在肺动脉高压和右心衰竭的实验模型中的干细胞治疗：旁分泌和神经激素环境在重塑过程中的作用。
Stem-cell therapy in an experimental model of pulmonary hypertension and right heart failure: role of paracrine and neurohormonal milieu in the remodeling process.
机构信息
Department of Medico-Diagnostic Sciences and Special Therapies, University of Padua, Italy.
出版信息
J Heart Lung Transplant. 2011 Nov;30(11):1281-93. doi: 10.1016/j.healun.2011.07.017.
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.
背景
在这项研究中，我们研究了人羊水干细胞（hAFS）和大鼠脂肪组织基质血管部分 GFP 阳性细胞（rSVC-GFP）治疗对肺动脉高压（PH）和右心衰竭（RHF）大鼠模型中心肺血管重塑的影响，以及旁分泌和神经激素环境的作用。
方法
Sprague-Dawley 大鼠注射单克隆肌球蛋白（MCT）。在 MCT 后 3 周，通过尾静脉注射 400 万个 hAFS 或 rSVC-GFP 细胞。通过 RV 肥大/扩张和脑钠肽（BNP）水平证实 RHF。通过多重分析评估细胞因子谱。通过免疫荧光研究干细胞（SC）分化。
结果
MCT 大鼠表现出偏心性 RV 肥大，RV 扩张增加（RV 质量/RV 体积[RVM/RVV]：MCT，1.46 ± 0.12；对照组，2.33 ± 0.24；p = 0.01），RV 肥大增加（LVM/RVM：MCT，1.58 ± 0.06；对照组，2.83 ± 0.1；p < 0.00001），BNP 增加（MCT，5.2 ± 1.2；对照组，1.5 ± 0.1；p < 0.001）和促炎和抗炎细胞因子均增加。SC 降低 BNP（hAFS，2.1 ± 0.7；rSVC-GFP，1.98 ± 1.3；p < 0.001）和促炎细胞因子。RV 重塑呈阳性，RV 扩张减少（RVM/RVV：hAFS，1.87 ± 0.44；rSVC-GFP，2.12 ± 0.24；p < 0.03 和 p < 0.05 与 MCT 相比）和 RV 肥大消退（LVM/RVM：hAFS，2.06 ± 0.08；rSVC-GFP，2.16 ± 0.08；p < 0.00001 与 MCT 相比），同时肺小动脉中膜厚度降低（hAFS，35.33 ± 2.78%；rSVC-GFP，37.15 ± 2.92%；p = 0.0001 与 MCT 相比）。
结论
植入肺部、心脏和骨骼肌的 SC 调节了促炎和抗炎细胞因子环境，并产生了积极的神经激素反应。这伴随着心脏和肺血管的积极重塑，主要形成新的血管细胞。
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