title: Genetically Engineered Mesenchymal Stem Cells Influence Gene Expression in Donor Cardiomyocytes and the Recipient Heart.
abstract: AIMS: Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) or mesenchymal stem cells (MSCs) facilitate post-infarct recovery, but the potential benefit of combination therapy using MSCs and hESC-CMs has not been examined. Our objective was to define the gene expression changes in donor and host-derived cells that are induced in vivo after co-transplantation of cardiomyocytes with and without mesenchymal stem cells expressing the prosurvival gene heme oxygenase 1.  METHODS AND RESULTS: Human MSCs were engineered to over-express heme oxygenase-1 (HO-1) following lentiviral vector-mediated transduction. Athymic nude rats were subjected to myocardial infarction and received hESC-CMs alone, hESC-CMs plus human MSCs, hESC-CMs plus MSCs overexpressing HO-1, or saline. Real time PCR identified gene expression changes. Cardiac function was assessed by angiography. Co-transplantation of unmodified MSCs plus hESC-CMs elevated CXCR4, HGF, and IGF expression over levels induced by injection of hESC-derived cardiomyocytes alone. In animals co-transplanted with MSC over-expressing HO-1, the expression of these genes was further elevated. Gene expression levels of VEGF, TGF-β, CCL2, SMAD7, STAT3 and cardiomyocyte transcription factors were highest in the HO-1 MSC plus hESC-CM group at 30 days. Human CD31+, CD34+, isl-1+, NXK2.5 and c-kit+ transcripts were elevated. Rodent genes encoding NKX2.5, troponin T and CD31 were elevated and cell cycle genes were induced. Ejection fraction improved by six to seven percent.  CONCLUSIONS: Co-administration of HO-1 MSCs plus hESC-CMs increased expression of pro-survival and angiogenesis-promoting genes in human cells and transcripts of cardiac and endothelial cell markers in rodent cells, consistent with activation of tissue repair in both transplanted hESC-CMs and the host heart.
authors.affiliation: Dept of Cardiothoracic Surgery, Childrens Hospital Los Angeles, Los Angeles, CA, USA  ;  Dept of Pathology and Human Anatomy, Loma Linda University School of Medicine, Loma Linda, CA, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Kearns-Jonker
authors.forename: Wangde
authors.initials: W
authors.lastname: Dai
authors.forename: Mirja
authors.initials: M
authors.lastname: Gunthart
authors.forename: Tania
authors.initials: T
authors.lastname: Fuentes
authors.forename: Hsiao-Yun
authors.initials: HY
authors.lastname: Yeh
authors.forename: Paul
authors.initials: P
authors.lastname: Gerczuk
authors.forename: Martin
authors.initials: M
authors.lastname: Pera
authors.forename: Christine
authors.initials: C
authors.lastname: Mummery
authors.forename: Robert A
authors.initials: RA
authors.lastname: Kloner