Patient-Specific iPSC-Derived Endothelial Cells Uncover Pathways that Protect against Pulmonary Hypertension in BMPR2 Mutation Carriers

Publication date: Available online 22 December 2016
Source:Cell Stem Cell
Author(s): Mingxia Gu, Ning-Yi Shao, Silin Sa, Dan Li, Vittavat Termglinchan, Mohamed Ameen, Ioannis Karakikes, Gustavo Sosa, Fabian Grubert, Jaecheol Lee, Aiqin Cao, Shalina Taylor, Yu Ma, Zhixin Zhao, James Chappell, Rizwan Hamid, Eric D. Austin, Joseph D. Gold, Joseph C. Wu, Michael P. Snyder, Marlene Rabinovitch
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.

Graphical abstract

Teaser

As part of the NHLBI NextGen consortium, Gu et al. report protective mechanisms of potential therapeutic significance in unaffected BMPR2 mutation carrier (UMC) iPSC-derived endothelial cells (iPSC-ECs) versus iPSC-ECs from family members with pulmonary arterial hypertension (FPAH). Their findings about changes in specific regulators could inform future therapy development.


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