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

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• 作者：Noemi Pavo ; Matthias Zimmermann ; Dietmar Pils ; Michael Mildner ; Zsolt Petr谩si ; 脰rs Petneh谩zy ; J谩nos Fuzik ; Andr谩s Jakab ; Christian Gabriel ; Wolfgang Sipos ; Gerald Maurer ; Mariann Gy枚ngy枚si ; Hendrik Jan Ankersmit
• 关键词：Cell-free regeneration therapy ; Gene expression ; Immunomodulation ; Myocardial infarction ; Remodeling ; Animal model
• 刊名：Biomaterials
• 出版年：April, 2014
• 年：2014
• 卷：35
• 期：11
• 页码：3541-3550
• 全文大小：3176 K

文摘

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聽脳聽10⁹ 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聽=聽8) or medium solution (control; n聽=聽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聽<聽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聽卤聽5.9% vs. 37.4聽卤聽8.9%, p聽=聽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聽<聽0.05) and downregulated caspase genes (p聽<聽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.