Cell and Tissue Research

, Volume 331, Issue 1, pp 145–156 | Cite as

Lung stem cells

  • Darrell N. KottonEmail author
  • Alan Fine


The lung is a relatively quiescent tissue comprised of infrequently proliferating epithelial, endothelial, and interstitial cell populations. No classical stem cell hierarchy has yet been described for the maintenance of this essential tissue; however, after injury, a number of lung cell types are able to proliferate and reconstitute the lung epithelium. Differentiated mature epithelial cells and newly recognized local epithelial progenitors residing in specialized niches may participate in this repair process. This review summarizes recent discoveries and controversies, in the field of stem cell biology, that are not only challenging, but also advancing an understanding of lung injury and repair. Evidence supporting a role for the numerous cell types believed to contribute to lung epithelial homeostasis is reviewed, and initial studies employing cell-based therapies for lung disease are presented. As a detailed understanding of stem cell biology, lung development, lineage commitment, and epithelial differentiation emerges, an ability to modulate lung injury and repair is likely to follow.


Stem cells Lung Injury Development Bone marrow 


  1. Abe K, Niwa H, Iwase K, Takiguchi M, Mori M, Abé SI, et al (1996) Endoderm-specific gene expression in embryonic stem cells differentiated to embryoid bodies. Exp Cell Res 229:27–34PubMedGoogle Scholar
  2. Abe S, Boyer C, Liu X, Wen FQ, Kobayashi T, Fang Q, et al (2004) Cells derived from the circulation contribute to the repair of lung injury. Am J Respir Crit Care Med 170:1158–1163PubMedGoogle Scholar
  3. Adamson IYR, Bowden DH (1974) The type 2 cell as progenitor of alveolar epithelial regeneration. Lab Invest 30:35–42PubMedGoogle Scholar
  4. Adamson IYR, Bowden DH (1979) Bleomycin-induced injury and metaplasia of alveolar type 2 cells. Am J Pathol 96:531–544PubMedGoogle Scholar
  5. Aggarwal S, Pittenger MF (2005) Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105:1815–1822PubMedGoogle Scholar
  6. Ali NN, Edgar AJ, Samadikuchaksaraei A, Timson CM, Romanska HM, Polak JM, Bishop AE (2002) Derivation of type II alveolar epithelial cells from murine embryonic stem cells. Tissue Eng 8:541–550PubMedGoogle Scholar
  7. Asakura A, Seale P, Girgis-Gabardo A, Rudnicki MA (2002) Myogenic specification of side population cells in skeletal muscle. J Cell Biol 159:123–134PubMedGoogle Scholar
  8. Bailey AS, Jiang S, Afentoulis M, Baumann CI, Schroeder DA, Olson SB, et al (2004) Transplanted adult hematopoietic stems cells differentiate into functional endothelial cells. Blood 103:13–19PubMedGoogle Scholar
  9. Beckett T, Loi R, Prenovitz R, Poynter M, Goncz KK, Suratt BT, Weiss DJ (2005) Acute lung injury with endotoxin or NO2 does not enhance development of airway epithelium from bone marrow. Mol Ther 12:680–686PubMedGoogle Scholar
  10. Blenkinsopp WK (1967) Proliferation of respiratory tract epithelium in the rat. Exp Cell Res 46:144–154PubMedGoogle Scholar
  11. Boers JE, Ambergen AW, Thunnissen FB (1998) Number and proliferation of basal and parabasal cells in normal human airway epithelium. Am J Respir Crit Care Med 157:2000–2006PubMedGoogle Scholar
  12. Borthwick DW, Shahbazian M, Krantz QT, Dorin JR, Randell SH (2001) Evidence for stem-cell niches in the tracheal epithelium. Am J Respir Cell Mol Biol 24:662–670PubMedGoogle Scholar
  13. Breuer R, Zajicek G, Christensen TG, Lucey EC, Snider GL (1990) Cell kinetics of normal adult hamster bronchial epithelium in the steady state. Am J Respir Cell Mol Biol 2:51–58PubMedGoogle Scholar
  14. Brody JS (1975) Time course of and stimuli to compensatory growth of the lung after pneumonectomy. J Clin Invest 56:897–904PubMedCrossRefGoogle Scholar
  15. Brody JS, Williams MC (1992) Pulmonary alveolar epithelial cell differentiation. Annu Rev Physiol 54:351–371PubMedGoogle Scholar
