Generation of Multipotent Lung and Airway Progenitors from Mouse ESCs and Patient-Specific Cystic Fibrosis iPSCs

• Published in: Cell stem cell Vol. 10; no. 4; pp. 385 - 397
• Main Authors: Mou, Hongmei, Zhao, Rui, Sherwood, Richard, Ahfeldt, Tim, Lapey, Allen, Wain, John, Sicilian, Leonard, Izvolsky, Konstantin, Lau, Frank H., Musunuru, Kiran, Cowan, Chad, Rajagopal, Jayaraj
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 06.04.2012; Cell Press
• Subjects: Animals; Biological and medical sciences; Cell differentiation, maturation, development, hematopoiesis; Cell Line - metabolism; Cell Line - pathology; Cell physiology; Cystic Fibrosis - metabolism; Cystic Fibrosis - pathology; Embryonic Stem Cells - metabolism; Embryonic Stem Cells - pathology; Errors of metabolism; Fundamental and applied biological sciences. Psychology; Humans; Induced Pluripotent Stem Cells - metabolism; Induced Pluripotent Stem Cells - pathology; Induced Pluripotent Stem Cells - transplantation; Lung - metabolism; Lung - pathology; Medical sciences; Metabolic diseases; Mice; Mice, Inbred NOD; Mice, SCID; Miscellaneous hereditary metabolic disorders; Molecular and cellular biology; Multipotent Stem Cells - metabolism; Multipotent Stem Cells - pathology; Respiratory Mucosa - metabolism; Respiratory Mucosa - pathology; Signal Transduction; Stem Cell Transplantation; Transplantation, Heterologous; Transplantation, Homologous; Human; Respiratory disease; Lung; Rodentia; Metabolic diseases; Cystic fibrosis; Respiratory system; Genetic disease; Vertebrata; Mammalia; Mouse; Digestive diseases; Pancreatic disease
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2012.01.018

Deriving lung progenitors from patient-specific pluripotent cells is a key step in producing differentiated lung epithelium for disease modeling and transplantation. By mimicking the signaling events that occur during mouse lung development, we generated murine lung progenitors in a series of discrete steps. Definitive endoderm derived from mouse embryonic stem cells (ESCs) was converted into foregut endoderm, then into replicating Nkx2.1+ lung endoderm, and finally into multipotent embryonic lung progenitor and airway progenitor cells. We demonstrated that precisely-timed BMP, FGF, and WNT signaling are required for NKX2.1 induction. Mouse ESC-derived Nkx2.1+ progenitor cells formed respiratory epithelium (tracheospheres) when transplanted subcutaneously into mice. We then adapted this strategy to produce disease-specific lung progenitor cells from human Cystic Fibrosis induced pluripotent stem cells (iPSCs), creating a platform for dissecting human lung disease. These disease-specific human lung progenitors formed respiratory epithelium when subcutaneously engrafted into immunodeficient mice. [Display omitted] ► mESCs and CF iPSCs are converted into multipotent lung and airway progenitors ► ESC and iPSC-derived Nkx2.1+ cells are lung and not thyroid or brain progenitors ► Precisely-timed BMP, FGF, and WNT signaling is required for Nkx2.1 induction ► ESC and iPSC-derived airway progenitors generate respiratory epithelium