Abstract 14863: Genetically Engineered Mesenchymal Stem Cells Confer Beneficial Effects on Both Co-transplanted Human Embryonic Stem Cell Derived Cardiomyocytes as well as the Recipient Heart
Introduction: Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) or mesenchymal stem cells (MSCs) facilitate post-infarct recovery. MSCs produce paracrine factors that promote cardiac repair, but are insufficient for cardiac regeneration.
Hypothesis: Optimal cell therapy may require co-transplantation of MSCs together with hESC-CMs to facilitate angiogenesis and stem cell survival.
Methods: MSCs were engineered to over-express the cytoprotective gene hemeoxygenase-1 (HO-1) to promote cardiovascular repair. Gene expression changes in hESC-CMs in vivo were identified to reveal the mechanisms underlying apoptosis and survival. Four experimental groups of athymic nude rats were subjected to myocardial infarction (n=15 per group) and received hESC-CMs alone, hESC-CMs plus human MSCs, hESC-CMs plus MSCs overexpressing HO-1, or saline by intramyocardial injection. Real time PCR and laser capture microdissection identified gene expression changes. Cardiac function was assessed by angiography at 4 weeks.
Results: Sizable grafts of human cells were identifiable by histology at 30 days. Co-transplantation of unmodified MSCs plus hESC-CMs resulted in highly elevated Bcl2 and CCL5 levels in human cardiomyocytes relative to pre-transplant levels and a 25–30 fold increase in human collagen and fibronectin. In animals co-transplanted with MSC over-expressing HO-1, relative quantities of human VEGF, TGF-β, and CSF-1 transcripts were increased 5 fold and Bcl2 was increased logarithmically. STAT 3 and AKT transcripts were elevated. Human Isl-1 gene expression rose 1.7 fold. Laser capture microdissection revealed a 1.4 fold increase in human CD31 transcripts. Rat troponin T and rat CD31 gene expression increased by 1.9–2.7 fold and 1.2–1.5 fold respectively. Stem cell treatment improved ejection fraction by an absolute increase of 6.3 to 6.7 +/− 1.5 percentage points above controls.
Conclusions: Co-administration of HO-1 MSCs plus hESC-CMs increased the expression of pro-survival and angiogenesis-promoting genes in the transplanted human cells and increased endogenous cardiac and endothelial cell markers in rodent cells, consistent with activation of tissue repair in both the transplanted hESC-CMs as well as the host heart.
- © 2010 by American Heart Association, Inc.