  16. Brody JS, Kagan HM, Manalo AD, Hu CA, Franzblau C (1976) Lung lysyl oxidase and elastin synthesis during compensatory lung growth. Chest 69 (2 Suppl):271–272PubMedGoogle Scholar
  17. Brown LM, Rannels SR, Rannels DE (2001) Implications of post-pneumonectomy compensatory lung growth in pulmonary physiology and disease. Respir Res 2:340–347PubMedGoogle Scholar
  18. Bull TM, Golpon H, Hebbel RP, Solovey A, Cool CD, Tuder RM, et al (2003) Circulating endothelial cells in pulmonary hypertension. Thromb Haemost 90:698–703PubMedGoogle Scholar
  19. Cardoso WV, Lu J (2006) Regulation of early lung morphogenesis: questions, facts and controversies. Development 133:1611–1624PubMedGoogle Scholar
  20. Chang JC, Summer R, Sun X, Fitzsimmons K, Fine A (2005) Evidence that bone marrow cells do not contribute to the alveolar epithelium. Am J Respir Cell Mol Biol 33:335–342PubMedGoogle Scholar
  21. Coraux C, Nawrocki-Raby B, Hinnrasky J, Kileztky C, Gaillard D, Dani C, Puchelle E (2005) Embryonic stem cells generate airway epithelial tissue. Am J Respir Cell Mol Biol 32:87–92PubMedGoogle Scholar
  22. Czyz J, Wobus A (2001) Embryonic stem cell differentiation: the role of extracellular factors. Differentiation 68:167–174PubMedGoogle Scholar
  23. D’Amour KA, Agulnick AD, Eliazer S, Kelly OG, Kroon E, Baetge EE (2005) Efficient differentiation of human embryonic stem cells to definitive endoderm. Nat Biotechnol 23:1534–1541PubMedGoogle Scholar
  24. Danto SI, Zabski SM, Crandall ED (1992) Reactivity of alveolar epithelial cells in primary culture with type I cell monoclonal antibodies. Am J Respir Cell Mol Biol 6:296–306PubMedGoogle Scholar
  25. Danto SI, Shannon JM, Borok Z, Zabski SM, Crandall ED (1995) Reversible transdifferentiation of alveolar epithelial cells. Am J Respir Cell Mol Biol 12:497–502PubMedGoogle Scholar
  26. Davie NJ, Crossno JT Jr, Frid MG, Hofmeister SE, Reeves JT, Hyde DM, et al (2004) Hypoxia-induced pulmonary artery adventitial remodeling and neovascularization: contribution of progenitor cells. Am J Physiol Lung Cell Mol Physiol 286:L668–L678PubMedGoogle Scholar
  27. De Palma M, Venneri MA, Galli R, Sergi Sergi L, Politi LS, Sampaolesi M, Naldini L (2005) Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 8:211–226PubMedGoogle Scholar
  28. Denham M, Cole TJ, Mollard R (2006) Embryonic stem cells form glandular structures and express surfactant protein C following culture with dissociated fetal respiratory tissue. Am J Physiol Lung Cell Mol Physiol 290:L1210–L1215PubMedGoogle Scholar
  29. Dobbs LG, Williams MC, Brandt AE (1985) Changes in biochemical characteristics and pattern of lectin binding of alveolar type II cells with time in culture. Biochim Biophys Acta 846:155–166PubMedGoogle Scholar
  30. Dong QG, Bernasconi S, Lostaglio S, De Calmanovici RW, Martin-Padura I, Breviario F, et al (1997) A general strategy for isolation of endothelial cells from murine tissues. Characterization of two endothelial cell lines from the murine lung and subcutaneous sponge implants. Arterioscler Thromb Vasc Biol 17:1599–1604PubMedGoogle Scholar
  31. Dor Y, Brown J, Martinez OI, Melton DA (2004) Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature 429:41–46PubMedGoogle Scholar
  32. Eglitis MA, Mezey E (1997) Hematopoietic cells differentiate into both microglia and macroglia in the brains of adult mice. Proc Natl Acad Sci USA 94:4080–4085PubMedGoogle Scholar
  33. Engelhardt JF, Allen ED, Wilson JM (1991) Reconstitution of tracheal grafts with a genetically modified epithelium. Proc Natl Acad Sci USA 88:11192–11196PubMedGoogle Scholar
  34. Engelhardt JF, Schlossberg H, Yankaskas JR, Dudus L (1995) Progenitor cells of the adult human airway involved in submucosal gland development. Development 121:2031–2046PubMedGoogle Scholar
