Long-acting beneficial effect of percutaneously intramyocardially delivered secretome of apoptotic peripheral blood cells on porcine chronic ischemic left ventricular dysfunction.
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.
Department of Cardiology, Medical University of Vienna, Austria.
Noemi
N
Pavo
Department of Thoracic Surgery, Medical University of Vienna, Austria.
Matthias
M
Zimmermann
Department of Obstetrics and Gynecology - Molecular Oncology Group, Medical University of Vienna, Austria.
Dietmar
D
Pils
Department of Dermatology, Medical University of Vienna, Austria.
Michael
M
Mildner
Institute of Diagnostic Imaging and Radiation Oncology, University of Kaposvar, Hungary.
Zsolt
Z
Petrási
Institute of Diagnostic Imaging and Radiation Oncology, University of Kaposvar, Hungary.
Örs
Ö
Petneházy
Department of Cardiology, Medical University of Vienna, Austria.
János
J
Fuzik
Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Austria.
András
A
Jakab
RedCrossTransfusion Service for Upper Austria, Linz, Austria.
Christian
C
Gabriel
Clinical Department for Farm Animals and Herd Management, University of Veterinary Medicine, Vienna, Austria.
Wolfgang
W
Sipos
Department of Cardiology, Medical University of Vienna, Austria.
Gerald
G
Maurer
Department of Cardiology, Medical University of Vienna, Austria.
Mariann
M
Gyöngyösi
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.
Hendrik Jan
HJ
Ankersmit
D000279:Administration, Cutaneous; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001798:Blood Proteins / Q000378:metabolism*; D002908:Chronic Disease; D005786:Gene Expression Regulation; D006439:Hemodynamics; D007963:Leukocytes, Mononuclear / Q000378:metabolism* / Q000637:transplantation*; D008279:Magnetic Resonance Imaging; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy*; D017202:Myocardial Ischemia / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D018919:Neovascularization, Physiologic; D020411:Oligonucleotide Array Sequence Analysis; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D034421:Sus scrofa; D018487:Ventricular Dysfunction, Left / Q000150:complications / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*
D001798:Blood Proteins; D019009:Proto-Oncogene Proteins c-kit
Animal model; Cell-free regeneration therapy; Gene expression; Immunomodulation; Myocardial infarction; Remodeling