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Updated: Feb 25, 2026
Ultrasound-Guided Induced Pluripotent Stem Cell-Derived Cardiomyocyte Implantation in Myocardial Infarcted Mice
Published on: March 30, 2022
Paracrine Effects of the Pluripotent Stem Cell-Derived Cardiac Myocytes Salvage the Injured Myocardium
Atsushi Tachibana1, Michelle R Santoso1, Morteza Mahmoudi1
1From the Division of Cardiovascular Medicine (A.T., M.R.S., M.M., P.S., L.W., M.W., A.D.E., E.R., P.C.Y.), Division of Neonatal and Developmental Medicine (M.B.), and Department of Cardiothoracic Surgery (A.B.G., Y.J.W.), Stanford University, CA; Department of Radiological Sciences, Tokyo Metropolitan University, Japan (A.T., M.F.); Department of Critical Care Medicine, 2nd Affiliated Hospital of Guangzhou University of Chinese Medicine, China (L.W.); Department of Cardiology and Pneumonology, Göttingen University Medical Center, Germany (A.D.E.); and German Center for Cardiovascular Research, Partner Site Göttingen, Germany (A.D.E.).
Insights
Cardiac lineage cells, including human embryonic stem cell-derived cardiac myocytes (hCMs) and induced pluripotent stem cell-derived cardiac myocytes (iCMs), significantly improve heart function after myocardial injury. These differentiated cells are more effective than undifferentiated pluripotent stem cells due to paracrine effects.
Area of Science:
- Cardiovascular Research
- Stem Cell Biology
- Regenerative Medicine
Background:
- Pluripotent stem cells show potential for myocardial repair but mechanisms are unclear.
- Cardiac myocytes derived from stem cells may offer therapeutic benefits for heart damage.
Purpose of the Study:
- To compare the efficacy of cardiac-lineage differentiated cells versus undifferentiated pluripotent stem cells in restoring heart function after injury.
- To evaluate human embryonic stem cells (hESCs), hESC-derived cardiac myocytes (hCMs), induced pluripotent stem cells (iPSCs), and iPSC-derived cardiac myocytes (iCMs) in a murine myocardial injury model.
Main Methods:
- Myocardial infarction was induced in immunosuppressed mice.
- Intramyocardial injection of hESCs, iPSCs, hCMs, iCMs, or PBS control.
- Cardiac magnetic resonance imaging and manganese-enhanced magnetic resonance imaging assessed ejection fraction and myocardial viability.
Main Results:
- hCMs and iCMs significantly improved left ventricular ejection fraction and myocardial viability compared to undifferentiated stem cells and controls.
- Limited cell engraftment suggested paracrine mechanisms mediated the repair.
- Cardiac lineage cells upregulated pro-migratory, pro-angiogenic, and anti-apoptotic targets in the injured myocardium.
Conclusions:
- Cardiac-differentiated stem cells (hCMs, iCMs) are more effective in salvaging injured myocardium than undifferentiated stem cells.
- Differential paracrine effects of cardiac lineage cells underlie their superior therapeutic efficacy.
Rationale:
Cardiac myocytes derived from pluripotent stem cells have demonstrated the potential to mitigate damage of the infarcted myocardium and improve left ventricular ejection fraction. However, the mechanism underlying the functional benefit is unclear.
Objective:
To evaluate whether the transplantation of cardiac-lineage differentiated derivatives enhance myocardial viability and restore left ventricular ejection fraction more effectively than undifferentiated pluripotent stem cells after a myocardial injury. Herein, we utilize novel multimodality evaluation of human embryonic stem cells (hESCs), hESC-derived cardiac myocytes (hCMs), human induced pluripotent stem cells (iPSCs), and iPSC-derived cardiac myocytes (iCMs) in a murine myocardial injury model.
Methods And Results:
Permanent ligation of the left anterior descending coronary artery was induced in immunosuppressed mice. Intramyocardial injection was performed with (1) hESCs (n=9), (2) iPSCs (n=8), (3) hCMs (n=9), (4) iCMs (n=14), and (5) PBS control (n=10). Left ventricular ejection fraction and myocardial viability, measured by cardiac magnetic resonance imaging and manganese-enhanced magnetic resonance imaging, respectively, was significantly improved in hCM- and iCM-treated mice compared with pluripotent stem cell- or control-treated mice. Bioluminescence imaging revealed limited cell engraftment in all treated groups, suggesting that the cell secretions may underlie the repair mechanism. To determine the paracrine effects of the transplanted cells, cytokines from supernatants from all groups were assessed in vitro. Gene expression and immunohistochemistry analyses of the murine myocardium demonstrated significant upregulation of the promigratory, proangiogenic, and antiapoptotic targets in groups treated with cardiac lineage cells compared with pluripotent stem cell and control groups.
Conclusions:
This study demonstrates that the cardiac phenotype of hCMs and iCMs salvages the injured myocardium effectively than undifferentiated stem cells through their differential paracrine effects.
