How to Grow a Lung: Applying Principles of Developmental Biology to Generate Lung Lineages from Human Pluripotent Stem Cells

Current Pathobiology Reports

Volumn 4, Issue 2, 2016, Pages 47-57

  Dye, Briana R ^a   Miller, Alyssa J ^a   Spence, Jason R ^a  

^a UNIVERSITY OF MICHIGAN MEDICAL SCHOOL   (United States)

Author keywords

Airway; Alveoli; Directed differentiation; Human pluripotent stem cell; Lung development; Organoid

Indexed keywords

EID: 85011543648     PISSN: None     EISSN: 2167485X     Source Type: Journal    
DOI: 10.1007/s40139-016-0102-x     Document Type: Review

References (124)

1. Mercer RR, Russell ML, Roggli VL, Crapo JD (1994) Cell number and distribution in human and rat airways. Am J Respir Cell Mol Biol 10:613–624. doi:10.1165/ajrcmb.10.6.8003339
2. Wolff RK (1986) Effects of airborne pollutants on mucociliary clearance. Environ Health Perspect 66:223–237
3. Schum M, Yeh HC (1980) Theoretical evaluation of aerosol deposition in anatomical models of mammalian lung airways. Bull Math Biol 42:1–15
4. Rogers DF (1994) Airway goblet cells: responsive and adaptable front-line defenders. Eur Respir J 7:1690–1706
5. Rock JR, Onaitis MW, Rawlins EL et al (2009) Basal cells as stem cells of the mouse trachea and human airway epithelium. Proc Natl Acad Sci 106:12771–12775. doi:10.1073/pnas.0906850106
6. Hackett T-L, Shaheen F, Johnson A et al (2008) Characterization of side population cells from human airway epithelium. Stem Cells 26:2576–2585. doi:10.1634/stemcells.2008-0171
7. Hong KU, Reynolds SD, Watkins S et al (2004) Basal cells are a multipotent progenitor capable of renewing the bronchial epithelium. AJPA 164:577–588. doi:10.1016/S0002-9440(10)63147-1
8. 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 157:2000–2006. doi:10.1164/ajrccm.157.6.9707011
9. Pardo-Saganta A, Law BM, Tata PR et al (2015) Injury induces direct lineage segregation of functionally distinct airway basal stem/progenitor cell subpopulations. Cell Stem Cell 16:184–197. doi:10.1016/j.stem.2015.01.002
10. Nakajima M, Kawanami O, Jin E et al (1998) Immunohistochemical and ultrastructural studies of basal cells, Clara cells and bronchiolar cuboidal cells in normal human airways. Pathol Int 48:944–953
11. Evans MJ, Van Winkle LS, Fanucchi MV, Plopper CG (2001) Cellular and molecular characteristics of basal cells in airway epithelium. Exp Lung Res 27:401–415
12. Boers JE, Ambergen AW, Thunnissen FB (1999) Number and proliferation of clara cells in normal human airway epithelium. Am J Respir Crit Care Med 159:1585–1591. doi:10.1164/ajrccm.159.5.9806044
13. Linnoila RI (2006) Functional facets of the pulmonary neuroendocrine system. Lab Invest 86:425–444. doi:10.1038/labinvest.3700412
14. Domnik NJ, Cutz E (2011) Pulmonary neuroepithelial bodies as airway sensors: putative role in the generation of dyspnea. Curr Opin Pharmacol 11:211–217. doi:10.1016/j.coph.2011.04.003
15. Song H, Yao E, Lin C et al (2012) Functional characterization of pulmonary neuroendocrine cells in lung development, injury, and tumorigenesis. Proc Natl Acad Sci 109:17531–17536. doi:10.1073/pnas.1207238109
16. Branchfield K, Nantie L, Verheyden JM et al (2016) Pulmonary neuroendocrine cells function as airway sensors to control lung immune response. Science. doi:10.1126/science.aad7969
17. Williams MC (2003) Alveolar type I cells: molecular phenotype and development. Annu Rev Physiol 65:669–695. doi:10.1146/annurev.physiol.65.092101.142446
18. Féréol S, Fodil R, Pelle G et al (2008) Cell mechanics of alveolar epithelial cells (AECs) and macrophages (AMs). Respir Physiol Neurobiol 163:3–16. doi:10.1016/j.resp.2008.04.018
