Abstract
A variety of stem cells including Mesenchymal Stem Cells (MSCs) have been shown to have therapeutic potential in the treatment of myocardial damage. While the mechanism of action still remains unknown, MSCs have been shown to produce and secrete a broad variety of cytokines, chemokines and growth factors that may potentially be involved in cardiac repair. This has been confirmed by reports that human MSCs can exert favourable cardiac effects after myocardial infarction (MI) without persistence, engraftment, transdifferentation or cell fusion. Thus, the mechanisms responsible for their functional benefits appear to be attributable to paracrine effects. Secreted frizzled protein 2 (SFRP2) is expressed in MSCs following Akt gene transfer and has been shown to have paracrine protective effects. The objective of this study was to determine the effect of the ischemic environment on the engrafted MSC in order to understand the host - stem cell interaction. Using laser microdissection (LMD), the engrafted MSCs were retrieved from the injured myocardium 1 week post MI. To determine if SFRP2 was upregulated in our retrieved MSC population, RT PCR analysis of the retrieved MSCs Vs control MSCs was performed. SFRP2 was found to be 5,700 fold upregulated in MSCs exposed to the infarcted myocardium compared to control MSCs. Subsequent in vitro cardioprotection assays identified SFRP2 as a potent protector of cardiomyocytes during hypoxia treatment. Mitochondrial activity increased by 52% when neonatal rat cardiomyocytes were treated with SFRP2 recombinant protein during hypoxia treatment when compared to hypoxia alone. Caspase activity was also decreased in cardiomyocytes treated with SFRP2 during hypoxia. Cells also showed a healthy morphology and maintained beating after exposure to hypoxia. These data suggest that the injured host can induce MSCs to express cytoprotective factors such as SFRP2 and identify the host - stem cell interaction as an important determinant of the therapeutic effect of stem cell administration.
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