Lung regeneration: mechanisms, applications and emerging stem cell populations (original) (raw)

• Beers, M.F. & Morrisey, E.E. The three R's of lung health and disease: repair, remodeling, and regeneration. J. Clin. Invest. 121, 2065–2073 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Wansleeben, C., Barkauskas, C.E., Rock, J.R. & Hogan, B.L. Stem cells of the adult lung: their development and role in homeostasis, regeneration, and disease. Wiley Interdiscip. Rev. Dev. Biol. 2, 131–148 (2013).
  Article CAS PubMed Google Scholar
• Zaret, K.S. & Grompe, M. Generation and regeneration of cells of the liver and pancreas. Science 322, 1490–1494 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Peng, T. et al. Coordination of heart and lung co-development by a multipotent cardiopulmonary progenitor. Nature 500, 589–592 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Cardoso, W.V. & Lu, J. Regulation of early lung morphogenesis: questions, facts and controversies. Development 133, 1611–1624 (2006).
  Article CAS PubMed Google Scholar
• Goss, A.M. et al. Wnt2/2b and β-catenin signaling are necessary and sufficient to specify lung progenitors in the foregut. Dev. Cell 17, 290–298 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Harris-Johnson, K.S., Domyan, E.T., Vezina, C.M. & Sun, X. β-catenin promotes respiratory progenitor identity in mouse foregut. Proc. Natl. Acad. Sci. USA 106, 16287–16292 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Domyan, E.T. et al. Signaling through BMP receptors promotes respiratory identity in the foregut via repression of Sox2. Development 138, 971–981 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Sekine, K. et al. Fgf10 is essential for limb and lung formation. Nat. Genet. 21, 138–141 (1999).
  Article CAS PubMed Google Scholar
• Serls, A.E., Doherty, S., Parvatiyar, P., Wells, J.M. & Deutsch, G.H. Different thresholds of fibroblast growth factors pattern the ventral foregut into liver and lung. Development 132, 35–47 (2005).
  Article CAS PubMed Google Scholar
• Perl, A.K., Wert, S.E., Nagy, A., Lobe, C.G. & Whitsett, J.A. Early restriction of peripheral and proximal cell lineages during formation of the lung. Proc. Natl. Acad. Sci. USA 99, 10482–10487 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Metzger, R.J., Klein, O.D., Martin, G.R. & Krasnow, M.A. The branching programme of mouse lung development. Nature 453, 745–750 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Tompkins, D.H. et al. Sox2 activates cell proliferation and differentiation in the respiratory epithelium. Am. J. Respir. Cell Mol. Biol. 45, 101–110 (2011).
  Article CAS PubMed Google Scholar
• Tompkins, D.H. et al. Sox2 is required for maintenance and differentiation of bronchiolar Clara, ciliated, and goblet cells. PLoS ONE 4, e8248 (2009).
  Article PubMed PubMed Central CAS Google Scholar
• Que, J., Luo, X., Schwartz, R.J. & Hogan, B.L. Multiple roles for Sox2 in the developing and adult mouse trachea. Development 136, 1899–1907 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Que, J. et al. Multiple dose-dependent roles for Sox2 in the patterning and differentiation of anterior foregut endoderm. Development 134, 2521–2531 (2007).
  Article CAS PubMed Google Scholar
• Rockich, B.E. et al. Sox9 plays multiple roles in the lung epithelium during branching morphogenesis. Proc. Natl. Acad. Sci. USA 110, E4456–E4464 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Rawlins, E.L., Clark, C.P., Xue, Y. & Hogan, B.L. The Id2+ distal tip lung epithelium contains individual multipotent embryonic progenitor cells. Development 136, 3741–3745 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Mason, R., Williams, M.C. & Clements, J.A. Isolation and identification of type 2 alveolar epithelial cells. Chest 67, 36S–37S (1975).