19. Yang J, Hernandez BJ, Martinez Alanis D et al (2016) The development and plasticity of alveolar type 1 cells. Development 143:54–65. doi:10.1242/dev.130005
20. Branchfield K, Li R, Lungova V et al (2016) A three-dimensional study of alveologenesis in mouse lung. Dev Biol 409:429–441. doi:10.1016/j.ydbio.2015.11.017
21. Castranova V, Rabovsky J, Tucker JH, Miles PR (1988) The alveolar type II epithelial cell: a multifunctional pneumocyte. Toxicol Appl Pharmacol 93:472–483
22. Fehrenbach H (2001) Alveolar epithelial type II cell: defender of the alveolus revisited. Respir Res 2:33–46
23. Wells JM, Spence JR (2014) How to make an intestine. Development 141:752–760. doi:10.1242/dev.097386
24. Spence JR, Wells JM (2007) Translational embryology: using embryonic principles to generate pancreatic endocrine cells from embryonic stem cells. Dev Dyn 236:3218–3227. doi:10.1002/dvdy.21366
25. Finkbeiner SR, Spence JR (2013) A gutsy task: generating intestinal tissue from human pluripotent stem cells. Dig Dis Sci 58:1176–1184. doi:10.1007/s10620-013-2620-2
26. Zorn AM, Wells JM (2009) Vertebrate endoderm development and organ formation. Annu Rev Cell Dev Biol 25:221–251. doi:10.1146/annurev.cellbio.042308.113344
27. Metzger RJ, Klein OD, Martin GR, Krasnow MA (2008) The branching programme of mouse lung development. Nature 453:745–750. doi:10.1038/nature07005
28. Morrisey EE, Hogan BLM (2010) Preparing for the first breath: genetic and cellular mechanisms in lung development. Dev Cell 18:8–23. doi:10.1016/j.devcel.2009.12.010
29. Rawlins EL (2010) The building blocks of mammalian lung development. Dev Dyn 240:463–476. doi:10.1002/dvdy.22482
30. •• D’Amour KA, Agulnick AD, Eliazer S et al (2005) Efficient differentiation of human embryonic stem cells to definitive endoderm. Nat Biotechnol 23:1534–1541. doi:10.1038/nbt1163. This was the first report to show efficient endoderm differentiation from human embryonic stem cells
31. Cai J, Zhao Y, Liu Y et al (2007) Directed differentiation of human embryonic stem cells into functional hepatic cells. Hepatology 45:1229–1239. doi:10.1002/hep.21582
32. Kroon E, Martinson LA, Kadoya K et al (2008) Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol 26:443–452. doi:10.1038/nbt1393
33. Si-Tayeb K, Noto FK, Nagaoka M et al (2010) Highly efficient generation of human hepatocyte-like cells from induced pluripotent stem cells. Hepatology 51:297–305. doi:10.1002/hep.23354
34. Spence JR, Mayhew CN, Rankin SA et al (2011) Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro. Nature 470:105–109. doi:10.1038/nature09691
35. • Longmire TA, Ikonomou L, Hawkins F et al (2012) Efficient derivation of purified lung and thyroid progenitors from embryonic stem cells. Cell Stem Cell 10:398–411. doi:10.1016/j.stem.2012.01.019. This study demonstrated that mouse ESCs could be directed into lung lineages. mESC-derived endoderm was patterned into anterior foregut using BMP/TGFB inhibition, and then further specified into lung or thyroid lineages
36. • Wong AP, Bear CE, Chin S et al (2012) Directed differentiation of human pluripotent stem cells into mature airway epithelia expressing functional CFTR protein. Nat Biotechnol 30:875–881. doi:10.1038/nbt.2328. The authors used air-liquid interface cell culture to further differentiate the lung progenitors to mature airway cells that were polarized
