title: Tracking fusion of human mesenchymal stem cells after transplantation to the heart.
abstract: Evidence suggests that transplanted mesenchymal stem cells (MSCs) can aid recovery of damaged myocardium caused by myocardial infarction. One possible mechanism for MSC-mediated recovery is reprogramming after cell fusion between transplanted MSCs and recipient cardiac cells. We used a Cre/LoxP-based luciferase reporter system coupled to biophotonic imaging to detect fusion of transplanted human pluripotent stem cell-derived MSCs to cells of organs of living mice. Human MSCs, with transient expression of a viral fusogen, were delivered to the murine heart via a collagen patch. At 2 days and 1 week later, living mice were probed for bioluminescence indicative of cell fusion. Cell fusion was detected at the site of delivery (heart) and in distal tissues (i.e., stomach, small intestine, liver). Fusion was confirmed at the cellular scale via fluorescence in situ hybridization for human-specific and mouse-specific centromeres. Human cells in organs distal to the heart were typically located near the vasculature, suggesting MSCs and perhaps MSC fusion products have the ability to migrate via the circulatory system to distal organs and engraft with local cells. The present study reveals previously unknown migratory patterns of delivered human MSCs and associated fusion products in the healthy murine heart. The study also sets the stage for follow-on studies to determine the functional effects of cell fusion in a model of myocardial damage or disease.
  
  
  CONCLUSIONS
  Mesenchymal stem cells (MSCs) are transplanted to the heart, cartilage, and other tissues to recover lost function or at least limit overactive immune responses. Analysis of tissues after MSC transplantation shows evidence of fusion between MSCs and the cells of the recipient. To date, the biologic implications of cell fusion remain unclear. A newly developed in vivo tracking system was used to identify MSC fusion products in living mice. The migratory patterns of fusion products were determined both in the target organ (i.e., the heart) and in distal organs. This study shows, for the first time, evidence of fusion products at sites distal from the target organ and data to suggest that migration occurs via the vasculature. These results will inform and improve future, MSC-based therapeutics.
authors.affiliation: Department of Biomedical Engineering, Laboratory for Optical and Computational Instrumentation, and Material Sciences Program, University of Wisconsin-Madison, Madison, Wisconsin, USA; Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Freeman
authors.affiliation: Department of Biomedical Engineering, Laboratory for Optical and Computational Instrumentation, and Material Sciences Program, University of Wisconsin-Madison, Madison, Wisconsin, USA; Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Kouris
authors.affiliation: Department of Biomedical Engineering, Laboratory for Optical and Computational Instrumentation, and Material Sciences Program, University of Wisconsin-Madison, Madison, Wisconsin, USA; Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota, USA ogle@umn.edu.
authors.forename: Brenda M
authors.initials: BM
authors.lastname: Ogle
mesh_terms: D000818:Animals; D002459:Cell Fusion; D002465:Cell Movement; D058948:Cell Tracking; D006321:Heart; D064593:Heterografts; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009928:Organ Specificity; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism / Q000637:transplantation
keywords: Cardiac patch; Cell fusion; Cell transplantation; Cre/LoxP; Mesenchymal stem cells
references.citation: Nucl Med Biol. 2011 Oct;38(7):961-7
references.pmid: 21810549
references.citation: J Clin Invest. 2005 Mar;115(3):572-83
references.pmid: 15765139
references.citation: Nature. 2003 Oct 30;425(6961):968-73
references.pmid: 14555960
references.citation: J Invasive Cardiol. 2006 Nov;18(11):552-6
references.pmid: 17090821
references.citation: Regen Med. 2011 Sep;6(5):569-82
references.pmid: 21916593
