M. Wang1, Q. Li1, Y. Yang1, L. Yan1, M. Turrentine1, I. Wang1 1Indiana University School Of Medicine,Cardiothoracic/Surgery,Indianapolis, IN, USA
Introduction: Heart transplantation is the only gold standard of treatments for end-stage heart failure, but its use is limited by extreme shortage of donor organs. The current cold organ preservation limits the maximal storage to 4-6 hours, beyond which the ischemia/reperfusion (I/R) injury deteriorates graft and patient outcomes. Such time constraint lowers utilization of donor organs. Amelioration of I/R injury, therefore, will prolong preservation time and potentially increase donor heart utilization. Although mesenchymal stem cell (MSC)-derived paracrine actions are mainly responsible for MSC-mediated cardiac protection, currently, no study has reported using stem cell-derived secretome to mitigate ischemic injury in donor hearts during preservation. We aim to evaluate potential amelioration of I/R-damaged myocardial function by MSC conditioned medium (CM) using in vivo murine heterotopic heart transplantation model.
Methods: The CM were obtained from cultivation of human bone marrow-MSCs (3X104/cm2) in serum-free media for 72 hours. Donor hearts from C57BL/6 male mice were stored in University of Wisconsin solution at 0-4°C and randomly divided into three groups: 1) <1hr-cold storage/ischemia (control, n=3); 2) 6hr-cold storage/ischemia (6hr-I+vehicle, n=6); and 3) 6hr-cold storage/ischemia + MSC CM (6hr-I+CM, n=5). These preserved mouse hearts were then implanted into C57BL/6 male recipient mice using cervical heterotopic heart transplantation. At 24-hour post implantation, myocardial function (LVDP, heart rate, and +/-dP/dT) was detected in transplanted hearts by Millar pressure catheter. Native heart rate was recorded by ECG and pulse pressure difference of abdominal artery was measured in recipient mice. p<0.05=statistically significant.
Results: Six-hour cold ischemia significantly impaired myocardial function in heterotopically implanted hearts stored with vehicle vs. control: Fig A. prolonged delay in re-beating time (time of the implanted heart resumed heart beat after unclamping the vessel; B. decreased RPP; C. decreased heart rate; D. reduced dP/dt; and E. impaired –dP/dt. The addition of CM as an adjunct to preservation solution reversed detrimental effects of cold ischemia on myocardial function, as shown by restored parameters in Fig. A-E. There were no pulse pressure differences seen in the native hearts among the 3 groups, providing additional experimental control to exclude potential procedural variability.
Conclusion: Our results represent the first evidence that using MSC CM during ischemic cold storage confers improved myocardial preservation, suggesting protective role of the MSC secretome that may allow optimization of current storage methods to improve organ function and patient recovery.