37. • Mou H, Zhao R, Sherwood R et al (2012) Generation of multipotent lung and airway progenitors from mouse ESCs and patient-specific cystic fibrosis iPSCs. Cell Stem Cell 10:385–397. doi:10.1016/j.stem.2012.01.018. This study defined methods to generate both mouse and human lung progenitors from pluripotent stem cells, and was one of the first studies to report the use of patient specific iPSC lines to study a lung disease
38. • Huang SXL, Islam MN, O’Neill J, et al (2013) Efficient generation of lung and airway epithelial cells from human pluripotent stem cells. Nat Biotechnol doi: 10.1038/nbt.2754. By re-plating the cultures and changing growth factor combinations caused the cultures to express mature cell types including surfactant producing AECIIs
39. • Dye BR, Hill DR, Ferguson MA et al (2015) In vitro generation of human pluripotent stem cell derived lung organoids. Elife. doi:10.7554/eLife.05098. This was the first report to generate a three-dimensional model that possessed airway-like structures called human lung organoids. The lung organoids expressed pockets of distal epithelial cells and proximal airway-like structures surrounded by mesenchyme
40. • Konishi S, Gotoh S, Tateishi K et al (2016) Directed induction of functional multi-ciliated cells in proximal airway epithelial spheroids from human pluripotent stem cells. Stem Cell Rep 6:18–25. doi:10.1016/j.stemcr.2015.11.010. This study identified a cell surface marker allowing the purification of lung progenitor cells. Purified lung progenitor cells generated bronchospheres, and demonstrated mucociliary function
41. • Gotoh S, Ito I, Nagasaki T et al (2014) Generation of alveolar epithelial spheroids via isolated progenitor cells from human pluripotent stem cells. Stem Cell Rep 3:394–403. doi:10.1016/j.stemcr.2014.07.005. This study identified a cell surface marker allowing the purification of hPSC-derived lung progenitor cells. Purified lung progenitor cells were further differentiated into alveolus-like structures
42. • Ghaedi M, Mendez JJ, Bove PF et al (2014) Alveolar epithelial differentiation of human induced pluripotent stem cells in a rotating bioreactor. Biomaterials 35:699–710. doi:10.1016/j.biomaterials.2013.10.018. Tissue-derived and iPSC-derived alveolar type 2 cells were cultured in rotating bioreactor that mimicked in vivo respiratory conditions
43. • Ghaedi M, Calle EA, Mendez JJ et al (2013) Human iPS cell-derived alveolar epithelium repopulates lung extracellular matrix. J Clin Invest 123:4950–4962. doi:10.1172/JCI68793. hPSC were directed to differentiate into alveolar type II cells with high purity. ATII cells were seeded on acellular rat or human lung matrix, and were shown to proliferate and differentiate into alveolar cell types on the matrices
44. • Hannan NRF, Sampaziotis F, Segeritz C-P et al (2015) Generation of distal airway epithelium from multipotent human foregut stem cells. Stem Cells Dev 24:1680–1690. doi:10.1089/scd.2014.0512. This study demonstrated how to generate distal airway-like epithelium from hPSCs, and also showed some data with hPSC-derived lung organoids
45. • Firth AL, Dargitz CT, Qualls SJ et al (2014) Generation of multiciliated cells in functional airway epithelia from human induced pluripotent stem cells. Proc Natl Acad Sci 111:E1723–E1730. doi:10.1073/pnas.1403470111. This report demonstrated methods to generate endoderm, foregut endoderm, followed by differentiation of monolayers of upper airway-like pseudostratified epithelium that possessed abundant multiciliated cells
46. Schier AF (2003) Nodal signaling in vertebrate development. Annu Rev Cell Dev Biol 19:589–621. doi:10.1146/annurev.cellbio.19.041603.094522
