Efficient derivation of alveolar type II cells from embryonic stem cells for in vivo application.

In the present study, mouse embryonic stem cells (ESCs) were differentiated into alveolar epithelial type II (AEII) cells for endotracheal injection. These enriched lung-like populations expressed lung epithelial markers SP-A, SP-B, SP-C, and CC10. First we show that rapid differentiation of ESCs requires a dissociated seeding method instead of an embryoid body culture method. We then investigated a two-step differentiation of ESCs into definitive endoderm by activin or A549-conditioned medium as a precursor to lung epithelial cells. When conditioned medium from A549 cells was used to derive endoderm, yield was increased above that of activin alone. Further studies showed that Wnt3a may be one of the secreted factors produced by A549 cells and promotes definitive endoderm differentiation, in part, through suppression of primitive endoderm. Activin and Wnt3a together at appropriate doses with dissociated cell seeding promoted greater endoderm yield than activin alone. Next, fibroblast growth factor 2 was shown to induce a dose-dependent expression of SPC, and these cells contained lamellar bodies characteristic of mature AEII cells from ESC-derived endoderm. Finally, ES-derived lung cells were endotracheally injected into preterm mice with evidence of AEII distribution within the lung parenchyma. This study concludes that a recapitulation of development may enhance derivation of an enriched population of lung-like cells for use in cell-based therapy.

[1]  D. Warburton,et al.  Human Amniotic Fluid Stem Cells Can Integrate and Differentiate into Epithelial Lung Lineages , 2008, Stem cells.

[2]  J. Brickman,et al.  Anterior definitive endoderm from ESCs reveals a role for FGF signaling. , 2008, Cell stem cell.

[3]  E. Morrisey,et al.  A Gata6-Wnt pathway required for epithelial stem cell development and airway regeneration , 2008, Nature Genetics.

[4]  C. Finck,et al.  Novel methods for delivery of cell-based therapies. , 2008, The Journal of surgical research.

[5]  A. Kispert,et al.  Serum-free differentiation of murine embryonic stem cells into alveolar type II epithelial cells. , 2008, Cloning and stem cells.

[6]  A. Haverich,et al.  Type II pneumocyte-restricted green fluorescent protein expression after lentiviral transduction of lung epithelial cells. , 2008, Human gene therapy.

[7]  D. Closa,et al.  Intratracheal transplantation of alveolar type II cells reverses bleomycin-induced lung fibrosis. , 2007, American journal of respiratory and critical care medicine.

[8]  Ali Samadikuchaksaraei,et al.  Effects of growth factors on the differentiation of murine ESC into type II pneumocytes. , 2007, Cloning and stem cells.

[9]  C. Finck,et al.  A tissue-engineered model of fetal distal lung tissue. , 2007, American journal of physiology. Lung cellular and molecular physiology.

[10]  Steven J. M. Jones,et al.  A systematic screen for genes expressed in definitive endoderm by Serial Analysis of Gene Expression (SAGE) , 2007, BMC Developmental Biology.

[11]  C. Baum.  What are the consequences of the fourth case? , 2007, Molecular therapy : the journal of the American Society of Gene Therapy.

[12]  J. Wrana,et al.  Foxh1 recruits Gsc to negatively regulate Mixl1 expression during early mouse development , 2007, The EMBO journal.

[13]  A. Trounson,et al.  The differentiation of distal lung epithelium from embryonic stem cells. , 2007, Current protocols in stem cell biology.

[14]  C. Baum.  I could die for you: new prospects for suicide in gene therapy. , 2007, Molecular therapy : the journal of the American Society of Gene Therapy.

[15]  A. Burns,et al.  A pure population of lung alveolar epithelial type II cells derived from human embryonic stem cells , 2007, Proceedings of the National Academy of Sciences.

[16]  S. Keshavjee,et al.  Cell-based tissue engineering for lung regeneration. , 2007, American journal of physiology. Lung cellular and molecular physiology.

[17]  Patrick J. Paddison,et al.  Wnt and TGF-β signaling are required for the induction of an in vitro model of primitive streak formation using embryonic stem cells , 2006, Proceedings of the National Academy of Sciences.

[18]  L. Doyle,et al.  Bronchopulmonary Dysplasia in Very Low Birth Weight Subjects and Lung Function in Late Adolescence , 2006, Pediatrics.

[19]  Charles A Vacanti,et al.  Tissue-engineered lung: an in vivo and in vitro comparison of polyglycolic acid and pluronic F-127 hydrogel/somatic lung progenitor cell constructs to support tissue growth. , 2006, Tissue engineering.

[20]  A. Tangoku,et al.  Lung regeneration: implantation of fetal rat lung fragments into adult rat lung parenchyma. , 2006, The Journal of thoracic and cardiovascular surgery.

[21]  G. Eide,et al.  Better care of immature infants; has it influenced long-term pulmonary outcome? , 2006, Acta paediatrica.

[22]  J. Lü,et al.  Regulation of early lung morphogenesis: questions, facts and controversies , 2006, Development.

