Jeffrey Whitsett

Molecular Determinants of Lung Morphogenesis

Abstract During the 8-month period of gestation, the fetal lung is formed from a primordial mass of cells, arising as a small bud of foregut endoderm, which becomes an elaborately branched gas exchange unit with a delicately entwined vascular tree consisting of dozens of cell types. Failure to complete the task of lung morphogenesis often presents at the time of birth, when the newborn must adapt to airbreathing. In this chapter, the major events taking place during lung morphogenesis and differentiation are summarized. Dominant signaling and transcriptional pathways that direct the proliferation, migration, and differentiation of multiple cell types to form the adult lung are described and linked to congenital malformations and lung immaturity. Impaired lung formation and function often present as lung disorders in the neonatal period and infancy. The roles of coding and noncoding portions of the genome, including the epigenome, are integrated to coordinate gene expression during lung development, specifying cell identities and functions necessary for postnatal life. Throughout the chapter, we highlight how these developmental processes are relevant to congenital malformations and disorders of lung function, providing the framework for how the mature lung responds to injury and disease.

The Genetic Programs Regulating Embryonic Lung Development and Induced Pluripotent Stem Cell Differentiation

This chapter reviews the current knowledge of the molecular mechanisms controlling embryonic lung development in animal models from the initial specification of a small number of respiratory progenitor cells in the ventral foregut endoderm through the formation of the mature adult lung with regionally specialized epithelial, interstitial, and vascular compartments. In the second half of this chapter we introduce induced pluripotent stem cells (iPSCs) as a compelling new platform to study human lung biology at developmental time-points previously inaccessible to researchers. iPSCs offer the potential to generate functional lung tissue in vitro by translating the knowledge gained from studying respiratory system development in different animal models where many of the signaling pathways or airway branching mechanisms are evolutionarily conserved. There are many exciting possible applications of iPSC-derived lung tissue, including the ability to model human lung disease, screen novel drug therapies, and ultimately generate functional, transplantable lung cells or 3-D tissues for those suffering from one of the many forms of end-stage lung disease.