title: Dysfunctional resident lung mesenchymal stem cells contribute to pulmonary microvascular remodeling.
abstract: Pulmonary vascular remodeling and oxidative stress are common to many adult lung diseases. However, little is known about the relevance of lung mesenchymal stem cells (MSCs) in these processes. We tested the hypothesis that dysfunctional lung MSCs directly participate in remodeling of the microcirculation. We employed a genetic model to deplete extracellular superoxide dismutase (EC-SOD) in lung MSCs coupled with lineage tracing analysis. We crossed (floxp)sod3 and mT/mG reporter mice to a strain expressing Cre recombinase under the control of the ABCG2 promoter. We demonstrated In vivo that depletion of EC-SOD in lung MSCs resulted in their contribution to microvascular remodeling in the smooth muscle actin positive layer. We further characterized lung MSCs to be multipotent vascular precursors, capable of myofibroblast, endothelial and pericyte differentiation in vitro. EC-SOD deficiency in cultured lung MSCs accelerated proliferation and apoptosis, restricted colony-forming ability, multilineage differentiation potential and promoted the transition to a contractile phenotype. Further studies correlated cell dysfunction to alterations in canonical Wnt/β-catenin signaling, which were more evident under conditions of oxidative stress. Our data establish that lung MSCs are a multipotent vascular precursor population, a population which has the capacity to participate in vascular remodeling and their function is likely regulated in part by the Wnt/β-catenin signaling pathway. These studies highlight an important role for microenviromental regulation of multipotent MSC function as well as their potential to contribute to tissue remodeling.
authors: Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA.
authors: Kelsey
authors: K
authors: Chow
authors: Joshua P
authors: JP
authors: Fessel
authors: Kaoriihida-Stansbury
authors: Eric P
authors: EP
authors: Schmidt
authors: Christa
authors: C
authors: Gaskill
authors: Diego
authors: D
authors: Alvarez
authors: Brian
authors: B
authors: Graham
authors: David G
authors: DG
authors: Harrison
authors: David H
authors: DH
authors: Wagner
authors: Eva
authors: E
authors: Nozik-Grayck
authors: James D
authors: JD
authors: West
authors: Dwight J
authors: DJ
authors: Klemm
authors: Susan M
authors: SM
authors: Majka
keywords: endothelial cell; extracellular superoxide dismutase; myofibroblast; niche; pericytes; pulmonary arterial hypertension; resident lung mesenchymal stem cells
references: Dev Dyn. 1998 Aug;212(4):482-94
references: 9707322
references: Am J Physiol Lung Cell Mol Physiol. 2006 Jun;290(6):L1183-92
references: 16428272
references: Am J Physiol Lung Cell Mol Physiol. 2003 Jul;285(1):L97-104
references: 12626330
references: Am J Physiol Heart Circ Physiol. 2007 Feb;292(2):H1120-8
references: 16980338
references: Am J Respir Cell Mol Biol. 2005 Jul;33(1):32-40
references: 15802552
references: Dev Biol. 2007 Jul 15;307(2):237-47
references: 17560563
references: Dev Biol. 2008 Jul 15;319(2):426-36
references: 18533146
references: Am J Physiol Lung Cell Mol Physiol. 2002 Oct;283(4):L777-84
references: 12225954
references: J Clin Invest. 2001 Jun;107(11):1395-402
references: 11390421
references: Stem Cells. 2005 Sep;23(8):1073-81
references: 15987674
references: Hypertension. 2011 Aug;58(2):232-9
references: 21730294
references: PLoS One. 2008 Jan 30;3(1):e1516
references: 18231602
references: J Clin Invest. 2011 Nov;121(11):4409-19
references: 21985786
references: Nat Med. 2001 Sep;7(9):1028-34
references: 11533706
references: Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):16970-5
references: 18957545
references: Am J Pathol. 2008 Oct;173(4):915-26
references: 18787098
references: Hypertension. 2008 Jan;51(1):19-25