  35. Eren S, Eren MN, Balci AE (2003) Pneumonectomy in children for destroyed lung and the long-term consequences. J Thorac Cardiovasc Surg 126:574–581PubMedGoogle Scholar
  36. Evans MJ, Kaufman MH (1981) Establishment in culture of pluripotential cells from mouse embryos. Nature 292:154–156PubMedGoogle Scholar
  37. Evans MJ, Cabral LJ, Stephens RJ, Freeman G (1973) Renewal of alveolar epithelium in the rat following exposure to NO2. Am J Pathol 70:175–198PubMedGoogle Scholar
  38. Evans MJ, Cabral LJ, Stephens RJ, Freeman G (1975) Transformation of alveolar type 2 cells to type 1 cells following exposure to NO2. Exp Mol Pathol 22:142–150PubMedGoogle Scholar
  39. Evans MJ, Johnson LV, Stephens RJ, Freeman G (1976) Renewal of the terminal bronchiolar epithelium in the rat following exposure to NO2 or O3. Lab Invest 35:246–257PubMedGoogle Scholar
  40. Evans MJ, Shami SG, Cabral-Anderson LJ, Dekker NP (1986) Role of nonciliated cells in renewal of the bronchial epithelium of rats exposed to NO2. Am J Pathol 123:126–133PubMedGoogle Scholar
  41. Forbes S, Vig P, Poulsom R, Thomas H, Alison M (2002) Hepatic stem cells. J Pathol 197:510–518PubMedGoogle Scholar
  42. Ford JR, Terzaghi-Howe M (1992) Basal cells are the progenitors of primary tracheal epithelial cell cultures. Exp Cell Res 198:69–77PubMedGoogle Scholar
  43. Gadue P, Huber TL, Nostro MC, Kattman S, Keller GM (2005) Germ layer induction from embryonic stem cells. Exp Hematol 33:955–964PubMedGoogle Scholar
  44. Gadue P, Huber TL, Paddison PJ, Keller GM (2006) Wnt and TGF-beta signaling are required for the induction of an in vitro model of primitive streak formation using embryonic stem cells. Proc Natl Acad Sci USA 103:16806–16811PubMedGoogle Scholar
  45. Giangreco A, Reynolds SD, Stripp BR (2002) Terminal bronchioles harbor a unique airway stem cell population that localizes to the bronchoalveolar duct junction. Am J Pathol 161:173–182PubMedGoogle Scholar
  46. Giangreco A, Shen H, Reynolds SD, Stripp BR (2003) Molecular phenotype of airway side population cells. Am J Physiol Lung Cell Mol Physiol 286:L624–L630PubMedGoogle Scholar
  47. Gomperts BN, Belperio JA, Rao PN, Randell SH, Fishbein MC, Burdick MD, Strieter RM (2006) Circulating progenitor epithelial cells traffic via CXCR4/CXCL12 in response to airway injury. J Immunol 176:1916–1927PubMedGoogle Scholar
  48. Goodell MA, Jackson KA, Majka SM, Mi T, Wang H, Pocius J, et al (2001) Stem cell plasticity in muscle and bone marrow. Ann N Y Acad Sci 938:208–218PubMedCrossRefGoogle Scholar
  49. Gouon-Evans V, Boussemart L, Gadue P, Nierhoff D, Koehler CI, Kubo A, et al (2006) BMP-4 is required for hepatic specification of mouse embryonic stem cell-derived definitive endoderm. Nat Biotechnol 24:1402–1411PubMedGoogle Scholar
  50. Grove JE, Lutzko C, Priller J, Henegariu O, Theise ND, Kohn DB, Krause DS (2002) Marrow-derived cells as vehicles for delivery of gene therapy to pulmonary epithelium. Am J Respir Cell Mol Biol 27:645–651PubMedGoogle Scholar
  51. Grunewald M, Avraham I, Dor Y, Bachar-Lustig E, Itin A, Jung S, et al (2006) VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells. Cell 124:175–189PubMedGoogle Scholar
  52. Gussoni E, Soneoka Y, Strickland CD, Buzney EA, Khan MK, Flint AF, et al (1999) Dystrophin expression in the mdx mouse restored by stem cell transplantation. Nature 401:390–394PubMedGoogle Scholar
  53. Hamazaki T, Iiboshi Y, Oka M, Papst PJ, Meacham AM, Zon LI, Terada N (2001) Hepatic maturation in differentiating embryonic stem cells in vitro. FEBS Lett 497:15–19PubMedGoogle Scholar
  54. Harris RG, Herzog EL, Bruscia EM, Grove JE, Van Arnam JS, Krause DS (2004) Lack of a fusion requirement for development of bone marrow-derived epithelia. Science 305:90–93PubMedGoogle Scholar
  55. Hashimoto N, Jin H, Liu T, Chensue SW, Phan SH (2004) Bone marrow-derived progenitor cells in pulmonary fibrosis. J Clin Invest 113:243–252PubMedGoogle Scholar