47. Schier AF, Shen MM (2000) Nodal signalling in vertebrate development. Nature 403:385–389. doi:10.1038/35000126
48. Aoki TO, David NB, Minchiotti G et al (2002) Molecular integration of casanova in the Nodal signalling pathway controlling endoderm formation. Development 129:275–286
49. Shen MM (2007) Nodal signaling: developmental roles and regulation. Development 134:1023–1034. doi:10.1242/dev.000166
50. Hagos EG, Dougan ST (2007) Time-dependent patterning of the mesoderm and endoderm by Nodal signals in zebrafish. BMC Dev Biol 7:22. doi:10.1186/1471-213X-7-22
51. McCracken KW, Catá EM, Crawford CM et al (2014) Modelling human development and disease in pluripotent stem-cell-derived gastric organoids. Nature 516:400–404. doi:10.1038/nature13863
52. Rossant J, Tam PPL (2009) Blastocyst lineage formation, early embryonic asymmetries and axis patterning in the mouse. Development 136:701–713. doi:10.1242/dev.017178
53. Yamamoto M, Saijoh Y, Perea-Gomez A et al (2004) Nodal antagonists regulate formation of the anteroposterior axis of the mouse embryo. Nature 428:387–392. doi:10.1038/nature02418
54. Perea-Gomez A, Vella FDJ, Shawlot W et al (2002) Nodal antagonists in the anterior visceral endoderm prevent the formation of multiple primitive streaks. Dev Cell 3:745–756
55. Tiso N, Filippi A, Pauls S et al (2002) BMP signalling regulates anteroposterior endoderm patterning in zebrafish. Mech Dev 118:29–37
56. Li Y, Rankin SA, Sinner D et al (2008) Sfrp5 coordinates foregut specification and morphogenesis by antagonizing both canonical and noncanonical Wnt11 signaling. Genes Dev 22:3050–3063. doi:10.1101/gad.1687308
57. •• Green MD, Chen A, Nostro M-C et al (2011) Generation of anterior foregut endoderm from human embryonic and induced pluripotent stem cells. Nat Biotechnol 29:267–272. doi:10.1038/nbt.1788. This study identified efficient methods to pattern hPSC-derived endoderm into foregut endoderm. This general approach has been adopted by many in order to derive anterior foregut lineages including lung tissue
58. McCracken KW, Howell JC, Wells JM, Spence JR (2011) Generating human intestinal tissue from pluripotent stem cells in vitro. Nat Protoc 6:1920–1928. doi:10.1038/nprot.2011.410
59. Schlessinger K, Hall A, Tolwinski N (2009) Wnt signaling pathways meet Rho GTPases. Genes Dev 23:265–277. doi:10.1101/gad.1760809
60. Li S, Muneoka K (1999) Cell migration and chick limb development: chemotactic action of FGF-4 and the AER. Developmental Biology 211:335–347. doi:10.1006/dbio.1999.9317
61. Sun X, Meyers EN, Lewandoski M, Martin GR (1999) Targeted disruption of Fgf8 causes failure of cell migration in the gastrulating mouse embryo. Genes Dev 13:1834–1846
62. Crump JG, Maves L, Lawson ND et al (2004) An essential role for Fgfs in endodermal pouch formation influences later craniofacial skeletal patterning. Development 131:5703–5716. doi:10.1242/dev.01444
63. Sherwood RI, Maehr R, Mazzoni EO, Melton DA (2011) Wnt signaling specifies and patterns intestinal endoderm. Mech Dev. doi:10.1016/j.mod.2011.07.005
64. Lazzaro D, Price M, de Felice M, Di Lauro R (1991) The transcription factor TTF-1 is expressed at the onset of thyroid and lung morphogenesis and in restricted regions of the foetal brain. Development 113:1093–1104
65. Minoo P, Su G, Drum H et al (1999) Defects in tracheoesophageal and lung morphogenesis in Nkx2.1(-/-) mouse embryos. Dev Biol 209:60–71. doi:10.1006/dbio.1999.9234
66. Rankin SA, Zorn AM (2014) Gene regulatory networks governing lung specification. J Cell Biochem 115:1343–1350. doi:10.1002/jcb.24810
