title: Patient-Specific iPSC-Derived Endothelial Cells Uncover Pathways that Protect against Pulmonary Hypertension in BMPR2 Mutation Carriers.
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.
authors.affiliation: 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.
authors.forename: Mingxia
authors.initials: M
authors.lastname: Gu
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Ning-Yi
authors.initials: NY
authors.lastname: Shao
authors.affiliation: 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.
authors.forename: Silin
authors.initials: S
authors.lastname: Sa
authors.affiliation: 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.
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Vittavat
authors.initials: V
authors.lastname: Termglinchan
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Ameen
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Karakikes
authors.affiliation: 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.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Sosa
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Fabian
authors.initials: F
authors.lastname: Grubert
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Jaecheol
authors.initials: J
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Aiqin
authors.initials: A
authors.lastname: Cao
authors.affiliation: 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.
authors.forename: Shalina
authors.initials: S
authors.lastname: Taylor
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Zhixin
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: James
authors.initials: J
authors.lastname: Chappell
authors.affiliation: Department of Pediatrics, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Rizwan
authors.initials: R
authors.lastname: Hamid
authors.affiliation: Department of Pediatrics, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Austin
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Gold
authors.affiliation: 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.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Snyder
authors.affiliation: 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.
authors.forename: Marlene
authors.initials: M
authors.lastname: Rabinovitch
mesh_terms: D001483:Base Sequence; D055415:Bone Morphogenetic Protein 4 / Q000494:pharmacology; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D000072669:Gene Editing; D005786:Gene Expression Regulation / Q000187:drug effects; D006579:Heterozygote; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control*; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D017423:Sequence Analysis, RNA; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D055415:Bone Morphogenetic Protein 4; D051785:Smad Proteins; D048051:p38 Mitogen-Activated Protein Kinases; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II
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