references: 17998475
references: Nature. 2010 Aug 12;466(7308):829-34
references: 20703299
references: Cell. 2007 Jan 26;128(2):325-39
references: 17254970
references: Stem Cells. 2011 Apr;29(4):725-35
references: 21312316
references: Physiol Genomics. 2007 Apr 24;29(2):128-38
references: 17179208
references: Am J Pathol. 2002 Mar;160(3):985-1000
references: 11891196
references: Circ Res. 2010 Oct 15;107(8):943-52
references: 20947863
references: Am J Respir Cell Mol Biol. 2007 Aug;37(2):152-9
references: 17395889
references: Stem Cells. 2007 Oct;25(10):2511-23
references: 17556597
references: Am J Pathol. 2010 Aug;177(2):598-607
references: 20595636
references: Am J Physiol Lung Cell Mol Physiol. 2007 Oct;293(4):L941-51
references: 17693487
references: Stem Cells. 2004;22(5):849-60
references: 15342948
references: Am J Respir Crit Care Med. 2011 Mar 15;183(6):723-33
references: 20889911
references: Dev Biol. 2011 May 15;353(2):242-58
references: 21385574
references: Am J Respir Crit Care Med. 2009 Dec 1;180(11):1131-42
references: 19713449
references: Nat Rev Mol Cell Biol. 2011 Feb;12(2):126-31
references: 21253000
references: Am J Physiol Lung Cell Mol Physiol. 2004 Apr;286(4):L624-30
references: 12909587
references: Proc Natl Acad Sci U S A. 2009 Sep 22;106(38):16357-62
references: 19721001
references: J Clin Invest. 2011 Jun;121(6):2065-73
references: 21633173
references: Dev Cell. 2011 Aug 16;21(2):193-215
references: 21839917
references: Nature. 2003 May 22;423(6938):409-14
references: 12717450
references: Cell Stem Cell. 2008 Sep 11;3(3):301-13
references: 18786417
references: Antioxid Redox Signal. 2008 Feb;10(2):343-54
references: 17999630
references: Am J Physiol Lung Cell Mol Physiol. 2007 Apr;292(4):L972-83
references: 17142352
references: Cell Stem Cell. 2009 Jul 2;5(1):54-63
references: 19570514
references: Expert Opin Biol Ther. 2010 Oct;10(10):1441-51
references: 20836622
references: Proc Natl Acad Sci U S A. 2010 Aug 17;107(33):14781-6
references: 20679227
references: Trends Cardiovasc Med. 2009 Jan;19(1):26-30
references: 19467451
references: Stem Cells. 2006 Jun;24(6):1556-63
references: 16484343
references: Proc Natl Acad Sci U S A. 2007 Sep 25;104(39):15436-41
references: 17881570
references: Stem Cells. 2012 Feb;30(2):210-21
references: 22134889
references: Circ Res. 2007 Sep 14;101(6):581-9
references: 17673669
references: Am J Physiol Lung Cell Mol Physiol. 2008 Sep;295(3):L422-30
references: 18599502
references: Nature. 2005 Apr 14;434(7035):843-50
references: 15829953
references: Am J Respir Crit Care Med. 2009 Dec 1;180(11):1122-30
references: 19713447
references: Hypertension. 2011 Aug;58(2):303-9
references: 21730301
references: J Dermatol Sci. 2012 Feb;65(2):126-33
references: 22251572
references: Stem Cells. 2009 Mar;27(3):623-33
references: 19074419
references: Development. 2005 May;132(9):2157-66
references: 15800000
references: Dev Biol. 2006 Nov 1;299(1):52-62
references: 16989802
references: Am J Respir Cell Mol Biol. 2011 Apr;44(4):500-8
references: 20539010
references: J Clin Invest. 2009 Apr;119(4):772-87
references: 19287097
references: Free Radic Biol Med. 2003 Oct 1;35(7):763-71
references: 14583340
references: Proc Natl Acad Sci U S A. 2010 Aug 31;107(35):15571-6
references: 20713693
references: Am J Pathol. 2011 Jun;178(6):2897-909
references: 21550017
references: Science. 2005 May 20;308(5725):1181-4
references: 15905404
references: J Cardiovasc Pharmacol. 2011 Aug;58(2):181-91
references: 21562428
references: Stem Cells. 2007 Jul;25(7):1753-60
references: 17395776
references: Gene. 2009 Mar 15;433(1-2):1-7
references: 19135507
references: Cytotherapy. 2008;10(2):140-51
references: 18368593
references: J Clin Invest. 2011 Sep;121(9):3456-66
references: 21865646
references: J Cell Biochem. 2007 Aug 1;101(5):1109-24
references: 17546602