67. Domyan ET, Ferretti E, Throckmorton K et al (2011) Signaling through BMP receptors promotes respiratory identity in the foregut via repression of Sox2. Development 138:971–981. doi:10.1242/dev.053694
68. Serls AE, Doherty S, Parvatiyar P et al (2005) Different thresholds of fibroblast growth factors pattern the ventral foregut into liver and lung. Development 132:35–47. doi:10.1242/dev.01570
69. Min H, Danilenko DM, Scully SA et al (1998) Fgf-10 is required for both limb and lung development and exhibits striking functional similarity to Drosophila branchless. Genes Dev 12:3156–3161
70. Sekine K, Ohuchi H, Fujiwara M et al (1999) Fgf10 is essential for limb and lung formation. Nat Genet 21:138–141. doi:10.1038/5096
71. Shifley ET, Kenny AP, Rankin SA, Zorn AM (2012) Prolonged FGF signaling is necessary for lung and liver induction in Xenopus. BMC Dev Biol 12:27. doi:10.1186/1471-213X-12-27
72. Goss AM, Tian Y, Tsukiyama T et al (2009) Wnt2/2b and β-catenin signaling are necessary and sufficient to specify lung progenitors in the foregut. Dev Cell 17:290–298. doi:10.1016/j.devcel.2009.06.005
73. Harris-Johnson KS, Domyan ET, Vezina CM, Sun X β-Catenin promotes respiratory progenitor identity in mouse foregut
74. Rankin SA, Gallas AL, Neto A et al (2012) Suppression of Bmp4 signaling by the zinc-finger repressors Osr1 and Osr2 is required for Wnt/ -catenin-mediated lung specification in Xenopus. Development 139:3010–3020. doi:10.1242/dev.078220
75. Miller MF, Cohen ED, Baggs JE et al (2012) Wnt ligands signal in a cooperative manner to promote foregut organogenesis. Proc Natl Acad Sci 109:15348–15353. doi:10.1073/pnas.1201583109
76. Chen F, Cao Y, Qian J et al (2010) A retinoic acid-dependent network in the foregut controls formation of the mouse lung primordium. J Clin Invest 120:2040–2048. doi:10.1172/JCI40253
77. Chen F, Desai TJ, Qian J et al (2007) Inhibition of Tgf beta signaling by endogenous retinoic acid is essential for primary lung bud induction. Development 134:2969–2979. doi:10.1242/dev.006221
78. Motoyama J, Liu J, Mo R et al (1998) Essential function of Gli2 and Gli3 in the formation of lung, trachea and oesophagus. Nat Genet 20:54–57. doi:10.1038/1711
79. Rockich BE, Hrycaj SM, Shih HP et al (2013) Sox9 plays multiple roles in the lung epithelium during branching morphogenesis. Proc Natl Acad Sci 110:E4456–E4464. doi:10.1073/pnas.1311847110
80. Okubo T (2005) Nmyc plays an essential role during lung development as a dosage-sensitive regulator of progenitor cell proliferation and differentiation. Development 132:1363–1374. doi:10.1242/dev.01678
81. Perl AKT, Kist R, Shan Z et al (2005) Normal lung development and function after Sox9 inactivation in the respiratory epithelium. Genesis 41:23–32. doi:10.1002/gene.20093
82. Rawlins EL, Clark CP, Xue Y, Hogan BLM (2009) The Id2+ distal tip lung epithelium contains individual multipotent embryonic progenitor cells. Development 136:3741–3745. doi:10.1242/dev.037317
83. Weaver M, Yingling JM, Dunn NR et al (1999) Bmp signaling regulates proximal-distal differentiation of endoderm in mouse lung development. Development 126:4005–4015
84. Mucenski ML, Wert SE, Nation JM et al (2003) beta-Catenin is required for specification of proximal/distal cell fate during lung morphogenesis. J Biol Chem 278:40231–40238. doi:10.1074/jbc.M305892200
85. De Langhe SP, Reynolds SD (2008) Wnt signaling in lung organogenesis. Organogenesis 4:100–108
86. Kadzik RS, Cohen ED, Morley MP et al (2014) Wnt ligand/Frizzled 2 receptor signaling regulates tube shape and branch-point formation in the lung through control of epithelial cell shape. Proc Natl Acad Sci 111:12444–12449. doi:10.1073/pnas.1406639111
