Development and bioengineering of lung regeneration

The limited ability of the lung to respond to devastating degenerative disease entities provides the impetus to develop new cell-based restorative therapies. Approaches to meet this need could include either production of stem/progenitor cells for delivery to the damaged native lung to regenerate damaged tissue or engineering of a de novo transplantable organ. In either case, an understanding of normal lung development provides a road map for directing pluripotent stem cells (PSCs) to differentiate to lung epithelium in vitro. Lung epithelium is derived from the endodermal germ layer, which in turn is formed during gastrulation as cells migrate through the primitive streak. Through precisely coordinated temporospatial exposure to key agonists and antagonists of the WNT, FGF, BMP, and RA pathways, a subset of definitive endoderm cells are induced to express Nkx2-1, the earliest known marker of primordial lung progenitor cells, before further differentiation to mature cell types comprising the proximal and distal lung compartments. Novel culture systems, such as decellularized lung scaffolds and in vitro organoids, offer unprecedented opportunities for achieving multilineage differentiation and tissue-like structure formation together with functional evaluation of PSC-derived lung progenitors. Combined with advances in our ability to model lung development in vitro with human PSCs, emerging bioengineering techniques are rapidly transforming the field and are likely both to further our understanding of normal development and to facilitate therapeutic applications of these in the years to come.