  56. Herzog EL, Chai L, Krause DS (2003) Plasticity of marrow-derived stem cells. Blood 102:3483–3493PubMedGoogle Scholar
  57. Herzog EL, Van Arnam J, Hu B, Krause DS (2006) Threshold of lung injury required for the appearance of marrow-derived lung epithelia. Stem Cells 24:1986–1992PubMedGoogle Scholar
  58. Herzog EL, Van Arnam J, Hu B, Zhang J, Chen Q, Haberman AM, Krause DS (2007) Lung-specific nuclear reprogramming is accompanied by heterokaryon formation and Y chromosome loss following bone marrow transplantation and secondary inflammation. FASEB J 21:2592–2601PubMedGoogle Scholar
  59. Hescheler J, Fleischmann BK, Lentini S, Maltsev VA, Rohwedel J, Wobus AM, Addicks K (1997) Embryonic stem cells: a model to study structural and functional properties in cardiomyogenesis. Cardiovasc Res 36:149–162PubMedGoogle Scholar
  60. Hilbe W, Dirnhofer S, Oberwasserlechner F, Schmid T, Gunsilius E, Hilbe G, et al (2004) CD133 positive endothelial progenitor cells contribute to the tumour vasculature in non-small cell lung cancer. J Clin Pathol 57:965–969PubMedGoogle Scholar
  61. Hong KU, Reynolds SD, Giangreco A, Hurley CM, Stripp BR (2001) 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 24:671–681PubMedGoogle Scholar
  62. Hong KU, Reynolds SD, Watkins S, Fuchs E, Stripp BR (2003) In vivo differentiation potential of tracheal basal cells: evidence for multipotent and unipotent subpopulations. Am J Physiol Lung Cell Mol Physiol 286:L643–L649PubMedGoogle Scholar
  63. Hori Y, Rulifson IC, Tsai BC, Heit JJ, Cahoy JD, Kim SK (2002) Growth inhibitors promote differentiation of insulin-producing tissue from embryonic stem cells. Proc Natl Acad Sci USA 99:16105–16110PubMedGoogle Scholar
  64. Hsia CC (2004a) Signals and mechanisms of compensatory lung growth. J Appl Physiol 97:1992–1998PubMedGoogle Scholar
  65. Hsia CC (2004b) Lessons from a canine model of compensatory lung growth. Curr Top Dev Biol 64:17–32PubMedGoogle Scholar
  66. Ishizawa K, Kubo H, Yamada M, Kobayashi S, Numasaki M, Ueda S, et al (2004) Bone marrow-derived cells contribute to lung regeneration after elastase-induced pulmonary emphysema. FEBS Lett 556:249–252PubMedGoogle Scholar
  67. Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, et al (2002) Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 418:41–49PubMedGoogle Scholar
  68. Johnson NF, Hubbs AF (1990) Epithelial progenitor cells in the rat trachea. Am J Respir Cell Mol Biol 3:579–585PubMedGoogle Scholar
  69. Jones EA, Tosh D, Wilson DI, Lindsay S, Forrester LM (2002) Hepatic differentiation of murine embryonic stem cells. Exp Cell Res 272:15–22PubMedGoogle Scholar
  70. Keller GM (1995) In vitro differentiation of embryonic stem cells. Curr Opin Cell Biol 7:862–869PubMedGoogle Scholar
  71. Keller G, Kennedy M, Papayannopoulou T, Wiles MV (1993) Hematopoietic commitment during embryonic stem cell differentiation in culture. Mol Cell Biol 13:473–486PubMedGoogle Scholar
  72. Kim CF, Jackson EL, Woolfenden AE, Lawrence S, Babar I, Vogel S, et al (2005) Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 121:823–835PubMedGoogle Scholar
  73. Kotton DN, Ma BY, Cardoso WV, Sanderson EA, Summer RS, Williams MC, Fine A (2001) Bone marrow-derived cells as progenitors of lung alveolar epithelium. Development 128:5181–5188PubMedGoogle Scholar
  74. Kotton DN, Summer RS, Sun X, Ma BY, Fine A (2003) Stem cell antigen-1 expression in the pulmonary vascular endothelium. Am J Physiol Lung Cell Mol Physiol 284:L990–L996PubMedGoogle Scholar
  75. Kotton DN, Fabian AJ, Mulligan RC (2005a) A novel stem cell population in adult liver with potent hematopoietic reconstitution activity. Blood 106:1574–1580PubMedGoogle Scholar
  76. Kotton DN, Fabian AJ, Mulligan RC (2005b) Failure of bone marrow to reconstitute lung epithelium. Am J Respir Cell Mol Biol 33:328–334PubMedGoogle Scholar