87. Rajagopal J, Carroll TJ, Guseh JS et al (2008) Wnt7b stimulates embryonic lung growth by coordinately increasing the replication of epithelium and mesenchyme. Development 135:1625–1634. doi:10.1242/dev.015495
88. Shu W, Guttentag S, Wang Z et al (2005) Wnt/β-catenin signaling acts upstream of N-myc, BMP4, and FGF signaling to regulate proximal–distal patterning in the lung. Dev Biol 283:226–239. doi:10.1016/j.ydbio.2005.04.014
89. Bellusci S, Grindley J, Emoto H et al (1997) Fibroblast growth factor 10 (FGF10) and branching morphogenesis in the embryonic mouse lung. Development 124:4867–4878
90. Volckaert T, Campbell A, Dill E et al (2013) Localized Fgf10 expression is not required for lung branching morphogenesis but prevents differentiation of epithelial progenitors. Development 140:3731–3742. doi:10.1242/dev.096560
91. Shiratori M, Oshika E, Ung LP et al (1996) Keratinocyte growth factor and embryonic rat lung morphogenesis. Am J Respir Cell Mol Biol 15:328–338. doi:10.1165/ajrcmb.15.3.8810636
92. Yano T, Mason RJ, Pan T et al (2000) KGF regulates pulmonary epithelial proliferation and surfactant protein gene expression in adult rat lung. Am J Physiol Lung Cell Mol Physiol 279:L1146–L1158
93. Nyeng P, Norgaard GA, Kobberup S, Jensen J (2008) FGF10 maintains distal lung bud epithelium and excessive signaling leads to progenitor state arrest, distalization, and goblet cell metaplasia. BMC Dev Biol 8:2. doi:10.1186/1471-213X-8-2
94. Desai TJ, Chen F, Lü J et al (2006) Distinct roles for retinoic acid receptors alpha and beta in early lung morphogenesis. Dev Biol 291:12–24. doi:10.1016/j.ydbio.2005.10.045
95. Desai TJ, Brownfield DG, Krasnow MA (2014) Alveolar progenitor and stem cells in lung development, renewal and cancer. Nature. doi:10.1038/nature12930
96. Gonzales LW, Guttentag SH, Wade KC et al (2002) Differentiation of human pulmonary type II cells in vitro by glucocorticoid plus cAMP. Am J Physiol Lung Cell Mol Physiol 283:L940–L951. doi:10.1152/ajplung.00127.2002
97. Crowley P, Chalmers I, Keirse MJ (1990) The effects of corticosteroid administration before preterm delivery: an overview of the evidence from controlled trials. Br J Obstet Gynaecol 97:11–25
98. Wapner R (2004) Antenatal corticosteroids: we continue to learn. Am J Obstet Gynecol 190:875. doi:10.1016/j.ajog.2004.01.045
99. Barkauskas CE, Cronce MJ, Rackley CR et al (2013) Type 2 alveolar cells are stem cells in adult lung. J Clin Invest 123:3025–3036. doi:10.1172/JCI68782
100. Whitsett JA, Clark JC, Picard L et al (2002) Fibroblast growth factor 18 influences proximal programming during lung morphogenesis. J Biol Chem 277:22743–22749. doi:10.1074/jbc.M202253200
101. Guseh JS, Bores SA, Stanger BZ et al (2009) Notch signaling promotes airway mucous metaplasia and inhibits alveolar development. Development 136:1751–1759. doi:10.1242/dev.029249
102. Morimoto M, Liu Z, Cheng H-T et al (2010) 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. doi:10.1242/jcs.058669
103. Zhang S, Loch AJ, Radtke F et al (2013) Jagged1 is the major regulator of Notch-dependent cell fate in proximal airways. Dev Dyn 242:678–686. doi:10.1002/dvdy.23965
104. Tadokoro T, Wang Y, Barak LS et al (2014) IL-6/STAT3 promotes regeneration of airway ciliated cells from basal stem cells. Proc Natl Acad Sci 111:E3641–E3649. doi:10.1073/pnas.1409781111
105. Rock JR, Gao X, Xue Y et al (2011) Notch-dependent differentiation of adult airway basal stem cells. Cell Stem Cell 8:639–648. doi:10.1016/j.stem.2011.04.003
