Gu Mingxia, Shao Ning-Yi, Sa Silin, Li Dan, Termglinchan Vittavat, Ameen Mohamed, Karakikes Ioannis, Sosa Gustavo, Grubert Fabian, Lee Jaecheol, Cao Aiqin, Taylor Shalina, Ma Yu, Zhao Zhixin, Chappell James, Hamid Rizwan, Austin Eric D, Gold Joseph D, Wu Joseph C, Snyder Michael P, Rabinovitch Marlene
Vera Moulton Wall Center for Pulmonary Vascular Diseases, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Cell Stem Cell. 2017 Apr 6;20(4):490-504.e5. doi: 10.1016/j.stem.2016.08.019. Epub 2016 Dec 22.
In familial pulmonary arterial hypertension (FPAH), the autosomal dominant disease-causing BMPR2 mutation is only 20% penetrant, suggesting that genetic variation provides modifiers that alleviate the disease. Here, we used comparison of induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) from three families with unaffected mutation carriers (UMCs), FPAH patients, and gender-matched controls to investigate this variation. Our analysis identified features of UMC iPSC-ECs related to modifiers of BMPR2 signaling or to differentially expressed genes. FPAH-iPSC-ECs showed reduced adhesion, survival, migration, and angiogenesis compared to UMC-iPSC-ECs and control cells. The "rescued" phenotype of UMC cells was related to an increase in specific BMPR2 activators and/or a reduction in inhibitors, and the improved cell adhesion could be attributed to preservation of related signaling. The improved survival was related to increased BIRC3 and was independent of BMPR2. Our findings therefore highlight protective modifiers for FPAH that could help inform development of future treatment strategies.
在家族性肺动脉高压（FPAH）中，常染色体显性致病基因BMPR2突变的外显率仅为20%，这表明基因变异提供了减轻该疾病的修饰因子。在此，我们通过比较来自三个家族的诱导多能干细胞衍生的内皮细胞（iPSC-ECs）来研究这种变异，这些家族中有未受影响的突变携带者（UMCs）、FPAH患者以及性别匹配的对照。我们的分析确定了UMC iPSC-ECs中与BMPR2信号修饰因子或差异表达基因相关的特征。与UMC-iPSC-ECs和对照细胞相比，FPAH-iPSC-ECs的黏附、存活、迁移和血管生成能力降低。UMC细胞的“挽救”表型与特定BMPR2激活剂的增加和/或抑制剂的减少有关，细胞黏附的改善可归因于相关信号的保留。存活的改善与BIRC3的增加有关，且与BMPR2无关。因此，我们的研究结果突出了FPAH的保护性修饰因子，这有助于为未来治疗策略的开发提供信息。
