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Cell Stem Cell. 2017 Apr 6;20(4):490-504.e5. doi: 10.1016/j.stem.2016.08.019. Epub 2016 Dec 22.

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

Author information

1
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.
2
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
3
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
4
Department of Pediatrics, Vanderbilt University, Nashville, TN 37232, USA.
5
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
6
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: joewu@stanford.edu.
7
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: mpsnyder@stanford.edu.
8
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. Electronic address: marlener@stanford.edu.

Abstract

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:

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

PMID:
28017794
PMCID:
PMC5500296
DOI:
10.1016/j.stem.2016.08.019
[Indexed for MEDLINE]
Free PMC Article

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