title: BMP signaling and cellular dynamics during regeneration of airway epithelium from basal progenitors.
abstract: The pseudostratified epithelium of the lung contains ciliated and secretory luminal cells and basal stem/progenitor cells. To identify signals controlling basal cell behavior we screened factors that alter their self-renewal and differentiation in a clonal organoid (tracheosphere) assay. This revealed that inhibitors of the canonical BMP signaling pathway promote proliferation but do not affect lineage choice, whereas exogenous Bmp4 inhibits proliferation and differentiation. We therefore followed changes in BMP pathway components in vivo in the mouse trachea during epithelial regeneration from basal cells after injury. The findings suggest that BMP signaling normally constrains proliferation at steady state and this brake is released transiently during repair by the upregulation of endogenous BMP antagonists. Early in repair, the packing of epithelial cells along the basal lamina increases, but density is later restored by active extrusion of apoptotic cells. Systemic administration of the BMP antagonist LDN-193189 during repair initially increases epithelial cell number but, following the shedding phase, normal density is restored. Taken together, these results reveal crucial roles for both BMP signaling and cell shedding in homeostasis of the respiratory epithelium.
authors.affiliation: Department of Cell Biology, Duke Medicine, Durham, NC 27710, USA.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Tadokoro
authors.affiliation: Department of Cell Biology, Duke Medicine, Durham, NC 27710, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Medicine-Cardiovascular Medicine, Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN 37212, USA.
authors.forename: Charles C
authors.initials: CC
authors.lastname: Hong
authors.affiliation: Department of Medicine, Division of Cardiology, Duke Medicine, Durham, NC 27710, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Hotten
authors.affiliation: Department of Cell Biology, Duke Medicine, Durham, NC 27710, USA brigid.hogan@duke.edu.
authors.forename: Brigid L M
authors.initials: BL
authors.lastname: Hogan
mesh_terms: D000818:Animals; D017209:Apoptosis; D001485:Basement Membrane / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D008024:Ligands; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011720:Pyrazoles / Q000737:chemistry; D011743:Pyrimidines / Q000737:chemistry; D012038:Regeneration; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism*; D014132:Trachea / Q000378:metabolism / Q000473:pathology
chemical_list: D019485:Bone Morphogenetic Proteins; C554430:LDN 193189; D008024:Ligands; D011720:Pyrazoles; D011743:Pyrimidines; D049452:Green Fluorescent Proteins
keywords: Airway epithelium; Apoptosis; BMP signaling; Basal cells; Cell shedding; Homeostasis; Regeneration; SO2 injury
references.citation: Proc Natl Acad Sci U S A. 2014 Sep 2;111(35):E3641-9
references.pmid: 25136113
references.citation: J Cell Sci. 2014 Feb 15;127(Pt 4):709-17
references.pmid: 24532814
references.citation: J Pharmacol Exp Ther. 2014 Dec;351(3):549-58
references.pmid: 25271257
references.citation: Cell Stem Cell. 2014 Nov 6;15(5):619-33
references.pmid: 25312496
references.citation: Sci Transl Med. 2014 Dec 3;6(265):265sr6
references.pmid: 25473038
references.citation: Ann Am Thorac Soc. 2014 Dec;11 Suppl 5:S259-62
references.pmid: 25525729
references.citation: Development. 2015 Jan 15;142(2):258-67
references.pmid: 25564622
references.citation: Cell Stem Cell. 2015 Feb 5;16(2):184-97
references.pmid: 25658372
references.citation: Cell. 2015 Apr 9;161(2):277-90
references.pmid: 25860610
references.citation: Trends Cell Biol. 2015 May;25(5):249-64