  77. Kramer J, Hegert C, Guan K, Wobus AM, Muller PK, Rohwedel J (2000) Embryonic stem cell-derived chondrogenic differentiation in vitro: activation by BMP-2 and BMP-4. Mech Dev 92:193–205PubMedGoogle Scholar
  78. Krause DS, Theise ND, Collector MI, Henegariu O, Hwang S, Gardner R, et al (2001) Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 105:369–377PubMedGoogle Scholar
  79. Kubo A, Shinozaki K, Shannon JM, Kouskoff V, Kennedy M, Woo S, et al (2004) Development of definitive endoderm from embryonic stem cells in culture. Development 131:1651–1662PubMedGoogle Scholar
  80. Kuboi S, Mizuuchi A, Mizuuchi T, Taguchi T, Thurlbeck WM, Kida K (1992) DNA synthesis and related enzymes altered in compensatory lung growth in rats. Scand J Clin Lab Invest 52:707–715PubMedGoogle Scholar
  81. Lagasse E, Connors H, Al Dhalimy M, Reitsma M, Dohse M, Osborne L, et al (2000) Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med 6:1229–1234PubMedGoogle Scholar
  82. Lama VN, Smith L, Badri L, Flint A, Andrei AC, Murray S, et al (2007) Evidence for tissue-resident mesenchymal stem cells in human adult lung from studies of transplanted allografts. J Clin Invest 117:989–996PubMedGoogle Scholar
  83. Laros CD, Westermann CJ (1987) Dilatation, compensatory growth, or both after pneumonectomy during childhood and adolescence. A thirty-year follow-up study. J Thorac Cardiovasc Surg 93:570–576PubMedGoogle Scholar
  84. Laros CD, Westermann CJ (1989) Postpneumonectomy compensatory lung growth. Am Rev Respir Dis 139:1569–1570PubMedGoogle Scholar
  85. Le Blanc K, Rasmusson I, Sundberg B, Gotherstrom C, Hassan M, Uzunel M, Ringden O (2004) Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 363:1439–1441PubMedGoogle Scholar
  86. Liu JY, Nettesheim P, Randell SH (1994) Growth and differentiation of tracheal epithelial progenitor cells. Am J Physiol 266:L296–L307PubMedGoogle Scholar
  87. Loi R, Beckett T, Goncz KK, Suratt BT, Weiss DJ (2006) Limited restoration of cystic fibrosis lung epithelium in vivo with adult bone marrow-derived cells. Am J Respir Crit Care Med 173:171–179PubMedGoogle Scholar
  88. Lumelsky N, Blondel O, Laeng P, Velasco I, Ravin R, McKay R (2001) Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets. Science 292:1389–1394PubMedGoogle Scholar
  89. MacPherson H, Keir P, Webb S, Samuel K, Boyle S, Bickmore W, et al (2005) Bone marrow-derived SP cells can contribute to the respiratory tract of mice in vivo. J Cell Sci 118:2441–2450PubMedGoogle Scholar
  90. Marshman E, Booth C, Potten CS (2002) The intestinal epithelial stem cell. Bioessays 24:91–98PubMedGoogle Scholar
  91. Mason RJ, Williams MC (1977) Type II alveolar cell. Defender of the alveolus. Am Rev Respir Dis 115:81–91PubMedGoogle Scholar
  92. Mason R, Williams MC, Clements JA (1975) Isolation and identification of type 2 alveolar epithelial cells. Chest 67 (2 Suppl):36S–37SPubMedGoogle Scholar
  93. Mezey E, Chandross KJ, Harta G, Maki RA, McKercher SR (2000) Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science 290:1779–1782PubMedGoogle Scholar
  94. Morrison SJ, Uchida N, Weissman IL (1995) The biology of hematopoietic stem cells. Annu Rev Cell Dev Biol 11:35–71PubMedGoogle Scholar
  95. Nakano T, Kodama H, Honjo T (1994) Generation of lymphohematopoietic cells from embryonic stem cells in culture. Science 265:1098–1101PubMedGoogle Scholar
  96. Nishikawa SI, Nishikawa S, Hirashima M, Matsuyoshi N, Kodama H (1998) Progressive lineage analysis by cell sorting and culture identifies FLK1+VE-cadherin+ cells at a diverging point of endothelial and hemopoietic lineages. Development 125:1747–1757PubMedGoogle Scholar
  97. Oh H, Bradfute SB, Gallardo TD, Nakamura T, Gaussin V, Mishina Y, et al (2003) Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. Proc Natl Acad Sci USA 100:12313–12318PubMedGoogle Scholar
  98. Okabe S, Forsberg-Nilsson K, Spiro AC, Segal M, McKay RD (1996) Development of neuronal precursor cells and functional postmitotic neurons from embryonic stem cells in vitro. Mech Dev 59:89–102PubMedGoogle Scholar
