Abstract
Background: Self-assembling three-dimensional cardiospheres (CSps) are known to be effective in improving function and attenuating remodeling as adjunctive therapy in acute myocardial infarction (MI), and they exert functional benefits in large animals with convalescent MI. The effect of cardiospheres in chronically-remodeled myocardium post-MI, and the mechanisms of benefit are unknown. Methods: We performed permanent LAD ligation in Wistar Kyoto female rats. One month later the animals underwent repeat thoracotomy and were randomly assigned to one of two groups: vehicle-treated controls, or CSp-treated, where CSps (at a seeding dose of 2X10 6 cells) were injected in the peri-infarct area. Mechanisms were also probed in vitro . Results: CSps downregulated the canonical Tgfβ1-smad2/3 pathway in co-cultures with fibroblasts and reduced fibroblast proliferation in vitro . Soluble endoglin, abundantly expressed in CSps, was found to limit the Tgfβ1-induced fibrosis in a dose-dependent manner. In vivo , left ventricular function gradually increased one month post-CSp injection with further improvement after up to six months of follow up. Immunoblots verified Tgfβ1/smad cascade downregulation one month post-CSp injection and upregulation of soluble endoglin. In addition, scar mass was reduced one month post-CSp injection compared to controls. Collagen density was attenuated within the infarcted region of the treated group, while immunostaining showed enhanced vessel density in the same region. Six months post-transplantation, cardiomyocyte hypertrophy was reduced in the CSp-treated group compared to control. Conclusions: CSps injected into the peri-infarct zone enhance angiogenesis and reduce established fibrosis in chronically-infarcted myocardium, thereby reversing, at least partially, adverse remodeling of the heart. The underlying mechanism involves modification of Tgfβ1/smad signaling, a key pathway in the cardiac response to injury.
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