Direct evaluation of myocardial viability and stem cell engraftment demonstrates salvage of the injured myocardium

Circ Res. 2015 Mar 27;116(7):e40-50. doi: 10.1161/CIRCRESAHA.116.304668. Epub 2015 Feb 5.


Rationale: 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.

Methods and 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.

Conclusion: 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.

Keywords: magnetic resonance imaging; molecular imaging; multimodal imaging.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Separation / methods
  • Cell Survival
  • Coronary Stenosis / complications
  • Disease Models, Animal
  • Female
  • Gene Expression Profiling
  • Genes, Reporter
  • Graft Survival
  • Heterografts
  • Humans
  • Induced Pluripotent Stem Cells / transplantation*
  • Ligation
  • Luminescent Measurements
  • Magnetic Resonance Imaging / methods*
  • Male
  • Manganese
  • Mesenchymal Stem Cell Transplantation*
  • Mesenchymal Stem Cells / chemistry
  • Mesenchymal Stem Cells / cytology*
  • Mice
  • Mice, Mutant Strains
  • Mice, SCID
  • Multimodal Imaging*
  • Myocardial Infarction / etiology
  • Myocardial Infarction / pathology
  • Myocardial Infarction / physiopathology
  • Myocardial Infarction / therapy*
  • Myocardium / pathology*
  • Placenta / cytology
  • Pregnancy
  • Proto-Oncogene Proteins c-kit / analysis
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Telomere Homeostasis
  • Ventricular Function, Left


  • Manganese
  • Proto-Oncogene Proteins c-kit