title: Human CD34+ cells in experimental myocardial infarction: long-term survival, sustained functional improvement, and mechanism of action.
abstract: BACKGROUND
  Human CD34(+) cells have been used in clinical trials for treatment of myocardial infarction (MI). However, it is unknown how long the CD34(+) cells persist in hearts, whether the improvement in cardiac function is sustained, or what are the underlying mechanisms.
  
  
  OBJECTIVE
  We sought to track the fate of injected human CD34(+) cells in the hearts of severe combined immune deficiency (SCID) mice after experimental MI and to determine the mechanisms of action.
  
  
  RESULTS
  We used multimodality molecular imaging to track the fate of injected human CD34(+) cells in the hearts of SCID mice after experimental MI, and used selective antibody blocking to determine the mechanisms of action. Bioluminescence imaging showed that injected CD34(+) cells survived in the hearts for longer than 12 months. The PET signal from the injected cells was detected in the wall of the left ventricle. Cardiac MRI showed that left ventricular ejection fraction was significantly improved in the treated mice compared to the control mice for up to 52 weeks (P<0.05). Furthermore, treatment with anti-alpha4beta1 showed that generation of human-derived cardiomyocytes was inhibited, whereas anti-vascular endothelial growth factor (VEGF) treatment blocked the production of human-derived endothelial cells. However, the improvement in cardiac function was abolished only in the anti-VEGF, but not anti-alpha4beta1, treated group.
  
  
  CONCLUSIONS
  Angiogenesis and/or paracrine effect, but not myogenesis, is responsible for functional improvement following CD34(+) cells therapy.
authors.affiliation: University of Texas-MD Anderson Cancer Center, 1400 Pressler Blvd, Box 1451, Houston, TX 77030, USA.
authors.forename: Jingxiong
authors.initials: J
authors.lastname: Wang
authors.forename: Sui
authors.initials: S
authors.lastname: Zhang
authors.forename: Brian
authors.initials: B
authors.lastname: Rabinovich
authors.forename: Luc
authors.initials: L
authors.lastname: Bidaut
authors.forename: Suren
authors.initials: S
authors.lastname: Soghomonyan
authors.forename: Mian M
authors.initials: MM
authors.lastname: Alauddin
authors.forename: James A
authors.initials: JA
authors.lastname: Bankson
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Shpall
authors.forename: James T
authors.initials: JT
authors.lastname: Willerson
authors.forename: Juri G
authors.initials: JG
authors.lastname: Gelovani
authors.forename: Edward T H
authors.initials: ET
authors.lastname: Yeh
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism*; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D004195:Disease Models, Animal; D005260:Female; D006321:Heart / Q000000981:diagnostic imaging / Q000503:physiopathology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D051379:Mice; D016513:Mice, SCID; D009203:Myocardial Infarction / Q000401:mortality / Q000503:physiopathology* / Q000628:therapy*; D009206:Myocardium / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000502:physiology; D049268:Positron-Emission Tomography; D013318:Stroke Volume / Q000502:physiology; D015996:Survival Rate; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000637:transplantation*; D014057:Tomography, X-Ray Computed
chemical_list: D018952:Antigens, CD34
references.citation: IEEE Trans Med Imaging. 1997 Apr;16(2):187-98
references.pmid: 9101328
references.citation: Nat Med. 2005 Apr;11(4):367-8
references.pmid: 15812508
references.citation: Circulation. 2006 Nov 14;114(20):2163-9
references.pmid: 17075009
references.citation: Nat Protoc. 2007;2(2):416-23
references.pmid: 17406603
references.citation: Immunogenetics. 2006 Apr;58(2-3):81-8
references.pmid: 16470377
references.citation: Circulation. 2003 May 13;107(18):2294-302
references.pmid: 12707230
references.citation: Cell. 2008 Feb 22;132(4):537-43
references.pmid: 18295570
references.citation: Science. 2002 Feb 1;295(5556):868-72
references.pmid: 11786607
references.citation: Nat Med. 2001 Apr;7(4):430-6
references.pmid: 11283669
references.citation: Nat Protoc. 2007;2(10):2551-67
references.pmid: 17947998
references.citation: Cell. 2006 Apr 21;125(2):385-98
references.pmid: 16630824
references.citation: Stem Cells. 2008 May;26(5):1366-75
references.pmid: 18276802
references.citation: Transplantation. 2009 Mar 15;87(5):642-52
references.pmid: 19295307
references.citation: J Digit Imaging. 1996 Nov;9(4):185-98
references.pmid: 8951098
references.citation: Curr Opin Biotechnol. 2005 Feb;16(1):73-8
references.pmid: 15722018
references.citation: J Exp Med. 2006 Jan 23;203(1):153-63
references.pmid: 16401693
references.citation: Circulation. 2004 Sep 14;110(11 Suppl 1):II213-8
references.pmid: 15364865
references.citation: Circulation. 2005 May 3;111(17):2198-202
references.pmid: 15851598
references.citation: Blood. 2004 Aug 15;104(4):1217-23
references.pmid: 15100158
references.citation: Eur J Nucl Med Mol Imaging. 2004 May;31(5):740-51
references.pmid: 15014901
references.citation: Circulation. 2005 Jul 26;112(4):521-6
references.pmid: 16027258
references.citation: Circulation. 2007 Jun 26;115(25):3165-72
references.pmid: 17562958
references.citation: Ann N Y Acad Sci. 2001 Jun;938:221-9; discussion 229-30
references.pmid: 11458511
references.citation: Circulation. 2004 Dec 21;110(25):3803-7
references.pmid: 15596566
references.citation: Circ Res. 2005 Feb 4;96(2):151-63
references.pmid: 15692093
references.citation: Stem Cells. 1993 Mar;11(2):112-9
references.pmid: 8384506
references.citation: Circ Res. 2007 Mar 16;100(5):693-702
references.pmid: 17303762
references.citation: Blood. 2003 Aug 1;102(3):867-72
references.pmid: 12676779
references.citation: N Engl J Med. 2006 Sep 21;355(12):1210-21
references.pmid: 16990384
references.citation: Arterioscler Thromb Vasc Biol. 2008 Feb;28(2):208-16
references.pmid: 17951319
references.citation: N Engl J Med. 2006 Sep 21;355(12):1222-32
references.pmid: 16990385
references.citation: Cancer Res. 1998 Oct 1;58(19):4333-41
references.pmid: 9766661
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14342-6
references.pmid: 18794521
references.citation: J Am Coll Cardiol. 2004 Oct 19;44(8):1690-9
references.pmid: 15489105
references.citation: Circulation. 2003 Oct 28;108(17):2070-3
references.pmid: 14568894