title: Human embryonic stem cells differentiated to lung lineage-specific cells ameliorate pulmonary fibrosis in a xenograft transplant mouse model.
abstract: BACKGROUND
  Our aim was to differentiate human (h) embryonic stem (ES) cells into lung epithelial lineage-specific cells [i.e., alveolar epithelial type I (AEI) and type II (AEII) cells and Clara cells] as the first step in the development of cell-based strategies to repair lung injury in the bleomycin mouse model of idiopathic pulmonary fibrosis (IPF). A heterogeneous population of non-ciliated lung lineage-specific cells was derived by a novel method of embryoid body (EB) differentiation. This differentiated human cell population was used to modulate the profibrotic phenotype in transplanted animals.
  
  
  RESULTS
  Omission or inclusion of one or more components in the differentiation medium skewed differentiation of H7 hES cells into varying proportions of AEI, AEII, and Clara cells. ICG-001, a small molecule inhibitor of Wnt/β-catenin/Creb-binding protein (CBP) transcription, changed marker expression of the differentiated ES cells from an AEII-like phenotype to a predominantly AEI-like phenotype. The differentiated cells were used in xenograft transplantation studies in bleomycin-treated Rag2γC(-/-) mice. Human cells were detected in lungs of the transplanted groups receiving differentiated ES cells treated with or without ICG-001. The increased lung collagen content found in bleomycin-treated mice receiving saline was significantly reduced by transplantation with the lung-lineage specific epithelial cells differentiated from ES cells. A significant increase in progenitor number was observed in the airways of bleomycin-treated mice after transplantation of differentiated hES cells.
  
  
  CONCLUSIONS
  This study indicates that ES cell-based therapy may be a powerful novel approach to ameliorate lung fibrosis.
authors.affiliation: Center for Allergy and Inflammation and Institute for Stem Cell and Regenerative Medicine, Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Ena Ray
authors.initials: ER
authors.lastname: Banerjee
authors.forename: Michael A
authors.initials: MA
authors.lastname: Laflamme
authors.forename: Thalia
authors.initials: T
authors.lastname: Papayannopoulou
authors.forename: Michael
authors.initials: M
authors.lastname: Kahn
authors.forename: Charles E
authors.initials: CE
authors.lastname: Murry
authors.forename: William R
authors.initials: WR
authors.lastname: Henderson
mesh_terms: D000818:Animals; D001761:Bleomycin; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002454:Cell Differentiation; D019070:Cell Lineage; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008168:Lung / Q000187:drug effects; D051379:Mice; D010641:Phenotype; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000628:therapy*; D011744:Pyrimidinones / Q000494:pharmacology; D033581:Stem Cell Transplantation; D014183:Transplantation, Heterologous
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; C492448:ICG 001; D011744:Pyrimidinones; D001761:Bleomycin; D003094:Collagen