  99. Ortiz LA, Gambelli F, McBride C, Gaupp D, Baddoo M, Kaminski N, Phinney DG (2003) Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc Natl Acad Sci USA 100:8407–8411PubMedGoogle Scholar
  100. Park KS, Wells JM, Zorn AM, Wert SE, Laubach VE, Fernandez LG, Whitsett JA (2006) Transdifferentiation of ciliated cells during repair of the respiratory epithelium. Am J Respir Cell Mol Biol 34:151–157PubMedGoogle Scholar
  101. Peake JL, Reynolds SD, Stripp BR, Stephens KE, Pinkerton KE (2000) Alteration of pulmonary neuroendocrine cells during epithelial repair of naphthalene-induced airway injury. Am J Pathol 156:279–286PubMedGoogle Scholar
  102. Perl AK, Tichelaar JW, Whitsett JA (2002a) Conditional gene expression in the respiratory epithelium of the mouse. Transgenic Res 11:21–29PubMedGoogle Scholar
  103. Perl AK, Wert SE, Nagy A, Lobe CG, Whitsett JA (2002b) Early restriction of peripheral and proximal cell lineages during formation of the lung. Proc Natl Acad Sci USA 99:10482–10487PubMedGoogle Scholar
  104. Perl AK, Wert SE, Loudy DE, Shan Z, Blair PA, Whitsett JA (2005) Conditional recombination reveals distinct subsets of epithelial cells in trachea, bronchi, and alveoli. Am J Respir Cell Mol Biol 33:455–462PubMedGoogle Scholar
  105. Petersen BE, Bowen WC, Patrene KD, Mars WM, Sullivan AK, Murase N, et al (1999) Bone marrow as a potential source of hepatic oval cells. Science 284:1168–1170PubMedGoogle Scholar
  106. Petersen BE, Grossbard B, Hatch H, Pi L, Deng J, Scott EW (2003) Mouse A6-positive hepatic oval cells also express several hematopoietic stem cell markers. Hepatology 37:632–640PubMedGoogle Scholar
  107. Phillips RJ, Burdick MD, Hong K, Lutz MA, Murray LA, Xue YY, et al (2004) Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis. J Clin Invest 114:438–446PubMedGoogle Scholar
  108. Pinto D, Clevers H (2005) Wnt control of stem cells and differentiation in the intestinal epithelium. Exp Cell Res 306:357–363PubMedGoogle Scholar
  109. Pinto D, Gregorieff A, Begthel H, Clevers H (2003) Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Genes Dev 17:1709–1713PubMedGoogle Scholar
  110. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et al (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284:143–147PubMedGoogle Scholar
  111. Qin M, Tai G, Collas P, Polak JM, Bishop AE (2005) Cell extract-derived differentiation of embryonic stem cells. Stem Cells 23:712–718PubMedGoogle Scholar
  112. Quaini F, Urbanek K, Beltrami AP, Finato N, Beltrami CA, Nadal-Ginard B, et al (2002) Chimerism of the transplanted heart. N Engl J Med 346:5–15PubMedGoogle Scholar
  113. Rannels DE, White DM, Watkins CA (1979) Rapidity of compensatory lung growth following pneumonectomy in adult rats. J Appl Physiol 46:326–333PubMedGoogle Scholar
  114. Rawlins EL, Hogan BL (2006) Epithelial stem cells of the lung: privileged few or opportunities for many? Development 133:2455–2465PubMedGoogle Scholar
  115. Rawlins EL, Ostrowski LE, Randell SH, Hogan BL (2007) Lung development and repair: contribution of the ciliated lineage. Proc Natl Acad Sci USA 104:410–417PubMedGoogle Scholar
  116. Reddy R, Buckley S, Doerken M, Barsky L, Weinberg K, Anderson KD, et al (2004) Isolation of a putative progenitor subpopulation of alveolar epithelial type 2 cells. Am J Physiol Lung Cell Mol Physiol 286:L658–L667PubMedGoogle Scholar
  117. Reynolds SD, Giangreco A, Power JH, Stripp BR (2000a) Neuroepithelial bodies of pulmonary airways serve as a reservoir of progenitor cells capable of epithelial regeneration. Am J Pathol 156:269–278PubMedGoogle Scholar
  118. Reynolds SD, Hong KU, Giangreco A, Mango GW, Guron C, Morimoto Y, Stripp BR (2000b) Conditional clara cell ablation reveals a self-renewing progenitor function of pulmonary neuroendocrine cells. Am J Physiol Lung Cell Mol Physiol 278:L1256–L1263PubMedGoogle Scholar
