脂联素基因修饰的脂肪干细胞对野百合碱诱导的肺动脉高压大鼠代谢模式的影响

Effect of adipose stem cells and APN gene-modified adipose stem cells transplantation on the metabolic profiles in MCT induced PAH rats

目的探讨脂联素(APN)基因修饰的脂肪干细胞(ADSCs)移植对肺动脉高压(PAH)大鼠代谢模式的影响。方法 40只SD大鼠,随机分为正常对照组(NC组)、PAH组、ADSCs组、导入空载慢病毒的脂肪干细胞治疗组(ADSCs-V组)和APN基因修饰的脂肪干细胞治疗组(ADSCs-APN组)。野百合碱(MCT)腹腔注射构建大鼠PAH模型,建模成功后14 d ADSCs组、ADSCs-V组和ADSCs-APN组分别经颈外静脉注射1 ml浓度为1×106cells/ml的ADSCs、ADSCs-V和ADSCs-APN。其他两组注射等量PBS。治疗3 w后分别收集各组大鼠血清,采用磁共振(NMR)技术进行血清NMR氢谱检测分析各组代谢物浓度。采用Chenomx NMR Suite 8.0软件对NMR数据进行PCA、PLS-DA统计分析,利用排列检测方法评价PLSDA模型的质量。结果 PAH组较正常对照组大鼠血清代谢物中血清葡萄糖、乳酸浓度明显升高,血清丙氨酸浓度明显降低。ADSCs-APN移植治疗能降低PAH大鼠血清葡萄糖、乳酸浓度,升高血清丙氨酸浓度。单纯ADSCs移植治疗不能明显改变PAH大鼠代谢模式。结论 APN基因修饰ADSCs移植治疗可以改善MCT诱导的PAH大鼠的Warburg效应和丙氨酸代谢异常,这是其进一步降低肺动脉压和改善血管重构的重要机制。单纯ADSCs移植治疗对PAH大鼠的代谢模式影响不明显。

Objective To observe the effect of adipose stem cells （ ADSCs） and APN gene-modified ADSCs transplantation on the metabolic profiles in MCT induced PAH rats.Methods Forty SD rats were randomly divided into normal control （ NC group） ,pulmonary hy-pertension group （ PAH group） ,ADSCs therapy group （ ADSCs group） ,empty lentiviral vector infected ADSCs group （ ADSCs-V group） and APN gene modified ADSCs （ADSCs-APN group）.1.0×10^6 cells/ml suspension,including with ADSCs,empty lentiviral vector infected AD-SCs or APN gene modified ADSCs,were injected into ADSCs group,ADSCs-V group or ADSCs-APN group through left jugular vein,respec-tively.Three weeks after cells transplantation,the serum was collected and the differences of plasma metabolites were detected by NMR-based metabonomics technology.Chenomx NMR Suite 8.0 software was used,the data of metabolites were analyzed by principal components analysis （ PCA） and partial least squares-discriminate analysis （ PLS-DA） .The quality of PLS-DA model was evaluated by arrangement detection test （ Permutation test） method.Results The levels of serum glucose and serum lactate were significantly elevated,and the levels of serum ala-nine were significantly reduced in PAH rats.Transplantation of APN gene-modified ADSCs could significantly decrease the levels of serum glucose and serum lactate and increase the levels of serum alanine.ADSCs transplantation therapy alone did not significantly alter the meta-bolic profiles in PAH rats.Conclusions The transplantation of APN gene-modified ADSCs could improve Warburg effect and alanine metab-olism in PAH rats,which is an important mechanism to further reduce pulmonary artery pressure and improve vascular remodeling.ADSCs transplantation obviously has no effect on metabolism profiles in PAH rats.