title: Fetal cells traffic to injured maternal myocardium and undergo cardiac differentiation.
abstract: BACKGROUND
  Fetal cells enter the maternal circulation during pregnancy and may persist in maternal tissue for decades as microchimeras.
  
  
  OBJECTIVE
  Based on clinical observations of peripartum cardiomyopathy patients and the high rate of recovery they experience from heart failure, our objective was to determine whether fetal cells can migrate to the maternal heart and differentiate to cardiac cells.
  
  
  RESULTS
  We report that fetal cells selectively home to injured maternal hearts and undergo differentiation into diverse cardiac lineages. Using enhanced green fluorescent protein (eGFP)-tagged fetuses, we demonstrate engraftment of multipotent fetal cells in injury zones of maternal hearts. In vivo, eGFP+ fetal cells form endothelial cells, smooth muscle cells, and cardiomyocytes. In vitro, fetal cells isolated from maternal hearts recapitulate these differentiation pathways, additionally forming vascular tubes and beating cardiomyocytes in a fusion-independent manner; ≈40% of fetal cells in the maternal heart express Caudal-related homeobox2 (Cdx2), previously associated with trophoblast stem cells, thought to solely form placenta.
  
  
  CONCLUSIONS
  Fetal maternal stem cell transfer appears to be a critical mechanism in the maternal response to cardiac injury. Furthermore, we have identified Cdx2 cells as a novel cell type for potential use in cardiovascular regenerative therapy.
authors.affiliation: Mount Sinai School of Medicine, One Gustave L Levy Place, Box 1030, New York, NY 10029, USA.
authors.forename: Rina J
authors.initials: RJ
authors.lastname: Kara
authors.forename: Paola
authors.initials: P
authors.lastname: Bolli
authors.forename: Ioannis
authors.initials: I
authors.lastname: Karakikes
authors.forename: Iwao
authors.initials: I
authors.lastname: Matsunaga
authors.forename: Joseph
authors.initials: J
authors.lastname: Tripodi
authors.forename: Omar
authors.initials: O
authors.lastname: Tanweer
authors.forename: Perry
authors.initials: P
authors.lastname: Altman
authors.forename: Neil S
authors.initials: NS
authors.lastname: Shachter
authors.forename: Austin
authors.initials: A
authors.lastname: Nakano
authors.forename: Vesna
authors.initials: V
authors.lastname: Najfeld
authors.forename: Hina W
authors.initials: HW
authors.lastname: Chaudhry
mesh_terms: D000818:Animals; D000071616:CDX2 Transcription Factor; D002454:Cell Differentiation / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology; D005260:Female; D053686:Fetal Stem Cells / Q000166:cytology* / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008431:Maternal-Fetal Exchange / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D009203:Myocardial Infarction / Q000473:pathology*; D009206:Myocardium / Q000166:cytology*; D032383:Myocytes, Cardiac / Q000166:cytology; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular / Q000473:pathology*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D000071616:CDX2 Transcription Factor; C487514:Cdx2 protein, mouse; D018398:Homeodomain Proteins; D014157:Transcription Factors; D049452:Green Fluorescent Proteins
references.citation: Dev Biol. 2004 Jan 1;265(1):262-75
references.pmid: 14697368
references.citation: Nature. 2008 May 22;453(7194):524-8
references.pmid: 18432194
references.citation: J Heart Lung Transplant. 2005 Dec;24(12):2179-83
references.pmid: 16364868
references.citation: Circ Res. 2003 Jul 11;93(1):32-9
references.pmid: 12791707
references.citation: Circ Res. 2005 May 27;96(10):1039-41
references.pmid: 15879310
references.citation: Cell. 2008 Feb 22;132(4):537-43
references.pmid: 18295570
references.citation: Nucleic Acids Res. 2001 May 1;29(9):e45
references.pmid: 11328886
references.citation: Nature. 2001 Apr 5;410(6829):701-5
references.pmid: 11287958