  119. Rippon HJ, Polak JM, Qin M, Bishop AE (2006) Derivation of distal lung epithelial progenitors from murine embryonic stem cells using a novel three-step differentiation protocol. Stem Cells 24:1389–1398PubMedGoogle Scholar
  120. Rohwedel J, Maltsev V, Bober E, Arnold HH, Hescheler J, Wobus AM (1994) Muscle cell differentiation of embryonic stem cells reflects myogenesis in vivo: developmentally regulated expression of myogenic determination genes and functional expression of ionic currents. Dev Biol 164:87–101PubMedGoogle Scholar
  121. Rojas M, Xu J, Woods CR, Mora AL, Spears W, Roman J, Brigham KL (2005) Bone marrow-derived mesenchymal stem cells in repair of the injured lung. Am J Respir Cell Mol Biol 33:145–152PubMedGoogle Scholar
  122. Roper JM, Staversky RJ, Finkelstein JN, Keng PC, O’Reilly MA (2003) Identification and isolation of mouse type II cells on the basis of intrinsic expression of enhanced green fluorescent protein. Am J Physiol Lung Cell Mol Physiol 285:L691–L700PubMedGoogle Scholar
  123. Sakamaki Y, Matsumoto K, Mizuno S, Miyoshi S, Matsuda H, Nakamura T (2002) Hepatocyte growth factor stimulates proliferation of respiratory epithelial cells during postpneumonectomy compensatory lung growth in mice. Am J Respir Cell Mol Biol 26:525–533PubMedGoogle Scholar
  124. Samadikuchaksaraei A, Cohen S, Isaac K, Rippon HJ, Polak JM, Bielby RC, Bishop AE (2006) Derivation of distal airway epithelium from human embryonic stem cells. Tissue Eng 12:867–875PubMedGoogle Scholar
  125. Schmidt M, Sun G, Stacey MA, Mori L, Mattoli S (2003) Identification of circulating fibrocytes as precursors of bronchial myofibroblasts in asthma. J Immunol 171:380–389PubMedGoogle Scholar
  126. Shigemura N, Okumura M, Mizuno S, Imanishi Y, Matsuyama A, Shiono H, et al (2006a) Lung tissue engineering technique with adipose stromal cells improves surgical outcome for pulmonary emphysema. Am J Respir Crit Care Med 174:1199–1205PubMedGoogle Scholar
  127. Shigemura N, Okumura M, Mizuno S, Imanishi Y, Nakamura T, Sawa Y (2006b) Autologous transplantation of adipose tissue-derived stromal cells ameliorates pulmonary emphysema. Am J Transplant 6:2592–2600PubMedGoogle Scholar
  128. Spees JL, Olson SD, Ylostalo J, Lynch PJ, Smith J, Perry A, et al (2003) Differentiation, cell fusion, and nuclear fusion during ex vivo repair of epithelium by human adult stem cells from bone marrow stroma. Proc Natl Acad Sci USA 100:2397–2402PubMedGoogle Scholar
  129. Stripp BR, Maxson K, Mera R, Singh G (1995) Plasticity of airway cell proliferation and gene expression after acute naphthalene injury. Am J Physiol 269:L791–L799PubMedGoogle Scholar
  130. Summer R, Kotton DN, Liang S, Fitzsimmons K, Sun X, Fine A (2005) Embryonic lung side population cells are hematopoietic and vascular precursors. Am J Respir Cell Mol Biol 33:32–40PubMedGoogle Scholar
  131. Summer R, Fitzsimmons K, Dwyer D, Murphy J, Fine A (2007) Isolation of an adult mouse lung mesenchymal progenitor cell population. Am J Respir Cell Mol Biol 37:152–159PubMedGoogle Scholar
  132. Tam PP, Behringer RR (1997) Mouse gastrulation: the formation of a mammalian body plan. Mech Dev 68:3–25PubMedGoogle Scholar
  133. Tamaki T, Akatsuka A, Ando K, Nakamura Y, Matsuzawa H, Hotta T, et al (2002) Identification of myogenic-endothelial progenitor cells in the interstitial spaces of skeletal muscle. J Cell Biol 157:571–577PubMedGoogle Scholar
  134. Theise ND, Henegariu O, Grove J, Jagirdar J, Kao PN, Crawford JM, et al (2002) Radiation pneumonitis in mice: a severe injury model for pneumocyte engraftment from bone marrow. Exp Hematol 30:1333–1338PubMedGoogle Scholar
  135. Van Vranken BE, Romanska HM, Polak JM, Rippon HJ, Shannon JM, Bishop AE (2005) Coculture of embryonic stem cells with pulmonary mesenchyme: a microenvironment that promotes differentiation of pulmonary epithelium. Tissue Eng 11:1177–1187PubMedGoogle Scholar
