Epicardial Placement Of Instantly Produced Fibrin Glue-Incorporating Mesenchymal Stromal Cells For The Treatment Of Heart Failure

Introduction: Transplantation of mesenchymal stromal cells (MSC) is an emerging treatment for heart failure, but the cell-delivery route needs to be optimized. Recent reports suggest that placement onto the heart surface (epicardial placement) may be more effective and safer than the current injection methods. This study aimed to explore the efficacy of epicardial placement of fibrin glue (FG)-incorporating MSC, which is produced instantly on the site of treatment. Mechanisms by which FG improves the effects of MSC-therapy were also examined in vivo and in vitro. Methods u0026 Results: Four weeks after induction of myocardial infarction, female rats were transplanted with 4x10 6 syngeneic male bone marrow MSC by means of FG-aided epicardial placement or intramyocardial injection. Sham treatment was also examined as control. Upon mixing fibrinogen, thrombin, and MSC suspensions on the exposed heart, this promptly formed adhesive fibrin-containing MSC and strongly adhered to the heart surface. This resulted in greater initial retention and subsequent presence of donor MSC compared to intramyocardial injection (93.0±7.2% vs 48.1±9.2% at 1 hour post-transplantation; 32.5±1.4% vs 10.3±1.2% at Day 7; 11.1±0.8% vs 0.7±0.2% at Day 28; % to the total transplanted cell number assessed by qPCR for Sry gene). This led to amplified recovery of cardiac function and structure as measured by echocardiography and catheterization. This effect was underpinned by enhanced repair of the failing myocardium (i.e. increased neovascular formation, attenuated pathological fibrosis, and reduced cardiomyocyte hypertrophy) in association with upregulation of repair-related genes (including Il10, Cxcl12, Igf1, Hif1a, Tgfb1, Vcam1, Timp1). In addition, in-vitro studies showed that culture in FG improved survival as well as secretional ability of MSC, which would contribute to the FG-amplified effect of MSC-therapy. Conclusions: These data suggest a great potential of epicardial placement of instantly produced MSC-FG complex for the treatment of ischemic heart failure. Not only FG supports physical retention of donor MSC in the heart, but also enhances their cellular competence. Further development of this user-friendly therapy is warranted toward clinical application.