Cell Stem Cell
Volume 20, Issue 4, 6 April 2017, Pages 490-504.e5
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Article
Patient-Specific iPSC-Derived Endothelial Cells Uncover Pathways that Protect against Pulmonary Hypertension in BMPR2 Mutation Carriers

https://doi.org/10.1016/j.stem.2016.08.019Get rights and content
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Highlights

  • Normal function distinguishes iPSC-ECs from unaffected BMPR2 mutation carrier (UMC)

  • Protective BMPR2 modifiers preserve pP38 signaling and adhesion in UMC iPSC-ECs

  • Increased BIRC3 in UMC iPSC-ECs is related to normalization of EC survival

  • Correction of the BMPR2 mutation in PAH iPSC-ECs restores signaling and EC function

Summary

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.

Keywords

pulmonary arterial hypertension
endothelial dysfunction
bone morphogenetic protein receptor 2
unaffected mutation carrier
penetrance
cell adhesion
cell survival
induced pluripotent stem cell-derived endothelial cell
transcriptomic analysis
cell signaling

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