  Article CAS PubMed Google Scholar
• Wang, J. et al. Differentiated human alveolar epithelial cells and reversibility of their phenotype in vitro. Am. J. Respir. Cell Mol. Biol. 36, 661–668 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Dobbs, L.G., Williams, M.C. & Brandt, A.E. Changes in biochemical characteristics and pattern of lectin binding of alveolar type II cells with time in culture. Biochim. Biophys. Acta 846, 155–166 (1985).
  Article CAS PubMed Google Scholar
• Adamson, I.Y. & Bowden, D.H. Derivation of type 1 epithelium from type 2 cells in the developing rat lung. Lab. Invest. 32, 736–745 (1975).
  CAS PubMed Google Scholar
• Adamson, I.Y. & Bowden, D.H. The type 2 cell as progenitor of alveolar epithelial regeneration. A cytodynamic study in mice after exposure to oxygen. Lab. Invest. 30, 35–42 (1974).
  CAS PubMed Google Scholar
• Mason, R.J. & Williams, M.C. Type II alveolar cell. Defender of the alveolus. Am. Rev. Respir. Dis. 115, 81–91 (1977).
  CAS PubMed Google Scholar
• Barkauskas, C.E. et al. Type 2 alveolar cells are stem cells in adult lung. J. Clin. Invest. 123, 3025–3036 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Desai, T.J., Brownfield, D.G. & Krasnow, M.A. Alveolar progenitor and stem cells in lung development, renewal and cancer. Nature 507, 190–194 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Treutlein, B. et al. Reconstructing lineage hierarchies of the distal lung epithelium using single-cell RNA-seq. Nature 509, 371–375 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Schachtner, S.K., Wang, Y. & Scott Baldwin, H. Qualitative and quantitative analysis of embryonic pulmonary vessel formation. Am. J. Respir. Cell Mol. Biol. 22, 157–165 (2000).
  Article CAS PubMed Google Scholar
• Anderson-Berry, A. et al. Vasculogenesis drives pulmonary vascular growth in the developing chick embryo. Dev. Dyn. 233, 145–153 (2005).
  Article CAS PubMed Google Scholar
• deMello, D.E., Sawyer, D., Galvin, N. & Reid, L.M. Early fetal development of lung vasculature. Am. J. Respir. Cell Mol. Biol. 16, 568–581 (1997).
  Article CAS PubMed Google Scholar
• Gebb, S.A. & Shannon, J.M. Tissue interactions mediate early events in pulmonary vasculogenesis. Dev. Dyn. 217, 159–169 (2000).
  Article CAS PubMed Google Scholar
• Adamson, I.Y. & Bowden, D.H. Origin of ciliated alveolar epithelial cells in bleomycin-induced lung injury. Am. J. Pathol. 87, 569–580 (1977).
  CAS PubMed PubMed Central Google Scholar
• Adamson, I.Y. & Bowden, D.H. Bleomycin-induced injury and metaplasia of alveolar type 2 cells. Relationship of cellular responses to drug presence in the lung. Am. J. Pathol. 96, 531–544 (1979).
  CAS PubMed PubMed Central Google Scholar
• Bowden, D.H., Adamson, I.Y. & Wyatt, J.P. Reaction of the lung cells to a high concentration of oxygen. Arch. Pathol. 86, 671–675 (1968).
  CAS PubMed Google Scholar
• Cabral-Anderson, L.J., Evans, M.J. & Freeman, G. Effects of NO2 on the lungs of rats. I. Morphology. Exp. Mol. Pathol. 27, 353–365 (1977).
  Article CAS PubMed Google Scholar
• Evans, M.J., Cabral, L.C., Stephens, R.J. & Freeman, G. Acute kinetic response and renewal of the alveolar epithelium following injury by nitrogen dioxide. Chest 65, 62S–65S (1974).
  Article CAS Google Scholar
• Evans, M.J., Cabral, L.J., Stephens, R.J. & Freeman, G. Renewal of alveolar epithelium in the rat following exposure to NO2 . Am. J. Pathol. 70, 175–198 (1973).
  CAS PubMed PubMed Central Google Scholar
• Evans, M.J., Cabral, L.J., Stephens, R.J. & Freeman, G. Transformation of alveolar type 2 cells to type 1 cells following exposure to NO2 . Exp. Mol. Pathol. 22, 142–150 (1975).