106. Hrvatin S, O’Donnell CW, Deng F et al (2014) Differentiated human stem cells resemble fetal, not adult, β cells. Proc Natl Acad Sci 111:3038–3043. doi:10.1073/pnas.1400709111
107. Finkbeiner SR, Hill DR, Altheim CH et al (2015) Transcriptome-wide analysis reveals hallmarks of human intestine development and maturation in vitro and in vivo. Stem Cell Rep. doi:10.1016/j.stemcr.2015.04.010
108. Camp JG, Badsha F, Florio M et al (2015) Human cerebral organoids recapitulate gene expression programs of fetal neocortex development. Proc Natl Acad Sci 112:15672–15677. doi:10.1073/pnas.1520760112
109. Kheradmand F, Rishi K, Werb Z (2002) Signaling through the EGF receptor controls lung morphogenesis in part by regulating MT1-MMP-mediated activation of gelatinase A/MMP2. J Cell Sci 115:839–848
110. Kim HY, Nelson CM (2012) Extracellular matrix and cytoskeletal dynamics during branching morphogenesis. Organogenesis 8:56–64
111. van Tuyl M, Groenman F, Wang J et al (2007) Angiogenic factors stimulate tubular branching morphogenesis of sonic hedgehog-deficient lungs. Dev Biol 303:514–526. doi:10.1016/j.ydbio.2006.11.029
112. Del Moral P-M, Sala FG, Tefft D et al (2006) VEGF-A signaling through Flk-1 is a critical facilitator of early embryonic lung epithelial to endothelial crosstalk and branching morphogenesis. Dev Biol 290:177–188. doi:10.1016/j.ydbio.2005.11.022
113. Franzdóttir SR, Axelsson IT, Arason AJ et al (2010) Airway branching morphogenesis in three dimensional culture. Respir Res 11:162. doi:10.1186/1465-9921-11-162
114. Lee J-H, Bhang DH, Beede A et al (2014) Lung stem cell differentiation in mice directed by endothelial cells via a BMP4-NFATc1-thrombospondin-1 axis. Cell 156:440–455. doi:10.1016/j.cell.2013.12.039
115. Bower DV, Lee H-K, Lansford R et al (2014) Airway branching has conserved needs for local parasympathetic innervation but not neurotransmission. BMC Biol 12:92. doi:10.1186/s12915-014-0092-2
116. Freem LJ, Escot S, Tannahill D et al (2010) The intrinsic innervation of the lung is derived from neural crest cells as shown by optical projection tomography in Wnt1-Cre;YFP reporter mice. J Anat 217:651–664. doi:10.1111/j.1469-7580.2010.01295.x
117. Aven L, Ai X (2013) Mechanisms of respiratory innervation during embryonic development. Organogenesis 9:194–198. doi:10.4161/org.24842
118. Petersen TH, Calle EA, Zhao L et al (2010) Tissue-engineered lungs for in vivo implantation. Science 329:538–541. doi:10.1126/science.1189345
119. Panoskaltsis-Mortari A, Weiss DJ (2010) Breathing new life into lung transplantation therapy. Mol Ther 18:1581–1583. doi:10.1038/mt.2010.177
120. Price AP, England KA, Matson AM et al (2010) Development of a decellularized lung bioreactor system for bioengineering the lung: the matrix reloaded. Tissue Eng Part A 16:2581–2591. doi:10.1089/ten.TEA.2009.0659
121. Song JJ, Kim SS, Liu Z et al (2011) Enhanced in vivo function of bioartificial lungs in rats. Ann Thorac Surg 92:998–1005. doi:10.1016/j.athoracsur.2011.05.018 discussion 1005–6
122. Ott HC, Clippinger B, Conrad C et al (2010) Regeneration and orthotopic transplantation of a bioartificial lung. Nat Med 16:927–933. doi:10.1038/nm.2193
123. Shirasaki Y, Yamagishi M, Suzuki N et al (2014) Real-time single-cell imaging of protein secretion. Sci Rep 4:4736. doi:10.1038/srep04736
124. Raphael MP, Christodoulides JA, Delehanty JB et al (2013) Quantitative imaging of protein secretions from single cells in real time. Biophys J 105:602–608. doi:10.1016/j.bpj.2013.06.022