title: 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.
authors.affiliation: Cardiovascular Department of Genzyme Corporation, Framingham, MA 01701, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Westrich
authors.forename: Peter
authors.initials: P
authors.lastname: Yaeger
authors.forename: Chufa
authors.initials: C
authors.lastname: He
authors.forename: Jeff
authors.initials: J
authors.lastname: Stewart
authors.forename: Raymond
authors.initials: R
authors.lastname: Chen
authors.forename: Gitta
authors.initials: G
authors.lastname: Seleznik
authors.forename: Shane
authors.initials: S
authors.lastname: Larson
authors.forename: Bruce
authors.initials: B
authors.lastname: Wentworth
authors.forename: Michael
authors.initials: M
authors.lastname: O'Callaghan
authors.forename: Sam
authors.initials: S
authors.lastname: Wadsworth
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Akita
authors.forename: Gyongyi
authors.initials: G
authors.lastname: Molnar
mesh_terms: D000818:Animals; D002470:Cell Survival; D018932:Chemokine CCL2 / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D017930:Genes, Reporter; D021621:Imaging, Three-Dimensional; D007267:Injections; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D049409:Luciferases, Firefly / Q000235:genetics / Q000378:metabolism; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D009203:Myocardial Infarction / Q000628:therapy; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D013997:Time Factors; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic; D042442:Vascular Endothelial Growth Factors / Q000378:metabolism
chemical_list: D018932:Chemokine CCL2; D015850:Interleukin-6; D016209:Interleukin-8; D042442:Vascular Endothelial Growth Factors; D016572:Cyclosporine; D049409:Luciferases, Firefly