  Article CAS PubMed Google Scholar
• Evans, M.J., Dekker, N.P., Cabral-Anderson, L.J. & Freeman, G. Quantitation of damage to the alveolar epithelium by means of type 2 cell proliferation. Am. Rev. Respir. Dis. 118, 787–790 (1978).
  Article CAS PubMed Google Scholar
• Rawlins, E.L. & Hogan, B.L. Epithelial stem cells of the lung: privileged few or opportunities for many? Development 133, 2455–2465 (2006).
  Article CAS PubMed Google Scholar
• Rawlins, E.L., Ostrowski, L.E., Randell, S.H. & Hogan, B.L. Lung development and repair: contribution of the ciliated lineage. Proc. Natl. Acad. Sci. USA 104, 410–417 (2007).
  Article CAS PubMed Google Scholar
• Rawlins, E.L. & Hogan, B.L. Ciliated epithelial cell lifespan in the mouse trachea and lung. Am. J. Physiol. Lung Cell. Mol. Physiol. 295, L231–L234 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Rawlins, E.L. et al. Epithelial stem/progenitor cells in lung postnatal growth, maintenance, and repair. Cold Spring Harb. Symp. Quant. Biol. 73, 291–295 (2008).
  Article CAS PubMed Google Scholar
• Borthwick, D.W., Shahbazian, M., Krantz, Q.T., Dorin, J.R. & Randell, S.H. Evidence for stem-cell niches in the tracheal epithelium. Am. J. Respir. Cell Mol. Biol. 24, 662–670 (2001).
  Article CAS PubMed Google Scholar
• Pardo-Saganta, A., Law, B.M., Gonzalez-Celeiro, M., Vinarsky, V. & Rajagopal, J. Ciliated cells of pseudostratified airway epithelium do not become mucous cells after ovalbumin challenge. Am. J. Respir. Cell Mol. Biol. 48, 364–373 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Liu, J.Y., Nettesheim, P. & Randell, S.H. Growth and differentiation of tracheal epithelial progenitor cells. Am. J. Physiol. 266, L296–L307 (1994).
  CAS PubMed Google Scholar
• Avril-Delplanque, A. et al. Aquaporin-3 expression in human fetal airway epithelial progenitor cells. Stem Cells 23, 992–1001 (2005).
  Article CAS PubMed Google Scholar
• Johnson, N.F. & Hubbs, A.F. Epithelial progenitor cells in the rat trachea. Am. J. Respir. Cell Mol. Biol. 3, 579–585 (1990).
  Article CAS PubMed Google Scholar
• Ford, J.R. & Terzaghi-Howe, M. Basal cells are the progenitors of primary tracheal epithelial cell cultures. Exp. Cell Res. 198, 69–77 (1992).
  Article CAS PubMed Google Scholar
• Rock, J.R. et al. Basal cells as stem cells of the mouse trachea and human airway epithelium. Proc. Natl. Acad. Sci. USA 106, 12771–12775 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Hong, K.U., Reynolds, S.D., Watkins, S., Fuchs, E. & Stripp, B.R. In vivo differentiation potential of tracheal basal cells: evidence for multipotent and unipotent subpopulations. Am. J. Physiol. Lung Cell. Mol. Physiol. 286, L643–L649 (2004).
  Article CAS PubMed Google Scholar
• Cole, B.B. et al. Tracheal basal cells: a facultative progenitor cell pool. Am. J. Pathol. 177, 362–376 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Weiss, D.J. et al. Stem cells and cell therapies in lung biology and lung diseases. Proc. Am. Thorac. Soc. 8, 223–272 (2011).
  Article PubMed PubMed Central Google Scholar
• Borok, Z. et al. Cell plasticity in lung injury and repair: report from an NHLBI workshop, April 19–20, 2010. Proc. Am. Thorac. Soc. 8, 215–222 (2011).
