title: Generation of multipotent lung and airway progenitors from mouse ESCs and patient-specific cystic fibrosis iPSCs.
abstract: 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.
authors.affiliation: Center for Regenerative Medicine, Massachusetts General Hospital, Boston, 02114, USA.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Mou
authors.forename: Rui
authors.initials: R
authors.lastname: Zhao
authors.forename: Richard
authors.initials: R
authors.lastname: Sherwood
authors.forename: Tim
authors.initials: T
authors.lastname: Ahfeldt
authors.forename: Allen
authors.initials: A
authors.lastname: Lapey
authors.forename: John
authors.initials: J
authors.lastname: Wain
authors.forename: Leonard
authors.initials: L
authors.lastname: Sicilian
authors.forename: Konstantin
authors.initials: K
authors.lastname: Izvolsky
authors.forename: Kiran
authors.initials: K
authors.lastname: Musunuru
authors.forename: Chad
authors.initials: C
authors.lastname: Cowan
authors.forename: Jayaraj
authors.initials: J
authors.lastname: Rajagopal
mesh_terms: D000818:Animals; D002460:Cell Line / Q000378:metabolism / Q000473:pathology; D003550:Cystic Fibrosis / Q000378:metabolism / Q000473:pathology; D053595:Embryonic Stem Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D039902:Multipotent Stem Cells / Q000378:metabolism / Q000473:pathology; D020545:Respiratory Mucosa / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D033581:Stem Cell Transplantation; D014183:Transplantation, Heterologous; D014184:Transplantation, Homologous