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Intramyocardial Injection of Allogenic Bone Marrow-Derived Mesenchymal Stem Cells Without Immunosuppression Preserves Cardiac Function in a Porcine Model of Myocardial Infarction

Division of Cardiology and Hematology, Cedars-Sinai Medical Center, and David Geffen School of Medicine at UCLA, Los Angeles, CA

Matthew J. Price, MD

Division of Cardiology and Hematology, Cedars-Sinai Medical Center, and David Geffen School of Medicine at UCLA, Los Angeles, CA

Michael Lill, MD

Division of Cardiology and Hematology, Cedars-Sinai Medical Center, and David Geffen School of Medicine at UCLA, Los Angeles, CA

Malka Frantzen, MS

Division of Cardiology and Hematology, Cedars-Sinai Medical Center, and David Geffen School of Medicine at UCLA, Los Angeles, CA

Kaname Takizawa, MD

Division of Cardiology and Hematology, Cedars-Sinai Medical Center, and David Geffen School of Medicine at UCLA, Los Angeles, CA

Thomas Kleisli, BS

Division of Cardiology and Hematology, Cedars-Sinai Medical Center, and David Geffen School of Medicine at UCLA, Los Angeles, CA

Jie Zheng, PhD

Division of Cardiology and Hematology, Cedars-Sinai Medical Center, and David Geffen School of Medicine at UCLA, Los Angeles, CA

Saibal Kar, MD

Division of Cardiology and Hematology, Cedars-Sinai Medical Center, and David Geffen School of Medicine at UCLA, Los Angeles, CA

Robert McClelan, MD

Division of Cardiology and Hematology, Cedars-Sinai Medical Center, and David Geffen School of Medicine at UCLA, Los Angeles, CA

Takeshi Miyamota, MD

Division of Cardiology and Hematology, Cedars-Sinai Medical Center, and David Geffen School of Medicine at UCLA, Los Angeles, CA

Justin Bick-Forrester, BS

Division of Cardiology and Hematology, Cedars-Sinai Medical Center, and David Geffen School of Medicine at UCLA, Los Angeles, CA

Michael C. Fishbein, MD

Division of Cardiology and Hematology, Cedars-Sinai Medical Center, and David Geffen School of Medicine at UCLA, Los Angeles, CA

Prediman K. Shah, MD

Division of Cardiology and Hematology, Cedars-Sinai Medical Center, and David Geffen School of Medicine at UCLA, Los Angeles, CA

James S. Forrester, MD

Division of Cardiology and Hematology, Cedars-Sinai Medical Center, and David Geffen School of Medicine at UCLA, Los Angeles, CA

Behrooz Sharifi, PhD

Division of Cardiology and Hematology, Cedars-Sinai Medical Center, and David Geffen School of Medicine at UCLA, Los Angeles, CA

Peng-Sheng Chen, MD

Division of Cardiology and Hematology, Cedars-Sinai Medical Center, and David Geffen School of Medicine at UCLA, Los Angeles, CA

Mohammed Qayyum, MD, PhD

Division of Cardiology and Hematology, Cedars-Sinai Medical Center, and David Geffen School of Medicine at UCLA, Los Angeles, CA

Background: We investigated the efficacy of directly injected allogenic bone marrow-derived mesenchymal stem cells in improving left ventricular function in a porcine model of myocardial infarction.

Methods: Left ventricular infarction was created in 16 adult Yorkshire pigs by coil embolization and thrombotic occlusion distal to the second diagonal artery. One month after myocardial infarction was induced, the animals were randomized to either direct injection of allogenic mesenchymal stem cells or sham treatment (culture medium). Allogenic bromodeoxyuridine-labeled mesenchymal stem cells (2 ± 0.1 x 10⁸) were directly injected into the infarct and peri-infarct areas during an open chest procedure. No immunosuppressive therapy was used. The left ventricular function was measured using serial biplane left ventricular angiography at baseline, 30, 60, and 90 days before sacrifice. Mesenchymal stem cells were localized using bromodeoxyuridine, and differentiation of mesenchymal stem cells was assessed by confocal microscopic colocalization of bromodeoxyuridine with immunofluorescent antibodies specific for cardiomyocytes (troponin I and MF-20) and endothelial cells (von Willebrand factor).

Results: Mesenchymal stem cells labeled with bromodeoxyuridine engrafted the peri-infarct zone and colocalized with both cardiomyocyte-specific and endothelial cell-specific immunofluorescence. No intramyocardial bromodeoxyuridine was observed in sham-treated animals. At the time of the mesenchymal stem cell injection 30 days after myocardial infarction, the left ventricular ejection fraction (LVEF) was 58% ± 3% in mesenchymal stem cell-treated pigs and 56% ± 2% in sham-treated pigs (P = NS). LVEF deteriorated progressively thereafter in untreated pigs (8.5% and 10.5% decline at 60 days and 90 days after myocardial infarction, respectively), but was preserved in mesenchymal stem cell-treated pigs (2.1% increase and -2.0% decline at 60 and 90 days post-MI respectively) (P < .05).

Conclusions: Direct intramyocardial injection of mesenchymal stem cells results in successful intramyocardial engraftment and differentiation into cardiomyocytes and endothelial cells and preserves left ventricular function after myocardial infarction in pigs.

Key Words: mesenchymal stem cells • myocardial infarction • remodeling

Journal of Cardiovascular Pharmacology and Therapeutics, Vol. 10, No. 4, 225-233 (2005)
DOI: 10.1177/107424840501000403


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