  Article PubMed PubMed Central Google Scholar
• Kumar, P.A. et al. Distal airway stem cells yield alveoli in vitro and during lung regeneration following H1N1 influenza infection. Cell 147, 525–538 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Rock, J.R. et al. Notch-dependent differentiation of adult airway basal stem cells. Cell Stem Cell 8, 639–648 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Reynolds, S.D., Reynolds, P.R., Pryhuber, G.S., Finder, J.D. & Stripp, B.R. Secretoglobins SCGB3A1 and SCGB3A2 define secretory cell subsets in mouse and human airways. Am. J. Respir. Crit. Care Med. 166, 1498–1509 (2002).
  Article PubMed Google Scholar
• Reynolds, S.D., Reynolds, P.R., Pryhuber, G.S., Finder, J.D. & Stripp, B.R. Secretoglobins SCGB3A1 and SCGB3A2 define secretory cell subsets in mouse and human airways. Am. J. Respir. Crit. Care Med. 166, 1498–1509 (2002).
  Article PubMed Google Scholar
• Giangreco, A., Reynolds, S.D. & Stripp, B.R. Terminal bronchioles harbor a unique airway stem cell population that localizes to the bronchoalveolar duct junction. Am. J. Pathol. 161, 173–182 (2002).
  Article PubMed PubMed Central Google Scholar
• Reynolds, S.D. et al. Conditional Clara cell ablation reveals a self-renewing progenitor function of pulmonary neuroendocrine cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 278, L1256–L1263 (2000).
  Article CAS PubMed Google Scholar
• Rawlins, E.L. et al. The role of Scgb1a1+ Clara cells in the long-term maintenance and repair of lung airway, but not alveolar, epithelium. Cell Stem Cell 4, 525–534 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Hong, K.U., Reynolds, S.D., Giangreco, A., Hurley, C.M. & Stripp, B.R. Clara cell secretory protein-expressing cells of the airway neuroepithelial body microenvironment include a label-retaining subset and are critical for epithelial renewal after progenitor cell depletion. Am. J. Respir. Cell Mol. Biol. 24, 671–681 (2001).
  Article CAS PubMed Google Scholar
• Giangreco, A., Reynolds, S.D. & Stripp, B.R. Terminal bronchioles harbor a unique airway stem cell population that localizes to the bronchoalveolar duct junction. Am. J. Pathol. 161, 173–182 (2002).
  Article PubMed PubMed Central Google Scholar
• Peake, J.L., Reynolds, S.D., Stripp, B.R., Stephens, K.E. & Pinkerton, K.E. Alteration of pulmonary neuroendocrine cells during epithelial repair of naphthalene-induced airway injury. Am. J. Pathol. 156, 279–286 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Reynolds, S.D., Giangreco, A., Power, J.H. & Stripp, B.R. Neuroepithelial bodies of pulmonary airways serve as a reservoir of progenitor cells capable of epithelial regeneration. Am. J. Pathol. 156, 269–278 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Reynolds, S.D. et al. Conditional Clara cell ablation reveals a self-renewing progenitor function of pulmonary neuroendocrine cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 278, L1256–L1263 (2000).
  Article CAS PubMed Google Scholar
• Guha, A. et al. Neuroepithelial body microenvironment is a niche for a distinct subset of Clara-like precursors in the developing airways. Proc. Natl. Acad. Sci. USA 109, 12592–12597 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Morimoto, M., Nishinakamura, R., Saga, Y. & Kopan, R. Different assemblies of Notch receptors coordinate the distribution of the major bronchial Clara, ciliated and neuroendocrine cells. Development 139, 4365–4373 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Volckaert, T. et al. Parabronchial smooth muscle constitutes an airway epithelial stem cell niche in the mouse lung after injury. J. Clin. Invest. 121, 4409–4419 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Giangreco, A. et al. Stem cells are dispensable for lung homeostasis but restore airways after injury. Proc. Natl. Acad. Sci. USA 106, 9286–9291 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Adamson, I.Y., Bowden, D.H. & Wyatt, J.P. Oxygen poisoning in mice. Ultrastructural and surfactant studies during exposure and recovery. Arch. Pathol. 90, 463–472 (1970).
