P503Stem cells homing, positive Skeletal muscle and cardiac remodelling, and cytokines profile in an animal model of heart failure

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Abstract

Purpose

Heart failure is characterized by limited exercise tolerance and by a skeletal muscle myopathy with muscle atrophy and inflammatory status with elevated pro-inflammatory cytokines and exaggerated free radicals production. Aim of our study was to investigate role of human amniotic stem cell (hAFC, like embryonic stem cells) and rat vascular stromal adipocite GFP positive cells (rGFP, vascular progenitor cells) in a well established model of rat heart failure.

Methods

28 male Sprague-Dowley rats were injected with monocrotaline (MCT) to develop right heart failure. Four millions hAFC or rGFP cells were injected via tail vein three weeks after MCT injection. Stem cells differentiation was studied by double immunofluorescence technique. Heart failure syndrome was confirmed on transverse heart histologic sections looking at RV hypetrophy /dilatation, muscle fibre cross sectional area (CSA) and BNP plasma levels. Cytokine profile was assessed by Multiplex array on sera.

Results

MCT treated rats showed higher degree of RV hypertrophy and dilatation compared to controls, as demonstrated by RVM/RVV (1.46 ± 0.12 MCT vs 2.33 ± 0.24 controls P =0.01) and LVM/RVM (1.58 ± 0.06 MCT vs 2.83 ± 0.1 P < 0.00001). Stem cells-treated (SC) rats showed intermediate values between MCT and similar to controls. MCT-SC treated rats showed plasma brain natriuretic peptide (BNP) of 2.0 ± 1.3* ng/ml lower than MCT rats (5.2 ± 1.2*# ng/ml) and similar to the controls 1.56 ± 0.5 ng/ml# controls, p < 0.001*#.

Results

hAFC cells and rGFP cells were detected also in soleus and anterior tibial-skeletal muscle(SKM) with homing percentage of 0.36 ± 0.41 and 0.8 ± 0.4, respectively. In SKM Stem cells showed a differentiation toward smooth muscle and endothelial cells. SC-treated rats showed an increase in CSA (1093.1 ± 213.5 µm2) compared to MCT (842.6 ± 18.6 µm2) and intermediate to controls ( 1789.8 ± 175.5 µm2, p < 0.05). Using a Bio-Plex immune array we quantified the serum concentrations of the main inflammatory/immune mediators. MCT animals showed an increased serum levels of all cytokines measured, very likely as a consequence of a general inflammation triggered by toxin-induced hearth failure. Treatment with rGFP cells effectively prevented MCT-induced increase of cytokines serum levels.

Conclusions

stem cells treatment lead to modification of the extracellular milieu with modulation of the pro- and anti-inflammatory cytokine production, together with a positive neurohormonal response. The engrafted cells may have an endocrine/paracrine function with production of beneficial anti-inflammatory cytokines and positive skeletal muscle and cardiac remodeling.

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