Abstract
Myocardial hypertrophy is present in many heart diseases, representing a strong predictor of adverse cardiovascular outcomes. Regarding therapeutic intervention, mesenchymal stem cells (MSCs) have been suggested to significantly reduce cardiac hypertrophy and progression to heart failure. Preconditioning of MSCs was previously demonstrated to highly improve their paracrine activity resulting in modulation of immune responses and the progression of diseases. Here, we studied the effects of bone marrow-derived preconditioned MSCs on hypertrophied induced pluripotent stem cell-derived cardiomyocytes (iPS-CM) and also sought to identify MSC-derived antihypertrophic molecules. Phenylephrine (PE) was used to induce hypertrophy in murine iPS-CM, and markers of hypertrophy were identified by microarray analysis. Murine MSCs were treated with IFN-γ and IL-1β to enhance their paracrine activity, and transcriptional profiling was performed by microarray analysis. Hypertrophied iPS-CM were subsequently cocultured with preconditioned MSCs or MSC-conditioned medium (CM), respectively. Effects on hypertrophied iPS-CM were studied by cell area quantification, real-time PCR, and western blot. In some experiments, cells were incubated with fractions of MSC-CM obtained by ultrafiltration or by MSC-CM supplemented with inhibitory antibodies. Intracellular and extracellular levels of vascular endothelial growth factor (VEGF) were evaluated by western blot and ELISA. PE-induced hypertrophy in iPS-CM was associated with an upregulation of neuron-derived orphan receptor (Nor1) expression, activation of Akt, and inhibition of both strongly prevented hypertrophy induction in iPS-CM. VEGF secreted by preconditioned MSCs provoked hypertrophy regression in iPS-CM, and a negative correlation between Nor1 expression and hypertrophic growth could be evidenced. Our results demonstrate that Nor1 expression strongly supports hypertrophy in iPS-CM. Moreover, the secretome of preconditioned MSCs triggered regression of hypertrophy in iPS-CM in a VEGF-dependent manner. We suggest that the delivery of the MSC-derived secretome may represent a therapeutic strategy to limit cardiac hypertrophy. However, additional in vivo studies are needed to prove this hypothesis.
Highlights
Left ventricular hypertrophy (LVH) is a common manifestation of many forms of cardiac disease, including myocardial infarction and hypertension [1]
We further investigated whether preconditioned mesenchymal stem cells (MSCs) might reverse hypertrophy in induced pluripotent stem cell-derived cardiomyocytes (iPS-conditioned medium (CM)) and identified vascular endothelial growth factor (VEGF) as a major contributor of MSC-mediated hypertrophy regression
In some experiments, hypertrophied iPS-CM were cultured in medium supplemented with MSC-conditioned medium (CM) or fractions from MSCCM and PE (100 μM) in the presence or absence of polyclonal goat anti-mouse VEGF164 antibodies (R&D Systems)
Summary
Left ventricular hypertrophy (LVH) is a common manifestation of many forms of cardiac disease, including myocardial infarction and hypertension [1]. It is widely recognized as a major risk factor for the development of heart failure and cardiac sudden death representing an established predictor of cardiovascular morbidity and mortality. LVH is a complex and multifactorial condition involving a process of adaptive remodeling, which is usually a compensatory mechanism in response to increased hemodynamic load [2]. Since a variety of signaling pathways have been shown to be involved in the progression of cardiac hypertrophy [5], understanding the mechanisms underlying the development of cardiac hypertrophy is essential for the treatment of cardiovascular disease. Reversal of myocardial hypertrophy has been considered a therapeutic strategy for the reduction of adverse remodeling and prevention of heart failure [6]
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