Induction of multiciliated cells from induced pluripotent stem cells

The differentiation of induced pluripotent stem cells (iPSCs) to mature cell types—and ultimately to functional tissues and organs—holds great promise for personalized disease modeling, drug screening, and the development of cell-based therapies (1). Since Shinya Yamanaka described this Nobel Prize winning technology in 2006, there have been a number of advances in the field, especially in the differentiation of neural, cardiac and hepatic cell types (1). However, the differentiation of iPSCs and embryonic stem cells (ESCs) to lung cell types has lagged somewhat, and this is largely because the lungs are complex structures with many different cell types (2). Another challenge for the field is the differentiation of iPSCs to cells that are functionally competent. Anatomically and functionally, the lungs consist of distinct regions: the proximal airways that function in mucociliary clearance for host defense, the conducting airways, and the distal alveoli for gas exchange. There have been a series of papers published over the last 3 y (detailed below) that have developed protocols for iPSC and ESC differentiation to several lung cell types. In PNAS, Firth et al. (3) present another advance in the generation of proximal airway epithelium from iPSCs. Using the air-liquid interface (ALI) culture system, the authors demonstrate that putative lung progenitors obtained from iPSC-directed differentiation respond to inhibition of Notch signaling by promoting ciliogenesis and express the functional cystic fibrosis transmembrane regulator (CFTR) chloride channel. Studies in differentiation of iPSCs to functional airway epithelium are critical because the field holds great promise for developing personalized therapies for patients with respiratory diseases. Directed differentiation of human ESC and iPSC, along known lung developmental pathways, was first described by Green et al. (4) to transition definitive endoderm (DE) to anterior foregut epithelium (AFE) and then to lung progenitor cells. Activin A was used to induce DE, which …