[23]  J. Polak,et al.  Derivation of Distal Lung Epithelial Progenitors from Murine Embryonic Stem Cells Using a Novel Three‐Step Differentiation Protocol , 2006, Stem cells.

[24]  Mark Denham,et al.  Embryonic stem cells form glandular structures and express surfactant protein C following culture with dissociated fetal respiratory tissue. , 2006, American journal of physiology. Lung cellular and molecular physiology.

[25]  E. Kroon,et al.  Efficient differentiation of human embryonic stem cells to definitive endoderm , 2005, Nature Biotechnology.

[26]  Tsutomu Chiba,et al.  Induction and monitoring of definitive and visceral endoderm differentiation of mouse ES cells , 2005, Nature Biotechnology.

[27]  J. Polak,et al.  Coculture of embryonic stem cells with pulmonary mesenchyme: a microenvironment that promotes differentiation of pulmonary epithelium. , 2005, Tissue engineering.

[28]  E. Lucey,et al.  Engraftment of neonatal lung fibroblasts into the normal and elastase-injured lung. , 2005, American journal of respiratory cell and molecular biology.

[29]  J. Polak,et al.  Cell Extract–Derived Differentiation of Embryonic Stem Cells , 2005, Stem cells.

[30]  V. P. Eswarakumar,et al.  Cellular signaling by fibroblast growth factor receptors. , 2005, Cytokine & growth factor reviews.

[31]  Christof Niehrs,et al.  Fibroblast growth factor signaling during early vertebrate development. , 2005, Endocrine reviews.

[32]  J. Wells,et al.  Different thresholds of fibroblast growth factors pattern the ventral foregut into liver and lung , 2004, Development.

[33]  R. Geffers,et al.  CD4 T Lymphocyte-mediated lung disease: steady state between pathological and tolerogenic immune reactions. , 2004, American journal of respiratory and critical care medicine.

[34]  Gordon Keller,et al.  Development of definitive endoderm from embryonic stem cells in culture , 2004, Development.

[35]  J. Nick,et al.  By Binding SIRPα or Calreticulin/CD91, Lung Collectins Act as Dual Function Surveillance Molecules to Suppress or Enhance Inflammation , 2003, Cell.

[36]  A. Jobe.  Animal Models of Antenatal Corticosteroids: Clinical Implications , 2003, Clinical obstetrics and gynecology.

[37]  J. Polak,et al.  Derivation of type II alveolar epithelial cells from murine embryonic stem cells. , 2002, Tissue engineering.

[38]  C. Romagnoli,et al.  Effects of early dexamethasone therapy on pulmonary fibrogenic mediators and respiratory mechanics in preterm infants. , 2002, European cytokine network.

[39]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[40]  M. Katoh,et al.  Molecular cloning and characterization of human WNT3. , 2001, International journal of oncology.

[41]  Heinz Fehrenbach,et al.  Alveolar epithelial type II cell: defender of the alveolus revisited , 2001, Respiratory research.

[42]  K. Zaret,et al.  Initiation of mammalian liver development from endoderm by fibroblast growth factors. , 1999, Science.

[43]  E. Morrisey,et al.  GATA-6: a zinc finger transcription factor that is expressed in multiple cell lineages derived from lateral mesoderm. , 1996, Developmental biology.

[44]  J. Darnell,et al.  Expression of transcription factor HNF-4 in the extraembryonic endoderm, gut, and nephrogenic tissue of the developing mouse embryo: HNF-4 is a marker for primary endoderm in the implanting blastocyst. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[45]  J. Rossant,et al.  The formation and maintenance of the definitive endoderm lineage in the mouse: involvement of HNF3/forkhead proteins. , 1993, Development.

[46]  B. Hogan,et al.  Differential expression of multiple fork head related genes during gastrulation and axial pattern formation in the mouse embryo. , 1993, Development.

[47]  J. Floros,et al.  Localization of pulmonary surfactant proteins using immunohistochemistry and tissue in situ hybridization. , 1991, Experimental lung research.

[48]  Barry H. Smith,et al.  A continuous tumor‐cell line from a human lung carcinoma with properties of type II alveolar epithelial cells , 1976, International journal of cancer.

[49]  K. Boheler,et al.  Pluripotency of embryonic stem cells , 2007, Cell and Tissue Research.

[50]  Robert Opoka,et al.  FGF signaling is necessary for establishing gut tube domains alongthe anterior–posterior axis in vivo , 2006, Mechanisms of Development.

[51]  Ali Samadikuchaksaraei,et al.  Derivation and characterization of alveolar epithelial cells from murine embryonic stem cells in vitro. , 2006, Methods in molecular biology.

[52]  多田 真輔.  Characterization of mesendoderm : a diverging point of the definitive endoderm and mesoderm in embryonic stem cell differentiation culture , 2006 .

[53]  P. Carmeliet,et al.  Loss of HIF-2α and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice , 2002, Nature Medicine.