  CAS PubMed Google Scholar
• Xu, X. et al. Evidence for type II cells as cells of origin of K-Ras-induced distal lung adenocarcinoma. Proc. Natl. Acad. Sci. USA 109, 4910–4915 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Chapman, H.A. et al. Integrin α6β4 identifies an adult distal lung epithelial population with regenerative potential in mice. J. Clin. Invest. 121, 2855–2862 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Kim, C.F. et al. Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 121, 823–835 (2005).
  Article CAS PubMed Google Scholar
• Lee, J.H. et al. Lung stem cell differentiation in mice directed by endothelial cells via a BMP4-NFATc1-thrombospondin-1 axis. Cell 156, 440–455 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Rock, J.R. et al. Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition. Proc. Natl. Acad. Sci. USA 108, E1475–E1483 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Zheng, D. et al. Regeneration of alveolar type I and II cells from Scgb1a1-expressing cells following severe pulmonary damage induced by bleomycin and influenza. PLoS ONE 7, e48451 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Rock, J.R. et al. Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition. Proc. Natl. Acad. Sci. USA 108, E1475–E1483 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Tata, P.R. et al. Dedifferentiation of committed epithelial cells into stem cells in vivo. Nature 503, 218–223 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Zheng, D., Yin, L. & Chen, J. Evidence for Scgb1a1+ cells in the generation of p63+ cells in the damaged lung parenchyma. Am. J. Respir. Cell Mol. Biol. 50, 595–604 (2014).
  Article PubMed Google Scholar
• McQualter, J.L., Yuen, K., Williams, B. & Bertoncello, I. Evidence of an epithelial stem/progenitor cell hierarchy in the adult mouse lung. Proc. Natl. Acad. Sci. USA 107, 1414–1419 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Buhain, W.J. & Brody, J.S. Compensatory growth of the lung following pneumonectomy. J. Appl. Physiol. 35, 898–902 (1973).
  Article CAS PubMed Google Scholar
• Brody, J.S. Time course of and stimuli to compensatory growth of the lung after pneumonectomy. J. Clin. Invest. 56, 897–904 (1975).
  Article CAS PubMed PubMed Central Google Scholar
• Voswinckel, R. et al. Characterisation of post-pneumonectomy lung growth in adult mice. Eur. Respir. J. 24, 524–532 (2004).
  Article CAS PubMed Google Scholar
• Eisenhauer, P. et al. Endogenous distal airway progenitor cells, lung mechanics, and disproportionate lobar growth following long-term postpneumonectomy in mice. Stem Cells 31, 1330–1339 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Hoffman, A.M. et al. Matrix modulation of compensatory lung regrowth and progenitor cell proliferation in mice. Am. J. Physiol. Lung Cell. Mol. Physiol. 298, L158–L168 (2010).
  Article CAS PubMed Google Scholar
• Hsia, C.C., Herazo, L.F., Fryder-Doffey, F. & Weibel, E.R. Compensatory lung growth occurs in adult dogs after right pneumonectomy. J. Clin. Invest. 94, 405–412 (1994).
  Article CAS PubMed PubMed Central Google Scholar
• Butler, J.P. et al. Evidence for adult lung growth in humans. N. Engl. J. Med. 367, 244–247 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Ding, B.S. et al. Endothelial-derived angiocrine signals induce and sustain regenerative lung alveolarization. Cell 147, 539–553 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Nolen-Walston, R.D. et al. Cellular kinetics and modeling of bronchioalveolar stem cell response during lung regeneration. Am. J. Physiol. Lung Cell. Mol. Physiol. 294, L1158–L1165 (2008).
  Article CAS PubMed Google Scholar
• Koh, D.W., Roby, J.D., Starcher, B., Senior, R.M. & Pierce, R.A. Postpneumonectomy lung growth: a model of reinitiation of tropoelastin and type I collagen production in a normal pattern in adult rat lung. Am. J. Respir. Cell Mol. Biol. 15, 611–623 (1996).
