title: Donor mesenchymal stromal cells (MSCs) undergo variable cardiac reprogramming in vivo and predominantly co-express cardiac and stromal determinants after experimental acute myocardial infarction.
abstract: We previously showed the emergence of predominantly non-fused murine cells co-expressing cardiac and stromal determinants in co-cultures of murine mesenchymal stromal cells (MSCs) and rat embryonic cardiomyocytes. To determine whether a similar phenotype is detectable in vivo in ischemic myocardium, we infused green fluorescence protein (GFP)-marked MSCs intravenously into wild-type mice in an acute myocardial infarction (AMI) model generated by ischemia/reperfusion (I/R) or fixed coronary artery ligation. We found that infused GFP+ cells were confined strictly to ischemic areas and represented approximately 10% of total cellularity. We showed that over 60% of the cells co-expressed collagen type IV and troponin T or myosin heavy chain, characteristic of MSCs and cardiomyocytes, respectively, and were CD45(-). Nonetheless, up to 25% of the GFP+ donor cells expressed one of two cardiomyocyte markers, either myosin heavy chain or troponin T, in the absence of MSC determinants. We also observed a marked reduction in OCT4 expression in MSCs pre-infusion compared with those lodged in the myocardium, suggesting reduced stem cell properties. Despite the low frequency of lodged donor MSCs, left-ventricular end-diastolic pressure was significantly better in experimental versus saline animals for both AMI (12.10 ± 1.81 vs. 20.50 ± 1.53 mmHg, p < 0.001) and I/R models (8.75 ± 2.95 vs. 17.53 ± 3.85 mmHg, p = 0.004) when measured 21 days after MSC infusion and is consistent with a paracrine effect. Our data indicate that donor MSCs undergo variable degrees of cardiomyocyte reprogramming with the majority co-expressing cardiomyocyte and stromal markers. Further studies are needed to elucidate the factors mediating the extent of cardiomyocyte reprogramming and importance of the cellular changes on tissue repair.
authors.affiliation: Cell Therapy Program, Princess Margaret Hospital, University Health Network, University of Toronto, 610 University Ave, Suite 5-303, Toronto, ON, Canada, M5G 2M9.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Yannarelli
authors.forename: James N
authors.initials: JN
authors.lastname: Tsoporis
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Desjardins
authors.forename: Xing Hua
authors.initials: XH
authors.lastname: Wang
authors.forename: Ali
authors.initials: A
authors.lastname: Pourdjabbar
authors.forename: Sowmya
authors.initials: S
authors.lastname: Viswanathan
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Parker
authors.forename: Armand
authors.initials: A
authors.lastname: Keating
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D049452:Green Fluorescent Proteins / Q000096:biosynthesis; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism; D016277:Ventricular Function, Left; D017725:Ventricular Pressure
chemical_list: D015703:Antigens, CD; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D049452:Green Fluorescent Proteins