references.citation: J Clin Invest. 2005 Feb;115(2):326-38
references.pmid: 15690083
references.citation: Circ Res. 2004 Mar 19;94(5):678-85
references.pmid: 14739163
references.citation: J Cell Biochem. 2006 Aug 1;98(5):1076-84
references.pmid: 16619257
references.citation: J Korean Neurosurg Soc. 2010 Nov;48(5):391-8
references.pmid: 21286474
references.citation: Nat Med. 2005 Apr;11(4):367-8
references.pmid: 15812508
references.citation: Br J Radiol. 2007 Sep;80 Spec No 1:S49-55
references.pmid: 17704326
references.citation: J Pathol. 2009 Jan;217(2):318-24
references.pmid: 19023885
references.citation: Arch Intern Med. 2007 May 28;167(10):989-97
references.pmid: 17533201
references.citation: Nat Methods. 2014 Apr;11(4):393-5
references.pmid: 24509630
references.citation: Exp Hematol. 2008 Mar;36(3):350-9
references.pmid: 18179856
references.citation: Circulation. 2003 Mar 11;107(9):1247-9
references.pmid: 12628942
references.citation: Proc Natl Acad Sci U S A. 2005 Jun 21;102(25):8966-71
references.pmid: 15951423
references.citation: Stem Cells Int. 2012;2012:414038
references.pmid: 22701126
references.citation: Circulation. 2013 Jan 1;127(1):143-52
references.pmid: 23283859
references.citation: Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12313-8
references.pmid: 14530411
references.citation: Stem Cells. 2009 Oct;27(10):2614-23
references.pmid: 19650040
references.citation: Ann Thorac Surg. 2010 Jul;90(1):190-7
references.pmid: 20609773
references.citation: Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2397-402
references.pmid: 12606728
references.citation: Nucleic Acids Res. 1995 Dec 25;23(24):5080-1
references.pmid: 8559668
references.citation: FASEB J. 2004 Mar;18(3):548-50
references.pmid: 14715691
references.citation: Stem Cells. 2014 Aug;32(8):2123-34
references.pmid: 24578312
references.citation: J Cell Biol. 2004 Oct 25;167(2):351-63
references.pmid: 15492039
references.citation: Nat Med. 2004 May;10(5):494-501
references.pmid: 15107841
references.citation: Circulation. 1999 Nov 9;100(19 Suppl):II247-56
references.pmid: 10567312
references.citation: Ann Thorac Surg. 2002 Jun;73(6):1919-25; discussion 1926
references.pmid: 12078791
references.citation: J Vis Exp. 2012;(59):e3581
references.pmid: 22230968
references.citation: PLoS Negl Trop Dis. 2012;6(12):e1971
references.pmid: 23272265
references.citation: Circulation. 2004 Dec 21;110(25):3803-7
references.pmid: 15596566
references.citation: Proc Natl Acad Sci U S A. 2005 Aug 9;102(32):11474-9
references.pmid: 16061805
references.citation: FASEB J. 2006 Apr;20(6):661-9
references.pmid: 16581974
references.citation: Circulation. 2001 Aug 28;104(9):1046-52
references.pmid: 11524400
references.citation: Basic Res Cardiol. 2005 May;100(3):217-23
references.pmid: 15754085
references.citation: Mol Imaging. 2010 Oct;9(5):278-90
references.pmid: 20868628
references.citation: Circulation. 2005 Sep 6;112(10):1451-61
references.pmid: 16129797
references.citation: Am J Physiol. 1995 Dec;269(6 Pt 2):H2147-54
references.pmid: 8594926
references.citation: J Cell Biol. 2003 Jun 9;161(5):945-56
references.pmid: 12796480
references.citation: J Biol Chem. 2008 Mar 7;283(10):6418-27
references.pmid: 18165228
references.citation: Nature. 2002 Apr 4;416(6880):542-5
references.pmid: 11932747
references.citation: PLoS One. 2012;7(3):e33945
references.pmid: 22457803
references.citation: Am J Cardiol. 2004 Jul 1;94(1):92-5
references.pmid: 15219514
references.citation: J Virol. 2002 Dec;76(23):12300-11
references.pmid: 12414970
references.citation: Blood. 2004 Dec 1;104(12):3581-7
references.pmid: 15297308
references.citation: Hepatology. 2006 Jan;43(1):108-16
references.pmid: 16374873
references.citation: Biol Cell. 2010 Sep;102(9):525-37
references.pmid: 20590528
references.citation: Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14764-9
references.pmid: 9405687
references.citation: Am J Physiol Heart Circ Physiol. 2004 Dec;287(6):H2670-6
references.pmid: 15284059
references.citation: Circulation. 2003 May 13;107(18):2290-3
references.pmid: 12732608