Postinfarct intramyocardial injection of mesenchymal stem cells pretreated with TGF-alpha improves acute myocardial...

Stem cell-based therapies offer promising potential for myocardial infarction (MI), but endogenous molecules released in response to injury likely impair posttransplantation stem cell function. Stem cell-mediated cardioprotection occurs in part via paracrine effects, and transforming growth factor-alpha (TGF-alpha) has been shown to enhance paracrine function. However, it is unknown whether pretreating stem cells with TGF-alpha increases stem cell-mediated cardioprotection after acute MI. Mesenchymal stem cells (MSCs) were treated with TGF-alpha (250 ng/ml) for 24 h. Adult male Sprague-Dawley rat hearts were isolated and perfused using the Langendorff method. MI was induced by ligating the left anterior descending coronary artery. Postligation (30 min), vehicle or 1 x 10(6) MSCs with or without pretreatment were injected in the infarct border zones, and the hearts were perfused for an additional 60 min. Left ventricular function was continuously measured, and infarct size was assessed with Evans blue dye and 2,3,5-triphenyltetrazolium chloride staining. Myocardial production of interleukin (IL)-1beta and IL-6 and caspase 3 activation was also measured. Left ventricular function decreased significantly following coronary artery ligation but improved following injection of untreated MSCs and to a greater extent after injection of pretreated MSCs. In addition, the infarct area, myocardial caspase 3 activation, and IL-6 production were lowest in hearts injected with pretreated cells. Intramyocardial injection of TGF-alpha-pretreated MSCs after acute MI is associated with increased myocardial function and decreased myocardial injury. This strategy may be useful for optimizing the therapeutic efficacy of stem cells for the treatment of acute MI.