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.

Co-transplantation of Mesenchymal Stromal Cells and Induced Pluripotent Stem Cell-Derived Cardiomyocytes Improves Cardiac Function After Myocardial Damage

“…However, the therapeutic effects of cell combinations in individual studies were rather heterogeneous. Kearns-Jonker et al showed that co-transplantation of human MSC and ESC-derived CM was more beneficial than transplantation of CM alone in inducing the expression of genes in host cells that encode for factors that promote cardiac repairs, such as hepatocyte growth factor or IGF-1 (45). Notably, in contrast to our findings, synergistic effects from co-transplantation with respect to cardiac function (LVEF) have not been observed.…”

“…Our study quantitatively assesses the effect of co-transplanted MSC on survival and therapeutic effect of iPS-CM by serially and non-invasively monitoring the retention kinetics of viable luciferase-expressing CM using BLI and cardiac function via MRI. Among previous studies comparing the effects of single and combined cell therapies in animal models of MI (41,(43)(44)(45)(46)(47)(48)(49), only Kearns-Jonker et al investigated the added benefits of MSCs and ESC-derived CMs in a rat model of MI but they did not quantify cell retention (45). Ye and coworkers used quantitative PCR (qPCR) to assess cell retention in their study comparing therapeutic effects of human iPS-CM alone or in combination with iPSC-derived endothelial cells and smooth muscle cells in a pig model of ischemia/reperfusion injury (41).…”