Factors Affecting Residence Time of Mesenchymal Stromal Cells (MSC) Injected into the Myocardium

Abstract

The therapeutic mechanism of mesenchymal stromal/stem cells (MSC) for the treatment of acute myocardial infarction is not well understood. Our goal was to get insights into this mechanism by analyzing the survival kinetics of allogeneic and syngeneic cell transplants under different tissue conditions. Two MSC cell banks, stably and equally expressing the luciferase reporter construct, were developed for these studies and injected directly to the myocardium of Lewis rat recipients under syngeneic or allogeneic transplantation conditions. Cell survival was monitored by real-time fashion for up to 2 weeks, using optical imaging device (IVIS, Xenogen Corp.). We found that both syngeneic and allogeneic grafts reduced significantly in size during the first week of transplantation, either in the normal or in the late infarcted heart (5 days after MI) and allotransplants became always smaller than syngeneic grafts during this period. Low dose of cyclosporine A treatment had a benefit on both allo- and syngeneic graft sizes, suggesting that multiple mechanisms play a role in early graft reduction. The MSC characteristic factors IL-6, IL-8, MCP-1, and VEGF were well above the control level in the heart tissue at 4 days after cell injection, suggesting that the peak therapeutic effect of MSC can be expected during the first week of the administration. Although allogeneic cells induced immunoglobulin production, their biological effects (cell survival, factor productions) are very similar to the syngeneic transplants and therefore they could deliver the same therapeutic effect as the syngeneic cells. Finally, freshly infarcted tissue (30 min) supported better the survival of MSC than late postischemic tissue (5 days) but only "off the shelf" allogeneic cell transplants fits with this treatment strategy.

Allogeneic Mesenchymal Stromal Cells Transplanted Onto the Heart Surface Achieve Therapeutic Myocardial Repair Despite Immunologic Responses in Rats

“…In response to these issues, the use of allogeneic MSCs has been proposed on account of their immune‐modulating ability and their relatively low immunogenic phenotype 1, 3. Previous reports have shown that injection of allogeneic MSCs, without immunosuppressive treatment, improved cardiac function to the same extent as autologous (syngeneic) MSCs in experimental myocardial infarction (MI) models 4, 5, 6. Allogeneic MSCs have already been injected in patients with heart failure, and the safety and feasibility (and preliminary effect) of this treatment has been established 7, 8…”

“…Nevertheless, it has also been reported that the immune‐suppressive ability of MSCs observed in in vitro settings is not effective enough for transplanted allogeneic MSCs to establish immune privilege in various disease conditions in vivo 4, 5, 9, 10. Westrich et al observed that ≈1% of total injected allogeneic MSCs survived at day 2 after intramyocardial injection (a similar ratio to syngeneic MSCs, calculated from their data) in a rat subacute MI model, whereas most allogeneic, but not syngeneic, MSCs subsequently disappeared by day 7 4.…”

Stem Cells Therapies in Basic Science and Translational Medicine: Current Status and Treatment Monitoring Strategies

“…Human NIS is non-immunogenic and has restricted expression in the adult body, making NIS an ideal reporter for imaging. While a large number of studies focus on imaging of cells transplants in small animals [167], studies on large animals such as the porcine model, is of significance due to potential translation into clinics [168]. Serial non-invasive tracking of porcine bone marrow-derived mesenchymal stem cells delivered intra-myocardially and monitored by PET showed the presence of viable transplanted cells in porcine myocardium [169].…”

Tissue Engineering von Herzklappen und Myokard

“…Auch diese autologen Zellen sind leicht zugänglich. Es gibt aber bisher nur eingeschränkte Belege ihrer Differenzierbarkeit in Kardiomyozyten [62,63].…”