Abstract 706: Clinically Compliant Mesenchymal Stem Cell Conditioned Medium Reduces Myocardial Infarct Size in a Pig Model of Ischemia and Reperfusion Injury
Introduction Stem cell transplantation, including mesenchymal stem cell (MSC) transplantation, has the potential to limit progression of heart failure and restore cardiac tissue mass. It was recently suggested that MSCs induce reparative effects through secretion of paracrine factors. Therefore, administering secretions from MSC might be as efficacious as MSC transplantation, and will circumvent problems such as immune incompatibility, tumorigenicity, and costs and engender the development of universally available and affordable “off-the-shelf” therapeutics. In this study, we investigated potential infarct size reducing properties of MSC conditioned medium (CM) and assessed the effect of MSC-CM administration on myocardial salvage in a porcine model of ischemia and reperfusion injury.
Methods and Results Highly expandable MSC cultures that can be reproducibly derived from human embryonic stem cells were grown in a chemically defined, serum free, culture medium for three days and the conditioned media was concentrated ~25 fold by tangential flow filtration membranes (2–3K MWCO). Following sternotomy, 18 Dalland Landrace pigs (55– 60 kg) were subjected to 75 minutes of LCx coronary artery occlusion and subsequent reperfusion. Five minutes before the onset of reperfusion, the pigs were treated intravenously with MSC-CM (2.0 mg protein, 1 ml), non-CM or saline. Immediately after reperfusion, MSC-CM (4 ml, 8.0 mg protein, N=7), non-CM (N=6) or saline (N=7) was infused locally into the LCx coronary artery. The pigs were sacrificed 4 hours after reperfusion. Infarct size as assessed using Evans Blue and TTC staining, was markedly reduced in the pigs treated with MSC-CM (23.5 ± 6.1% vs. 62.4 ± 7.1% (non-CM; p=0.009) and vs. 63.3 ± 9.7% (saline; p=0.006)), although the area at risk did not differ.
Conclusion MSC-CM infusion markedly reduced infarct size compared to non-CM and saline infusion in a clinically applicable pig model of ischemia and reperfusion injury. These results support the “paracrine hypothesis” of stem cell transplantation and identify this CM as a clinically compliant therapeutic to reduce ischemia reperfusion injury.