references.citation: Hum Reprod. 2008 Apr;23(4):928-33
references.pmid: 18238907
references.citation: Trends Mol Med. 2009 Nov;15(11):510-8
references.pmid: 19828378
references.citation: Blood. 2001 Oct 15;98(8):2396-402
references.pmid: 11588036
references.citation: Stem Cell Rev. 2006;2(2):111-6
references.pmid: 17237549
references.citation: JAMA. 2004 Jul 7;292(1):75-80
references.pmid: 15238593
references.citation: Dev Cell. 2005 Mar;8(3):365-75
references.pmid: 15737932
references.citation: Cell. 2005 Dec 2;123(5):917-29
references.pmid: 16325584
references.citation: Blood. 1996 Dec 1;88(11):4102-9
references.pmid: 8943843
references.citation: J Cell Biol. 1991 Sep;114(5):1059-68
references.pmid: 1874786
references.citation: Transplant Proc. 1977 Mar;9(1):273-6
references.pmid: 325766
references.citation: Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):8145-9
references.pmid: 7690144
references.citation: Mol Hum Reprod. 2003 Aug;9(8):497-502
references.pmid: 12837927
references.citation: Circ Res. 2002 Sep 20;91(6):501-8
references.pmid: 12242268
references.citation: Proc Natl Acad Sci U S A. 2007 Feb 6;104(6):1871-6
references.pmid: 17267612
references.citation: Clin Genet. 2005 Aug;68(2):106-12
references.pmid: 15996204
references.citation: Nature. 2005 Feb 10;433(7026):647-53
references.pmid: 15703750
references.citation: Stem Cells. 2005 Nov-Dec;23(10):1443-52
references.pmid: 16091558
references.citation: Int J Clin Pract. 2004 Apr;58(4):363-5
references.pmid: 15161121
references.citation: Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12313-8
references.pmid: 14530411
references.citation: Science. 1998 Dec 11;282(5396):2072-5
references.pmid: 9851926
references.citation: Transfusion. 2001 Apr;41(4):499-503
references.pmid: 11316901
references.citation: Angiology. 2001 Nov;52(11):759-62
references.pmid: 11716328
references.citation: Cardiol Rev. 2006 Jan-Feb;14(1):35-42
references.pmid: 16371764
references.citation: Biol Reprod. 2009 Jul;81(1):26-32
references.pmid: 19279322
references.citation: Circ Res. 2007 Jun 22;100(12):1741-8
references.pmid: 17495221
references.citation: Science. 1990 Mar 9;247(4947):1219-22
references.pmid: 1690453
references.citation: Am J Pathol. 2003 May;162(5):1487-94
references.pmid: 12707031
references.citation: Proc Natl Acad Sci U S A. 1996 Jan 23;93(2):705-8
references.pmid: 8570620
references.citation: Stem Cell Res. 2007 Oct;1(1):9-24
references.pmid: 19383383
references.citation: Biochem Soc Trans. 2010 Apr;38(2):353-7
references.pmid: 20298182
references.citation: Nature. 1997 Mar 6;386(6620):84-7
references.pmid: 9052785
references.citation: Ann N Y Acad Sci. 2004 May;1015:182-9
references.pmid: 15201159
references.citation: Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13350-5
references.pmid: 14595015
references.citation: Development. 2010 Feb;137(3):395-403
references.pmid: 20081188
references.citation: Proc Natl Acad Sci U S A. 2004 May 18;101(20):7641-5
references.pmid: 15136723
references.citation: J Immunol. 2008 Jan 15;180(2):889-97
references.pmid: 18178828
references.citation: Biochem Biophys Res Commun. 2004 Dec 17;325(3):961-7
references.pmid: 15541383
references.citation: Development. 1993 Nov;119(3):969
references.pmid: 7910553
references.citation: Mol Cell Biol. 2003 Dec;23(24):9222-32
references.pmid: 14645532
references.citation: Cell. 2003 Sep 19;114(6):763-76
references.pmid: 14505575
references.citation: FASEB J. 2007 May;21(7):1345-57
references.pmid: 17284483
references.citation: Stroke. 2001 Nov;32(11):2682-8
references.pmid: 11692034
references.citation: Ann N Y Acad Sci. 2010 Nov;1211:113-26
references.pmid: 21062300
references.citation: Blood. 1991 Mar 15;77(6):1218-27
references.pmid: 1705833
references.citation: Development. 2005 May;132(9):2093-102
references.pmid: 15788452
references.citation: N Engl J Med. 2000 Apr 13;342(15):1077-84
references.pmid: 10760308