Human lung development is largely unknown and what is known has been interpreted from loss-of-function mouse models. my research program goal is to advance our understanding of the molecular and cellular processes that drive human lung development and disease, leading to improved derivation of lung tissue from pluripotent stem cells, and translating into novel stem cell-derived therapies for lung diseases.
Research program goal
To advance our understanding of the molecular and cellular processes that guide human lung development and disease, leading to improved derivation of lung tissue from pluripotent stem cells, and translating into novel stem cell-derived therapies for lung diseases.
The adult lung consists of more than 60 cell types organized in a complex branching system with multiple functions, including gas exchange, detoxification and immune surveillance. These functions are regulated by the cells that reside in the different regions of the lungs, from the multi-epithelial cell lineages forming the pseudostratified epithelium of the proximal airway to the thin monolayer of alveolar cells of the respiratory epithelium. How the lung arises from a sheet of embryonic endoderm and give rise to such an intricate organ with all the different cell types in the adult lung remains largely unknown. With improving single cell technologies, new cell types are being discovered, but the origins of these cells, their relationship with known cell types and their functions during development, disease and repair have yet to be determined.
Furthermore, human lung development remains largely unknown because embryonic and prenatal lung tissues are not easily accessible. Present knowledge of the genes and regulatory pathways that control lung development derives mostly from loss-of-function mouse models. However, the details of mouse lung development may not capture human processes, because mouse and human have distinct genetics, phenotypes, and lung structures. One way to circumvent mouse and human lung differences is to use human induced pluripotent stem (iPS) cells to model human development. I developed novel human models of lung derived from embryonic stem (ES) and iPS cells. My research program will use these models to discover the fundamental genetic and molecular processes that dictate how the human lung develops, how disease mutations such as CF affect lung development and progressive lung disease, and novel cell-based develop tools for personalized medicine.
Cystic Fibrosis (CF) is a genetic disorder affecting 1/2500 live births in Canada. While it is a multi-organ disease the main cause of morbity and mortality is due to the disease in the lungs. Mutation in the CF Transmembrane Conductance Regulator (CFTR) gene was identified as the primary genetic cause of CF. The CFTR protein is localized to the apical epithelial membrane and functions to transport ions and fluids across the epithelia. The loss of CFTR channel function or presence caused by disease mutations leads to mucus obstruction in the airways increasing the susceptibility to recurrent bacterial infections and chronic inflammation that ultimately destroys the lungs.
During lung development, CFTR has been implicated in mechanicosensory, lung morphogenesis and progenitor cell function however a direct link has not been shown. In utero gene transfer of anti-sense CFTR mRNA prevent lung development and cell differentiation in mouse lungs. Meanwhile over expression of CFTR in utero increases bronchial cell differentiation and proliferation at the expense of alveolar development.4 These studies implicate the role of CFTR in early lung development that may ultimately affect progressive lung deterioration and clinical responses to therapies.
My lab will define a deeper understanding of the progression of early human lung development from a pluripotent stem cell to the formation of mature lung using human stem cell-derived models that I have developed along with parallel animal models. These studies will shed critical insight into the genetic and molecular causes of lung diseases such as CF and ultimately translate into improved derivation of human lung tissues for modeling and novel stem cell-based therapies for lung diseases.
My research program will provide a comprehensive understanding of how specialized human lung epithelial cells are developed and contribute to diseases. This will inform strategies to generate novel relevant models to study personalized human lung diseases in a dish and therapy discoveries. My research program will provide an exciting interdisciplinary training environment, produce high-impact papers and lead to future clinical translation directly in lung disease.