Abstract
Somatic stem/progenitor cells are known to be present in most adult tissues. However, those in the lung have limited abilities for tissue regeneration after serious damage as a result of chronic disease. Therefore, regenerative medicine using exogenous stem cells has been suggested for the treatment of progressive lung diseases such as chronic obstructive pulmonary disease and pulmonary fibrosis. Embryonic stem (ES) cells and induced pluripotent stem cells, with their potent differentiation abilities, are promising sources for the generation of various tissue cells. In this study, we investigated the effects of various differentiation-inducing growth factors on the differentiation of lung cells from ES cells in vitro. Several factors, including activin, nodal, and noggin, significantly promoted the induction of Nkx2.1-positive lung progenitor cells when cells were cultured as embryoid bodies. Bone morphogenetic protein (BMP) 4 signaling controls the lineage commitment of lung cells along the proximal–distal axis. BMP4 promotes the induction of distal cell lineages of alveolar bud, such as Clara cells and mucus-producing goblet cells. These results suggest that several developmentally essential factors, including nodal/activin and BMP signaling, are important in the control of the differentiation of lung epithelial cells from mouse ES cells in vitro.
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Bellusci S.; Henderson R.; Winnier G.; Oikawa T.; Hogan B. L. Evidence from normal expression and targeted misexpression that bone morphogenetic protein (Bmp-4) plays a role in mouse embryonic lung morphogenesis. Development 122: 1693–1702; 1996.
Blaisdell C. J.; Gail D. B.; Nabel E. G. National Heart, Lung, and Blood Institute perspective: lung progenitor and stem cells—gaps in knowledge and future opportunities. Stem Cells 27: 2263–2270; 2009.
Coraux C.; Nawrocki-Raby B.; Hinnrasky J.; Kileztky C.; Gaillard D.; Dani C.; Puchelle E. Embryonic stem cells generate airway epithelial tissue. Am J Respir Cell Mol Biol 32: 87–92; 2005.
Gupta N.; Su X.; Popov B.; Lee J. W.; Serikov V.; Matthay M. A. Intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxin-induced acute lung injury in mice. J Immunol 179: 1855–1863; 2007.
Hyatt B. A.; Shangguan X.; Shannon J. M. FGF-10 induces SP-C and Bmp4 and regulates proximal-distal patterning in embryonic tracheal epithelium. Am J Physiol Lung Cell Mol Physiol 287: L1116–1126; 2004.
Kajstura J.; Rota M.; Hall S. R.; Hosoda T.; D’Amario D.; Sanada F.; Zheng H.; Ogorek B.; Rondon-Clavo C.; Ferreira-Martins J.; Matsuda A.; Arranto C.; Goichberg P.; Giordano G.; Haley K. J.; Bardelli S.; Rayatzadeh H.; Liu X.; Quaini F.; Liao R.; Leri A.; Perrella M. A.; Loscalzo J.; Anversa P. Evidence for human lung stem cells. N Engl J Med 364: 1795–1806; 2011.
Kessler D. S.; Melton D. A. Vertebrate embryonic induction: mesodermal and neural patterning. Science 266: 596–604; 1994.
Kim C. F.; Jackson E. L.; Woolfenden A. E.; Lawrence S.; Babar I.; Vogel S.; Crowley D.; Bronson R. T.; Jacks T. Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 121: 823–835; 2005.
Kotton D. N.; Fabian A. J.; Mulligan R. C. Failure of bone marrow to reconstitute lung epithelium. Am J Respir Cell Mol Biol 33: 328–334; 2005.
Kumar P. A.; Hu Y.; Yamamoto Y.; Hoe N. B.; Wei T. S.; Mu D.; Sun Y.; Joo L. S.; Dagher R.; Zielonka E. M.; de Wang Y.; Lim B.; Chow V. T.; Crum C. P.; Xian W.; McKeon F. Distal airway stem cells yield alveoli in vitro and during lung regeneration following H1N1 influenza infection. Cell 147: 525–538; 2011.
Maden M. Retinoids in lung development and regeneration. Curr Top Dev Biol 61: 153–189; 2004.
Mailleux A. A.; Kelly R.; Veltmaat J. M.; De Langhe S. P.; Zaffran S.; Thiery J. P.; Bellusci S. Fgf10 expression identifies parabronchial smooth muscle cell progenitors and is required for their entry into the smooth muscle cell lineage. Development 132: 2157–2166; 2005.
Masui S.; Shimosato D.; Toyooka Y.; Yagi R.; Takahashi K.; Niwa H. An efficient system to establish multiple embryonic stem cell lines carrying an inducible expression unit. Nucleic Acids Res 33: e43; 2005.
Min H.; Danilenko D. M.; Scully S. A.; Bolon B.; Ring B. D.; Tarpley J. E.; DeRose M.; Simonet W. S. Fgf-10 is required for both limb and lung development and exhibits striking functional similarity to Drosophila branchless. Genes Dev 12: 3156–3161; 1998.
