Induced Pluripotent Stem Cell Model of Pulmonary Arterial Hypertension Reveals Novel Gene Expression and Patient Specificity
Induced Pluripotent Stem Cell Model of Pulmonary Arterial Hypertension Reveals Novel Gene Expression and Patient Specificity
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DOI：
10.1164/rccm.201606-1200oc
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发表时间：
2017-04-01
影响因子：
24.7
通讯作者：
Rabinovitch, Marlene
中科院分区：
文献类型：
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作者：
Sa, Silin;Gu, Mingxia;Rabinovitch, Marlene
原理：特发性或遗传性肺动脉高压的特征是肺血管的损失和闭塞。内皮细胞功能障碍是病理生理学的关键，但不同的因果机制可能反映了对患者定制治疗的需求。目的：将从诱导多能干细胞分化的内皮细胞与来自同一特发性或遗传性肺动脉高压患者的肺动脉内皮细胞进行比较，以确定它们是否具有与未使用的供体细胞不同的功能异常和改变的基因表达模式。然后，我们研究了是否内皮细胞分化的多能细胞可以作为替代品，以测试新兴therapy.Methods：评估功能的变化，包括粘附，迁移，管的形成，和凋亡的倾向。骨形态发生蛋白受体2型（BMPR 2）及其靶点IV型胶原蛋白的表达，母体磷酸化形式的信号传导对抗十肢瘫痪蛋白（pSMAD 1/5），并且还分析了转录组谱。天然肺动脉和诱导多能干细胞-与对照受试者相比，来自特发性和遗传性肺动脉高压患者的内皮细胞显示出相似的粘附，迁移，存活和管形成，并降低BMPR 2和下游信号传导和胶原IV表达。转录组学分析揭示了与减少的迁移相关的高kisspeptin 1（KISS）和与患者细胞中受损的存活相关的低羧酸酯酶1（CES 1）。一个有益的血管生成反应的潜在疗法，FK 506和Elafin，是有关减少狭缝导向配体3（SLIT 3），antimigratory factor.Conclusions：尽管在肺部的疾病的网站，我们的研究表明，诱导多能干细胞衍生的内皮细胞是有用的替代品，发现新的功能相关的疾病机制，并更好地匹配患者的治疗。
Rationale: Idiopathic or heritable pulmonary arterial hypertension is characterized by loss and obliteration of lung vasculature. Endothelial cell dysfunction is pivotal to the pathophysiology, but different causal mechanisms may reflect a need for patient-tailored therapies.Objectives: Endothelial cells differentiated from induced pluripotent stem cells were compared with pulmonary arterial endothelial cells from the same patients with idiopathic or heritable pulmonary arterial hypertension, to determine whether they shared functional abnormalities and altered gene expression patterns that differed from those in unused donor cells. We then investigated whether endothelial cells differentiated from pluripotent cells could serve as surrogates to test emerging therapies.Methods: Functional changes assessed included adhesion, migration, tube formation, and propensity to apoptosis. Expression of bone morphogenetic protein receptor type, 2 (BMPR2) and its target, collagen IV, signaling of the phosphorylated form of the mothers against decapentaplegic proteins (pSMAD1/5), and transcriptomic profiles were also analyzed.Measurements and Main Results: Native pulmonary arterial and induced pluripotent stem cell-derived endothelial cells from patients with idiopathic and heritable pulmonary arterial hypertension compared with control subjects showed a similar reduction in adhesion, migration, survival, and tube formation, and decreased BMPR2 and downstream signaling and collagen IV expression. Transcriptomic profiling revealed high kisspeptin 1 (KISS]) related to reduced migration and low carboxylesterase 1 (CES1), to impaired survival in patient cells. A beneficial angiogenic response to potential therapies, FK506 and Elafin, was related to reduced slit guidance ligand 3 (SLIT3), an antimigratory factor.Conclusions: Despite the site of disease in the lung, our study indicates that induced pluripotent stem cell-derived endothelial cells are useful surrogates to uncover novel features related to disease mechanisms and to better match patients to therapies.