  Article CAS PubMed Google Scholar
• Kaza, A.K., Kron, I.L., Leuwerke, S.M., Tribble, C.G. & Laubach, V.E. Keratinocyte growth factor enhances post-pneumonectomy lung growth by alveolar proliferation. Circulation 106, I120–I124 (2002).
  Article PubMed CAS Google Scholar
• Kaza, A.K. et al. Epidermal growth factor augments postpneumonectomy lung growth. J. Thorac. Cardiovasc. Surg. 120, 916–922 (2000).
  Article CAS PubMed Google Scholar
• Zhang, Y. et al. A Gata6-Wnt pathway required for epithelial stem cell development and airway regeneration. Nat. Genet. 40, 862–870 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Zemke, A.C. et al. β-catenin is not necessary for maintenance or repair of the bronchiolar epithelium. Am. J. Respir. Cell Mol. Biol. 41, 535–543 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Tanjore, H. et al. β-catenin in the alveolar epithelium protects from lung fibrosis after intratracheal bleomycin. Am. J. Respir. Crit. Care Med. 187, 630–639 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Henderson, W.R. Jr. et al. Inhibition of Wnt/β-catenin/CREB binding protein (CBP) signaling reverses pulmonary fibrosis. Proc. Natl. Acad. Sci. USA 107, 14309–14314 (2010).
  Article PubMed PubMed Central Google Scholar
• Levänen, B., Wheelock, A.M., Eklund, A., Grunewald, J. & Nord, M. Increased pulmonary Wnt (wingless/integrated)-signaling in patients with sarcoidosis. Respir. Med. 105, 282–291 (2011).
  Article PubMed Google Scholar
• Königshoff, M. et al. Functional Wnt signaling is increased in idiopathic pulmonary fibrosis. PLoS ONE 3, e2142 (2008).
  Article PubMed PubMed Central CAS Google Scholar
• Chilosi, M. et al. Aberrant Wnt/β-catenin pathway activation in idiopathic pulmonary fibrosis. Am. J. Pathol. 162, 1495–1502 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Morimoto, M. et al. Canonical Notch signaling in the developing lung is required for determination of arterial smooth muscle cells and selection of Clara versus ciliated cell fate. J. Cell Sci. 123, 213–224 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Tsao, P.N. et al. Notch signaling controls the balance of ciliated and secretory cell fates in developing airways. Development 136, 2297–2307 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Tsao, P.N. et al. Notch signaling prevents mucous metaplasia in mouse conducting airways during postnatal development. Development 138, 3533–3543 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Ito, K. et al. Decreased histone deacetylase activity in chronic obstructive pulmonary disease. N. Engl. J. Med. 352, 1967–1976 (2005).
  Article CAS PubMed Google Scholar
• Wang, Y. et al. Development and regeneration of Sox2+ endoderm progenitors are regulated by a Hdac1/2-Bmp4/Rb1 regulatory pathway. Dev. Cell 24, 345–358 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Kubo, A. et al. Development of definitive endoderm from embryonic stem cells in culture. Development 131, 1651–1662 (2004).
  Article CAS PubMed Google Scholar
• Christodoulou, C. et al. Mouse ES and iPS cells can form similar definitive endoderm despite differences in imprinted genes. J. Clin. Invest. 121, 2313–2325 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Gouon-Evans, V. et al. BMP-4 is required for hepatic specification of mouse embryonic stem cell–derived definitive endoderm. Nat. Biotechnol. 24, 1402–1411 (2006).
  Article CAS PubMed Google Scholar
• Murry, C.E. & Keller, G. Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development. Cell 132, 661–680 (2008).
  Article CAS PubMed Google Scholar
• Green, M.D. et al. Generation of anterior foregut endoderm from human embryonic and induced pluripotent stem cells. Nat. Biotechnol. 29, 267–272 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Longmire, T.A. et al. Efficient derivation of purified lung and thyroid progenitors from embryonic stem cells. Cell Stem Cell 10, 398–411 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Mou, H. et al. Generation of multipotent lung and airway progenitors from mouse ESCs and patient-specific cystic fibrosis iPSCs. Cell Stem Cell 10, 385–397 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Wong, A.P. et al. Directed differentiation of human pluripotent stem cells into mature airway epithelia expressing functional CFTR protein. Nat. Biotechnol. 30, 876–882 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Baiguera, S. et al. Tissue engineered human tracheas for in vivo implantation. Biomaterials 31, 8931–8938 (2010).