Mollard R.; Ghyselinck N. B.; Wendling O.; Chambon P.; Mark M. Stage-dependent responses of the developing lung to retinoic acid signaling. Int J Dev Biol 44: 457–462; 2000.
Morrisey E. E.; Hogan B. L. Preparing for the first breath: genetic and cellular mechanisms in lung development. Dev Cell 18: 8–23; 2010.
Murry C. E.; Keller G. Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development. Cell 132: 661–680; 2008.
Niederreither K.; Dolle P. Retinoic acid in development: towards an integrated view. Nat Rev Genet 9: 541–553; 2008.
Nishimura Y.; Hamazaki T. S.; Komazaki S.; Kamimura S.; Okochi H.; Asashima M. Ciliated cells differentiated from mouse embryonic stem cells. Stem Cells 24: 1381–1388; 2006.
Nishimura Y.; Kurisaki A.; Nakanishi M.; Ohnuma K.; Ninomiya N.; Komazaki S.; Ishiura S.; Asashima M. Inhibitory Smad proteins promote the differentiation of mouse embryonic stem cells into ependymal-like ciliated cells. Biochem Biophys Res Commun 401: 1–6; 2010.
Nyeng P.; Norgaard G. A.; Kobberup S.; Jensen J. FGF10 maintains distal lung bud epithelium and excessive signaling leads to progenitor state arrest, distalization, and goblet cell metaplasia. BMC Dev Biol 8: 2; 2008.
Prockop D. J. “Stemness” does not explain the repair of many tissues by mesenchymal stem/multipotent stromal cells (MSCs). Clin Pharmacol Ther 82: 241–243; 2007.
Que J.; Choi M.; Ziel J. W.; Klingensmith J.; Hogan B. L. Morphogenesis of the trachea and esophagus: current players and new roles for noggin and Bmps. Differentiation 74: 422–437; 2006.
Rawlins E. L.; Okubo T.; Xue Y.; Brass D. M.; Auten R. L.; Hasegawa H.; Wang F.; Hogan B. L. 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.
Rippon H. J.; Ali N. N.; Polak J. M.; Bishop A. E. Initial observations on the effect of medium composition on the differentiation of murine embryonic stem cells to alveolar type II cells. Cloning Stem Cells 6: 49–56; 2004.
Rock J. R.; Barkauskas C. E.; Cronce M. J.; Xue Y.; Harris J. R.; Liang J.; Noble P. W.; Hogan B. L. Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition. Proc Natl Acad Sci U S A 108: E1475–1483; 2011.
Rock J. R.; Onaitis M. W.; Rawlins E. L.; Lu Y.; Clark C. P.; Xue Y.; Randell S. H.; Hogan B. L. Basal cells as stem cells of the mouse trachea and human airway epithelium. Proc Natl Acad Sci U S A 106: 12771–12775; 2009.
Sekine K.; Ohuchi H.; Fujiwara M.; Yamasaki M.; Yoshizawa T.; Sato T.; Yagishita N.; Matsui D.; Koga Y.; Itoh N.; Kato S. Fgf10 is essential for limb and lung formation. Nat Genet 21: 138–141; 1999.
Serikov V. B.; Mikhaylov V. M.; Krasnodembskay A. D.; Matthay M. A. Bone marrow-derived cells participate in stromal remodeling of the lung following acute bacterial pneumonia in mice. Lung 186: 179–190; 2008.
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.
Verma R. P.; McCulloch K. M.; Worrell L.; Vidyasagar D. Vitamin A deficiency and severe bronchopulmonary dysplasia in very low birthweight infants. Am J Perinatol 13: 389–393; 1996.
Weaver M.; Batts L.; Hogan B. L. Tissue interactions pattern the mesenchyme of the embryonic mouse lung. Dev Biol 258: 169–184; 2003.
Weaver M.; Yingling J. M.; Dunn N. R.; Bellusci S.; Hogan B. L. Bmp signaling regulates proximal-distal differentiation of endoderm in mouse lung development. Development 126: 4005–4015; 1999.
Wong A. P.; Bear C. E.; Chin S.; Pasceri P.; Thompson T. O.; Huan L. J.; Ratjen F.; Ellis J.; Rossant J. Directed differentiation of human pluripotent stem cells into mature airway epithelia expressing functional CFTRTR protein. Nat Biotechnol 30: 876–882; 2012.
Acknowledgments
We would like to thank Dr. Shinji Masui and Dr. Hitoshi Niwa for providing us with the plasmids and mouse ES cells. This work was supported in part by Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (M.A. and A.K.), grants from Ichiro Kanahara Foundation (A.K.), and grants from the Suzuken Memorial Foundation (A.K.).
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Editor: T. Okamoto
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Ninomiya, N., Michiue, T., Asashima, M. et al. BMP signaling regulates the differentiation of mouse embryonic stem cells into lung epithelial cell lineages. In Vitro Cell.Dev.Biol.-Animal 49, 230–237 (2013). https://doi.org/10.1007/s11626-013-9589-1
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DOI: https://doi.org/10.1007/s11626-013-9589-1