Patient-Specific iPSC-Derived Endothelial Cells Uncover Pathways that Protect against Pulmonary Hypertension in BMPR2 Mutation Carriers.
Patient-Specific iPSC-Derived Endothelial Cells Uncover Pathways that Protect against Pulmonary Hypertension in BMPR2 Mutation Carriers.
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DOI：
10.1016/j.stem.2016.08.019
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发表时间：
2017-04-06
期刊：
影响因子：
23.9
通讯作者：
Rabinovitch M
中科院分区：
文献类型：
--
作者：
Gu M;Shao NY;Sa S;Li D;Termglinchan V;Ameen M;Karakikes I;Sosa G;Grubert F;Lee J;Cao A;Taylor S;Ma Y;Zhao Z;Chappell J;Hamid R;Austin ED;Gold JD;Wu JC;Snyder MP;Rabinovitch M
在家族性肺动脉高压（FPAH）中，常染色体显性致病的BMPR2突变只有20%的渗透性，这表明遗传变异提供了缓解疾病的修饰因子。在这里，我们比较了来自三个未受影响突变携带者（UMCs）、FPAH患者和性别匹配对照的家族的诱导多能干细胞来源的内皮细胞（iPSC-ECs）来研究这种变异。我们的分析确定了UMC ipsc - ec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的粘附、存活、迁移和血管生成均有所降低。UMC细胞的“获救”表型与特异性BMPR2激活因子的增加和/或抑制剂的减少有关，并且细胞粘附的改善可归因于相关信号的保存。生存率的提高与BIRC3升高有关，与BMPR2无关。因此，我们的研究结果强调了FPAH的保护性调节剂，可以帮助制定未来的治疗策略。
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 independent of BMPR2. Our findings therefore highlight protective modifiers for FPAH that could help inform development of future treatment strategies.
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BMPR2在氧化过程中保留线粒体功能和DNA，以促进内皮细胞的存活和反向肺动脉高压。
影响因子：
29
作者：
Diebold I;Hennigs JK;Miyagawa K;Li CG;Nickel NP;Kaschwich M;Cao A;Wang L;Reddy S;Chen PI;Nakahira K;Alcazar MA;Hopper RK;Ji L;Feldman BJ;Rabinovitch M
通讯作者：
Rabinovitch M
DOI：
10.1083/jcb.121.1.163
发表时间：
1993-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Leavesley DI;Schwartz MA;Rosenfeld M;Cheresh DA
通讯作者：
Cheresh DA
影响因子：
10
作者：
Chaouat, A;Coulet, F;Humbert, M
通讯作者：
Humbert, M
影响因子：
48
作者：
Burridge, Paul W.;Matsa, Elena;Shukla, Praveen;Lin, Ziliang C.;Churko, Jared M.;Ebert, Antje D.;Lan, Feng;Diecke, Sebastian;Huber, Bruno;Mordwinkin, Nicholas M.;Plews, Jordan R.;Abilez, Oscar J.;Cui, Bianxiao;Gold, Joseph D.;Wu, Joseph C.
通讯作者：
Wu, Joseph C.
影响因子：
7.3
作者：
Eichler, I;Wibawa, J;Köhler, R
通讯作者：
Köhler, R