Stem-cell therapy in an experimental model of pulmonary hypertension and right heart failure: role of paracrine and neurohormonal milieu in the remodeling process.

摘要

BACKGROUND: In this study we investigated the effect of human amniotic fluid stem (hAFS) cells and rat adipose tissue stromal vascular fraction GFP-positive cell (rSVC-GFP) therapy and the contribution of the paracrine and neurohormonal milieu to cardiac and pulmonary vascular remodeling in a rat model of pulmonary hypertension (PH) and right heart failure (RHF). METHODS: Sprague-Dawley rats were injected with monocrotaline (MCT). Four million hAFS or rSVC-GFP cells were injected via the tail vein 3 weeks after MCT. RHF was confirmed by RV hypertrophy/dilation and by brain natriuretic peptide (BNP) level. Cytokine profile was assessed by Multiplex array. Stem cell (SC) differentiation was studied by immunofluorescence. RESULTS: MCT rats showed eccentric RV hypertrophy with increased RV dilation (measured as right ventricular mass/right ventricular volume [RVM/RVV]: MCT, 1.46 +/- 0.12; control, 2.33 +/- 0.24; p = 0.01), and increased RV hypertrophy (measured as LVM/RVM: MCT, 1.58 +/- 0.06; control, 2.83 +/- 0.1; p < 0.00001), increased BNP (MCT, 5.2 +/- 1.2; control, 1.5 +/- 0.1; p < 0.001) and both pro- and anti-inflammatory cytokines. SC produced a fall of BNP (hAFS, 2.1 +/- 0.7; rSVC-GFP, 1.98 +/- 1.3; p < 0.001) and pro-inflammatory cytokines. Positive RV remodeling with decreased RV dilation (RVM/RVV: hAFS, 1.87 +/- 0.44; rSVC-GFP, 2.12 +/- 0.24; p < 0.03 and p < 0.05 vs MCT) and regression of RV hypertrophy (LVM/RVM: hAFS, 2.06 +/- 0.08; rSVC-GFP, 2.16 +/- 0.08; p < 0.00001 vs MCT) was seen together with a decrease in medial wall thickness of pulmonary arterioles (hAFS, 35.33 +/- 2.78%; rSVC-GFP, 37.15 +/- 2.92%; p = 0.0001 vs MCT). CONCLUSIONS: SC engrafted in the lung, heart and skeletal muscle modulated the pro- and anti-inflammatory cytokine milieu, and produced a positive neurohormonal response. This was accompanied by positive cardiac and pulmonary vascular remodeling, with formation mainly of new vascular cells.