title: Direct evaluation of myocardial viability and stem cell engraftment demonstrates salvage of the injured myocardium.
abstract: BACKGROUND
  The mechanism of functional restoration by stem cell therapy remains poorly understood. Novel manganese-enhanced MRI and bioluminescence reporter gene imaging were applied to follow myocardial viability and cell engraftment, respectively. Human-placenta-derived amniotic mesenchymal stem cells (AMCs) demonstrate unique immunoregulatory and precardiac properties. In this study, the restorative effects of 3 AMC-derived subpopulations were examined in a murine myocardial injury model: (1) unselected AMCs, (2) ckit(+)AMCs, and (3) AMC-derived induced pluripotent stem cells (MiPSCs).
  
  
  OBJECTIVE
  To determine the differential restorative effects of the AMC-derived subpopulations in the murine myocardial injury model using multimodality imaging.
  
  
  RESULTS
  SCID (severe combined immunodeficiency) mice underwent left anterior descending artery ligation and were divided into 4 treatment arms: (1) normal saline control (n=14), (2) unselected AMCs (n=10), (3) ckit(+)AMCs (n=13), and (4) MiPSCs (n=11). Cardiac MRI assessed myocardial viability and left ventricular function, whereas bioluminescence imaging assessed stem cell engraftment during a 4-week period. Immunohistological labeling and reverse transcriptase polymerase chain reaction of the explanted myocardium were performed. The unselected AMC and ckit(+)AMC-treated mice demonstrated transient left ventricular functional improvement. However, the MiPSCs exhibited a significantly greater increase in left ventricular function compared with all the other groups during the entire 4-week period. Left ventricular functional improvement correlated with increased myocardial viability and sustained stem cell engraftment. The MiPSC-treated animals lacked any evidence of de novo cardiac differentiation.
  
