types of specialized cells. Misregulation of progenitor cell division results in changes to the lung structure which can contribute to important lung diseases, including asthma, emphysema and COPD (Chronic Obstructive Pulmonary Disease). Our work uses the power of mouse genetics to understand the control of lung progenitor cell division in both growing and adult lungs. This fundamental research is essential for understanding the changes that can occur in our lungs as they become diseased, and for the development of cell-based therapies for lung repair.

Selected publications:

Rawlins EL, Clark CP, Xue Y and Hogan BLM (2009) The Id2 distal tip lung epithelium contains individual multipotent embryonic progenitor cells. Development 136, 3741-3745

Rawlins EL, Okubo T, Xue Y, Brass DM, Auten RL, Hasegawa H, Wang F and Hogan BLM (2009) The role of Scgb1a1+ Clara cells in the long-term maintenance and repair of lung airway, but not alveolar, epithelium. Cell Stem Cell 4, 525-534

Rawlins EL and Hogan BLM (2008) Ciliated epithelial cell lifespan in the mouse trachea and lung. American Journal of Physiology: Lung Cell Molecular Physiology 295, L231-234

Rawlins EL, Ostrowski LE, Randell SH and Hogan BLM (2007) Lung development and repair: contribution of the ciliated lineage. Proc Natl Acad Sci USA 104, 410-417

Rawlins EL and Hogan BLM (2006) Epithelial stem cells of the lung: privileged few or opportunities for many? Development 133, 2455-65

Lineage-labeled bronchiolar cells (green) in the adult mouse lung. These cells are descended from progenitor cells which both self-renew and make new ciliated cells throughout the lifespan of the animal.

Lineage-labeled bronchiolar cells (green) in the growing mouse lung. These cells are descended from an embryonic-specific progenitor cell population.

Lung bronchiolar cells (red) and alveolar cells (green) are located in close proximity. However, we have shown that these lung compartments are maintained by separate progenitor cells.