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Biomaterials. 2014 Apr;35(11):3541-50. doi: 10.1016/j.biomaterials.2013.12.071. Epub 2014 Jan 16.

Long-acting beneficial effect of percutaneously intramyocardially delivered secretome of apoptotic peripheral blood cells on porcine chronic ischemic left ventricular dysfunction.

Author information

1
Department of Cardiology, Medical University of Vienna, Austria.
2
Department of Thoracic Surgery, Medical University of Vienna, Austria.
3
Department of Obstetrics and Gynecology - Molecular Oncology Group, Medical University of Vienna, Austria.
4
Department of Dermatology, Medical University of Vienna, Austria.
5
Institute of Diagnostic Imaging and Radiation Oncology, University of Kaposvar, Hungary.
6
Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Austria.
7
RedCrossTransfusion Service for Upper Austria, Linz, Austria.
8
Clinical Department for Farm Animals and Herd Management, University of Veterinary Medicine, Vienna, Austria.
9
Department of Thoracic Surgery, Medical University of Vienna, Austria; Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Vienna, Austria. Electronic address: hendrik.ankersmit@meduniwien.ac.at.

Abstract

The quantity of cells with paracrine effects for use in myocardial regeneration therapy is limited. This study investigated the effects of catheter-based endomyocardial delivery of secretome of 2.5 × 10(9) apoptotic peripheral blood mononuclear cells (APOSEC) on porcine chronic post-myocardial infarction (MI) left ventricular (LV) dysfunction and on gene expression. Closed-chest reperfused MI was induced in pigs by 90-min occlusion followed by reperfusion of the mid-LAD (day 0). At day 30, animals were randomized to receive porcine APOSEC (n = 8) or medium solution (control; n = 8) injected intramyocardially into the MI border zone using 3D NOGA guidance. At day 60, cardiac MRI with late enhancement and diagnostic NOGA (myocardial viability) were performed. Gene expression profiling of the infarct core, border zone, and normal myocardium was performed using microarray analysis and confirmed by quantitative real-time PCR. Injection of APOSEC significantly decreased infarct size (p < 0.05) and improved cardiac index and myocardial viability compared to controls. A trend towards higher LV ejection fraction was observed in APOSEC vs. controls (45.4 ± 5.9% vs. 37.4 ± 8.9%, p = 0.052). Transcriptome analysis revealed significant downregulation of caspase-1, tumor necrosis factor and other inflammatory genes in APOSEC-affected areas. rtPCR showed higher expression of myogenic factor Mefc2 (p < 0.05) and downregulated caspase genes (p < 0.05) in APOSEC-treated pigs. In conclusion, overexpression of MEF2c and repression of caspase was related to decreased infarct size and improved cardiac function in secretome-treated animals. Altered gene expression 1-month post-APOSEC treatment proved the long-acting effects of cell-free therapy with paracrine factors.

KEYWORDS:

Animal model; Cell-free regeneration therapy; Gene expression; Immunomodulation; Myocardial infarction; Remodeling

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