  Article CAS PubMed Google Scholar
• Macchiarini, P. et al. Clinical transplantation of a tissue-engineered airway. Lancet 372, 2023–2030 (2008).
  Article PubMed Google Scholar
• Ott, H.C. et al. Regeneration and orthotopic transplantation of a bioartificial lung. Nat. Med. 16, 927–933 (2010).
  Article CAS PubMed Google Scholar
• Petersen, T.H. et al. Tissue-engineered lungs for in vivo implantation. Science 329, 538–541 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Daly, A.B. et al. Initial binding and recellularization of decellularized mouse lung scaffolds with bone marrow–derived mesenchymal stromal cells. Tissue Eng. Part A 18, 1–16 (2012).
  Article CAS PubMed Google Scholar
• Wallis, J.M. et al. Comparative assessment of detergent-based protocols for mouse lung de-cellularization and re-cellularization. Tissue Eng. Part C Methods 18, 420–432 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Cortiella, J. et al. Influence of acellular natural lung matrix on murine embryonic stem cell differentiation and tissue formation. Tissue Eng. Part A 16, 2565–2580 (2010).
  Article CAS PubMed Google Scholar
• Ghaedi, M. et al. Human iPS cell-derived alveolar epithelium repopulates lung extracellular matrix. J. Clin. Invest. 123, 4950–4962 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Weiss, D.J. & Ortiz, L.A. Cell therapy trials for lung diseases: progress and cautions. Am. J. Respir. Crit. Care Med. 188, 123–125 (2013).
  Article PubMed PubMed Central Google Scholar
• Bianco, P. et al. The meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine. Nat. Med. 19, 35–42 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Lama, V.N. et al. Evidence for tissue-resident mesenchymal stem cells in human adult lung from studies of transplanted allografts. J. Clin. Invest. 117, 989–996 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Caplan, A.I. What's in a name? Tissue Eng. Part A 16, 2415–2417 (2010).
  Article PubMed Google Scholar
• Ohle, S.J., Anandaiah, A., Fabian, A.J., Fine, A. & Kotton, D.N. Maintenance and repair of the lung endothelium does not involve contributions from marrow-derived endothelial precursor cells. Am. J. Respir. Cell Mol. Biol. 47, 11–19 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Comroe, J.H. Jr. & Dripps, R.D. Scientific basis for the support of biomedical science. Science 192, 105–111 (1976).
  Article PubMed Google Scholar
• Perl, A.K. et al. Conditional recombination reveals distinct subsets of epithelial cells in trachea, bronchi, and alveoli. Am. J. Respir. Cell Mol. Biol. 33, 455–462 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Flodby, P. et al. Directed expression of Cre in alveolar epithelial type 1 cells. Am. J. Respir. Cell Mol. Biol. 43, 173–178 (2010).
  Article CAS PubMed Google Scholar
• Somers, A. et al. Generation of transgene-free lung disease-specific human iPS cells using a single excisable lentiviral stem cell cassette. Stem Cells 28, 1728–1740 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Rashid, S.T. et al. Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells. J. Clin. Invest. 120, 3127–3136 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Yusa, K. et al. Targeted gene correction of α1-antitrypsin deficiency in induced pluripotent stem cells. Nature 478, 391–394 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Lachmann, N. et al. Gene correction of human induced pluripotent stem cells repairs the cellular phenotype in pulmonary alveolar proteinosis. Am. J. Respir. Crit. Care Med. 189, 167–182 (2014).
  CAS PubMed Google Scholar
• Suzuki, T. et al. Use of induced pluripotent stem cells to recapitulate pulmonary alveolar proteinosis pathogenesis. Am. J. Respir. Crit. Care Med. 189, 183–193 (2014).
  CAS PubMed PubMed Central Google Scholar