alexa Repeated direct endomyocardial transplantation of allogeneic mesenchymal stem cells: safety of a high dose, "off-the-shelf", cellular cardiomyoplasty strategy.


Journal of Clinical & Experimental Cardiology

Author(s): Poh KK, Sperry E, Young RG, Freyman T, Barringhaus KG,

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Abstract BACKGROUND: Efficacy of cellular cardiomyoplasty seems to occur in a dose-related manner. However, the safety of multiple transendomyocardial transplantation procedures to administer high cell dosages has not been previously reported. The aims of this study were to assess the short- and intermediate-term results of a repeated cell administration strategy and evaluate the safety of an "off-the-shelf" allogeneic mesenchymal stem cell (MSC) source. METHODS: Porcine bone marrow-derived MSCs were culture-expanded through three cycles in vitro before transplantation. Yorkshire swine weighing 30-40 kg were allocated to receive the total dose during 1 injection procedure or divided over 2 procedures separated by 14 days, as follows: (i) 400x10(6) allogeneic MSC (n=5), (ii) 800x10(6) allogeneic MSC divided in 2 doses (n=5), (iii) cryopreservant vehicle containing 10\% DMSO, 5\% porcine serum and 85\% PlasmaLyte A, 14 days apart (n=2), or (iv) sterile saline 14 days apart (n=2). During each procedure, twenty 0.5 ml aliquots of the assigned injectant were administered using the Stiletto Endocardial Direct Injection Catheter System, targeting at the left ventricular anterior, septal and lateral walls under fluoroscopy. Vital signs and electrocardiograms were recorded during the procedure and at 24 h. The animals were examined daily and cardiac enzymes were measured immediately post-procedure, and on days 1, 15 and 90. Necropsy and histopathology were performed at day 90. RESULTS: Mean transendocardial injection procedure time was 40+/-10 min. All ventricular target areas were accessed by the Stiletto system. Ventricular ectopic beats and/or non-sustained ventricular tachycardia associated with catheter contact or endomyocardial injections were observed in all cases. However, no sustained ventricular arrhythmia, anaphylaxis, or significant cardiac enzyme release was seen. One mortality resulted from air embolism during the procedure. All other swine survived from the time of recovery until planned sacrifice at day 90 and had normal physical examination findings. The 3-month histopathology showed no evidence of rejection, calcification, teratoma or myocardial infarction. CONCLUSION: Repeated endomyocardial transplantation of high dose, bone marrow-derived allogeneic cells appeared safe in a large animal, human surrogate model. Such cellular cardiomyoplasty strategy warrants further investigation. This article was published in Int J Cardiol and referenced in Journal of Clinical & Experimental Cardiology

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