  136. Vittet D, Prandini MH, Berthier R, Schweitzer A, Martin-Sisteron H, Uzan G, Dejana E (1996) Embryonic stem cells differentiate in vitro to endothelial cells through successive maturation steps. Blood 88:3424–3431PubMedGoogle Scholar
  137. Voswinckel R, Ziegelhoeffer T, Heil M, Kostin S, Breier G, Mehling T, et al (2003) Circulating vascular progenitor cells do not contribute to compensatory lung growth. Circ Res 93:372–379PubMedGoogle Scholar
  138. Voswinckel R, Motejl V, Fehrenbach A, Wegmann M, Mehling T, Fehrenbach H, Seeger W (2004) Characterisation of post-pneumonectomy lung growth in adult mice. Eur Respir J 24:524–532PubMedGoogle Scholar
  139. Wagers AJ, Weissman IL (2004) Plasticity of adult stem cells. Cell 116:639–648PubMedGoogle Scholar
  140. Wagers AJ, Sherwood RI, Christensen JL, Weissman IL (2002) Little evidence for developmental plasticity of adult hematopoietic stem cells. Science 297:2256–2259PubMedGoogle Scholar
  141. Wang D, Haviland DL, Burns AR, Zsigmond E, Wetsel RA (2007) A pure population of lung alveolar epithelial type II cells derived from human embryonic stem cells. Proc Natl Acad Sci USA 104:4449–4454PubMedGoogle Scholar
  142. Wang G, Bunnell BA, Painter RG, Quiniones BC, Tom S, Lanson NA Jr, et al (2005) Adult stem cells from bone marrow stroma differentiate into airway epithelial cells: potential therapy for cystic fibrosis. Proc Natl Acad Sci USA 102:186–191PubMedGoogle Scholar
  143. Wang X, Foster M, Al Dhalimy M, Lagasse E, Finegold M, Grompe M (2003) The origin and liver repopulating capacity of murine oval cells. Proc Natl Acad Sci USA 100 (Suppl 1):11881–11888PubMedGoogle Scholar
  144. Weiss DJ, Berberich MA, Borok Z, Gail DB, Kolls JK, Penland C, Prockop DJ (2006) Adult stem cells, lung biology, and lung disease. NHLBI/Cystic Fibrosis Foundation Workshop. Proc Am Thorac Soc 3:193–207PubMedGoogle Scholar
  145. Welm BE, Tepera SB, Venezia T, Graubert TA, Rosen JM, Goodell MA (2002) Sca-1(pos) cells in the mouse mammary gland represent an enriched progenitor cell population. Dev Biol 245:42–56PubMedGoogle Scholar
  146. Werner HA, Pirie GE, Nadel HR, Fleisher AG, LeBlanc JG (1993) Lung volumes, mechanics, and perfusion after pulmonary resection in infancy. J Thorac Cardiovasc Surg 105:737–742PubMedGoogle Scholar
  147. Wiles MV, Keller G (1991) Multiple hematopoietic lineages develop from embryonic stem (ES) cells in culture. Development 111:259–267PubMedGoogle Scholar
  148. Xu J, Woods CR, Mora AL, Joodi R, Brigham KL, Iyer S, Rojas M (2007) Prevention of endotoxin-induced systemic response by bone marrow derived mesenchymal stem cells in mice. Am J Physiol Lung Cell Mol Physiol 293:L131–L141PubMedGoogle Scholar
  149. Yasunaga M, Tada S, Torikai-Nishikawa S, Nakano Y, Okada M, Jakt LM, et al (2005) Induction and monitoring of definitive and visceral endoderm differentiation of mouse ES cells. Nat Biotechnol 23:1542–1550PubMedGoogle Scholar
  150. Yuhgetsu H, Ohno Y, Funaguchi N, Asai T, Sawada M, Takemura G, et al (2006) Beneficial effects of autologous bone marrow mononuclear cell transplantation against elastase-induced emphysema in rabbits. Exp Lung Res 32:413–426Google Scholar
  151. Zepeda ML, Chinoy MR, Wilson JM (1995) Characterization of stem cells in human airway capable of reconstituting a fully differentiated bronchial epithelium. Somat Cell Mol Genet 21:61–73PubMedGoogle Scholar
  152. Zhao YD, Courtman DW, Deng Y, Kugathasan L, Zhang Q, Stewart DJ (2005) Rescue of monocrotaline-induced pulmonary arterial hypertension using bone marrow-derived endothelial-like progenitor cells: efficacy of combined cell and eNOS gene therapy in established disease. Circ Res 96:442–450PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  1. 1.Boston University Pulmonary CenterBoston University School of MedicineBostonUSA

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