references.pmid: 25592806
references.citation: Development. 2015 Jul 1;142(13):2352-63
references.pmid: 26092849
references.citation: Cell Rep. 2015 Jul 7;12(1):90-101
references.pmid: 26119728
references.citation: Nature. 2015 Jul 30;523(7562):597-601
references.pmid: 26147083
references.citation: Cell Tissue Res. 2015 Aug;361(2):427-38
references.pmid: 25693894
references.citation: J Cell Biol. 2015 Nov 9;211(3):669-82
references.pmid: 26527742
references.citation: Am J Respir Cell Mol Biol. 2001 Jun;24(6):662-70
references.pmid: 11415930
references.citation: Mol Ther. 2003 Oct;8(4):637-45
references.pmid: 14529837
references.citation: Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9337-42
references.pmid: 9689081
references.citation: Proc Natl Acad Sci U S A. 2007 Jan 9;104(2):410-7
references.pmid: 17194755
references.citation: Proc Natl Acad Sci U S A. 2007 Sep 25;104(39):15418-23
references.pmid: 17881565
references.citation: Nat Rev Immunol. 2008 Mar;8(3):193-204
references.pmid: 18301423
references.citation: J Biol Chem. 2008 Jul 25;283(30):20948-58
references.pmid: 18436533
references.citation: Nat Med. 2008 Dec;14(12):1363-9
references.pmid: 19029982
references.citation: Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3591-6
references.pmid: 19208806
references.citation: Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12771-5
references.pmid: 19625615
references.citation: ACS Chem Biol. 2010 Feb 19;5(2):245-53
references.pmid: 20020776
references.citation: Int J Dev Biol. 2010;54(5):931-8
references.pmid: 20336610
references.citation: Nat Med. 2014 Aug;20(8):847-56
references.pmid: 25100530
references.citation: Cell Stem Cell. 2014 Aug 7;15(2):199-214
references.pmid: 24953182
references.citation: Cell Stem Cell. 2014 Aug 7;15(2):123-38
references.pmid: 25105578
references.citation: Dis Model Mech. 2010 Sep-Oct;3(9-10):545-56
references.pmid: 20699479
references.citation: Int J Biochem Cell Biol. 2010 Nov;42(11):1802-7
references.pmid: 20691279
references.citation: Blood. 2011 May 5;117(18):4915-23
references.pmid: 21393479
references.citation: Cell Stem Cell. 2011 Jun 3;8(6):639-48
references.pmid: 21624809
references.citation: Nature. 2011 Nov 10;479(7372):189-93
references.pmid: 21983963
references.citation: Proc Natl Acad Sci U S A. 2011 Dec 27;108(52):E1475-83
references.pmid: 22123957
references.citation: Nature. 2012 Apr 26;484(7395):546-9
references.pmid: 22504183
references.citation: Clin Immunol. 2014 Mar;151(1):1-15
references.pmid: 24503171
references.citation: Am J Respir Cell Mol Biol. 2014 May;50(5):857-69
references.pmid: 24467704
references.citation: PLoS One. 2014;9(7):e102368
references.pmid: 25033192
references.citation: Curr Biol. 2014 Sep 8;24(17):R815-25
references.pmid: 25202877
references.citation: FEBS Lett. 2012 Jul 4;586(14):1846-59
references.pmid: 22710174
references.citation: Science. 2012 Oct 5;338(6103):108-13
references.pmid: 22956684
references.citation: Am J Respir Cell Mol Biol. 2012 Dec;47(6):864-8
references.pmid: 22984086
references.citation: Cell Stem Cell. 2012 Dec 7;11(6):751-64
references.pmid: 23217421
references.citation: Proc Natl Acad Sci U S A. 2013 Jan 22;110(4):1351-6
references.pmid: 23292934
references.citation: Nature. 2013 Jan 24;493(7433):547-51
references.pmid: 23235830
references.citation: Reprod Sci. 2013 Jun;20(6):675-9
references.pmid: 23171678
references.citation: Am J Respir Cell Mol Biol. 2013 Nov;49(5):788-97
references.pmid: 23742075
references.citation: Curr Top Dev Biol. 2014;108:153-83
references.pmid: 24512709
references.citation: J Invest Dermatol. 2014 Mar;134(3):827-37
references.pmid: 24126843
references.citation: Dev Cell. 2014 Jul 28;30(2):151-65
references.pmid: 25043474