  
  CONCLUSIONS
  The functional restoration seen in MiPSCs was characterized by increased myocardial viability and sustained engraftment without de novo cardiac differentiation, indicating salvage of the injured myocardium.
authors: From the Division of Cardiovascular Medicine, Department of Medicine, Stanford University Medical Center, CA (P.J.K., M.M., X.G., Y.M., I.T., S.M., N.G.K., M.V.M., E.R., P.C.Y.); Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, CA (J.R., C.H., H.B.); and Eagle Vision Pharmaceutical Corporation, Exton, PA (P.H.).
authors: Paul J
authors: PJ
authors: Kim
authors: From the Division of Cardiovascular Medicine, Department of Medicine, Stanford University Medical Center, CA (P.J.K., M.M., X.G., Y.M., I.T., S.M., N.G.K., M.V.M., E.R., P.C.Y.); Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, CA (J.R., C.H., H.B.); and Eagle Vision Pharmaceutical Corporation, Exton, PA (P.H.).
authors: Morteza
authors: M
authors: Mahmoudi
authors: From the Division of Cardiovascular Medicine, Department of Medicine, Stanford University Medical Center, CA (P.J.K., M.M., X.G., Y.M., I.T., S.M., N.G.K., M.V.M., E.R., P.C.Y.); Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, CA (J.R., C.H., H.B.); and Eagle Vision Pharmaceutical Corporation, Exton, PA (P.H.).
authors: Xiaohu
authors: X
authors: Ge
authors: From the Division of Cardiovascular Medicine, Department of Medicine, Stanford University Medical Center, CA (P.J.K., M.M., X.G., Y.M., I.T., S.M., N.G.K., M.V.M., E.R., P.C.Y.); Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, CA (J.R., C.H., H.B.); and Eagle Vision Pharmaceutical Corporation, Exton, PA (P.H.).
authors: Yuka
authors: Y
authors: Matsuura
authors: From the Division of Cardiovascular Medicine, Department of Medicine, Stanford University Medical Center, CA (P.J.K., M.M., X.G., Y.M., I.T., S.M., N.G.K., M.V.M., E.R., P.C.Y.); Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, CA (J.R., C.H., H.B.); and Eagle Vision Pharmaceutical Corporation, Exton, PA (P.H.).
authors: Ildiko
authors: I
authors: Toma
authors: From the Division of Cardiovascular Medicine, Department of Medicine, Stanford University Medical Center, CA (P.J.K., M.M., X.G., Y.M., I.T., S.M., N.G.K., M.V.M., E.R., P.C.Y.); Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, CA (J.R., C.H., H.B.); and Eagle Vision Pharmaceutical Corporation, Exton, PA (P.H.).
authors: Scott
authors: S
authors: Metzler
authors: From the Division of Cardiovascular Medicine, Department of Medicine, Stanford University Medical Center, CA (P.J.K., M.M., X.G., Y.M., I.T., S.M., N.G.K., M.V.M., E.R., P.C.Y.); Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, CA (J.R., C.H., H.B.); and Eagle Vision Pharmaceutical Corporation, Exton, PA (P.H.).
authors: Nigel G
authors: NG
authors: Kooreman
authors: From the Division of Cardiovascular Medicine, Department of Medicine, Stanford University Medical Center, CA (P.J.K., M.M., X.G., Y.M., I.T., S.M., N.G.K., M.V.M., E.R., P.C.Y.); Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, CA (J.R., C.H., H.B.); and Eagle Vision Pharmaceutical Corporation, Exton, PA (P.H.).
authors: John
authors: J
authors: Ramunas
authors: From the Division of Cardiovascular Medicine, Department of Medicine, Stanford University Medical Center, CA (P.J.K., M.M., X.G., Y.M., I.T., S.M., N.G.K., M.V.M., E.R., P.C.Y.); Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, CA (J.R., C.H., H.B.); and Eagle Vision Pharmaceutical Corporation, Exton, PA (P.H.).
authors: Colin
authors: C
authors: Holbrook
authors: From the Division of Cardiovascular Medicine, Department of Medicine, Stanford University Medical Center, CA (P.J.K., M.M., X.G., Y.M., I.T., S.M., N.G.K., M.V.M., E.R., P.C.Y.); Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, CA (J.R., C.H., H.B.); and Eagle Vision Pharmaceutical Corporation, Exton, PA (P.H.).
authors: Michael V
authors: MV
authors: McConnell
authors: From the Division of Cardiovascular Medicine, Department of Medicine, Stanford University Medical Center, CA (P.J.K., M.M., X.G., Y.M., I.T., S.M., N.G.K., M.V.M., E.R., P.C.Y.); Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, CA (J.R., C.H., H.B.); and Eagle Vision Pharmaceutical Corporation, Exton, PA (P.H.).
authors: Helen
authors: H
authors: Blau
authors: From the Division of Cardiovascular Medicine, Department of Medicine, Stanford University Medical Center, CA (P.J.K., M.M., X.G., Y.M., I.T., S.M., N.G.K., M.V.M., E.R., P.C.Y.); Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, CA (J.R., C.H., H.B.); and Eagle Vision Pharmaceutical Corporation, Exton, PA (P.H.).
authors: Phillip
authors: P
authors: Harnish
authors: From the Division of Cardiovascular Medicine, Department of Medicine, Stanford University Medical Center, CA (P.J.K., M.M., X.G., Y.M., I.T., S.M., N.G.K., M.V.M., E.R., P.C.Y.); Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, CA (J.R., C.H., H.B.); and Eagle Vision Pharmaceutical Corporation, Exton, PA (P.H.).
authors: Eric
authors: E
authors: Rulifson
authors: From the Division of Cardiovascular Medicine, Department of Medicine, Stanford University Medical Center, CA (P.J.K., M.M., X.G., Y.M., I.T., S.M., N.G.K., M.V.M., E.R., P.C.Y.); Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, CA (J.R., C.H., H.B.); and Eagle Vision Pharmaceutical Corporation, Exton, PA (P.H.). phillip@stanford.edu.
authors: Phillip C
authors: PC
authors: Yang
mesh_terms: D000818:Animals; D002469:Cell Separation / Q000379:methods; D002470:Cell Survival; D023921:Coronary Stenosis / Q000150:complications; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D017930:Genes, Reporter; D006085:Graft Survival; D064593:Heterografts; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000637:transplantation*; D008026:Ligation; D008163:Luminescent Measurements; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D008345:Manganese; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000737:chemistry / Q000166:cytology*; D051379:Mice; D008817:Mice, Mutant Strains; D016513:Mice, SCID; D064847:Multimodal Imaging; D009203:Myocardial Infarction / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000473:pathology*; D010920:Placenta / Q000166:cytology; D011247:Pregnancy; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059505:Telomere Homeostasis; D016277:Ventricular Function, Left
chemical_list: D008345:Manganese; D019009:Proto-Oncogene Proteins c-kit
keywords: magnetic resonance imaging; molecular imaging; multimodal imaging
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