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

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  • Additional Information
    • Source:
      Publisher: Cell Press Country of Publication: United States NLM ID: 101311472 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1875-9777 (Electronic) Linking ISSN: 18759777 NLM ISO Abbreviation: Cell Stem Cell Subsets: MEDLINE
    • Publication Information:
      Original Publication: Cambridge, MA : Cell Press
    • Subject Terms:
      Bone Morphogenetic Protein Receptors, Type II/*genetics ; Endothelial Cells/*cytology ; Hypertension, Pulmonary/*genetics ; Hypertension, Pulmonary/*prevention & control ; Induced Pluripotent Stem Cells/*cytology ; Mutation/*genetics; Base Sequence ; Bone Morphogenetic Protein 4/pharmacology ; Cell Adhesion/drug effects ; Cell Movement/drug effects ; Cell Shape/drug effects ; Cell Survival/drug effects ; Endothelial Cells/drug effects ; Endothelial Cells/metabolism ; Gene Editing ; Gene Expression Regulation/drug effects ; Heterozygote ; Humans ; Hypertension, Pulmonary/pathology ; Induced Pluripotent Stem Cells/drug effects ; Induced Pluripotent Stem Cells/metabolism ; Neovascularization, Physiologic/drug effects ; Neovascularization, Physiologic/genetics ; Phosphorylation/drug effects ; Sequence Analysis, RNA ; Signal Transduction/drug effects ; Smad Proteins/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism
    • 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.
      (Copyright © 2017 Elsevier Inc. All rights reserved.)
    • Comments:
      Comment in: Stem Cell Investig. 2017 May 05;4:35. doi: 10.21037/sci.2017.04.05. (PMID: 28607909)
      Comment in: Stem Cell Investig. 2017 Jun 13;4:53. doi: 10.21037/sci.2017.05.10. (PMID: 28725649)
      Comment in: Stem Cell Investig. 2017 Jun 14;4:56. doi: 10.21037/sci.2017.05.11. (PMID: 28725652)
    • References:
      J Biol Chem. 2013 Jan 11;288(2):1365-73. (PMID: 23148224)
      J Clin Invest. 2011 Sep;121(9):3735-46. (PMID: 21821917)
      J Cell Biol. 1993 Apr;121(1):163-70. (PMID: 7681432)
      Eur Heart J. 2015 Apr 1;36(13):806-16. (PMID: 25368203)
      Circ Res. 2012 Aug 17;111(5):564-74. (PMID: 22777006)
      Antioxid Redox Signal. 2002 Oct;4(5):833-43. (PMID: 12470512)
      Hum Mutat. 2009 Apr;30(4):649-54. (PMID: 19206171)
      Am J Respir Cell Mol Biol. 2012 Jul;47(1):20-7. (PMID: 22312021)
      Am J Respir Crit Care Med. 2015 Jun 1;191(11):1273-86. (PMID: 25853696)
      N Engl J Med. 2013 Jul 25;369(4):351-61. (PMID: 23883380)
      Am J Respir Crit Care Med. 2015 Aug 1;192(3):356-66. (PMID: 26030479)
      Nat Genet. 2000 Sep;26(1):81-4. (PMID: 10973254)
      Genet Med. 2008 May;10(5):359-65. (PMID: 18496036)
      Circulation. 2012 Oct 2;126(14):1695-704. (PMID: 22914687)
      Pharmacol Rev. 2001 Jun;53(2):319-56. (PMID: 11356987)
      Circ Res. 2012 Dec 7;111(12):1551-64. (PMID: 23011394)
      Thorax. 2004 May;59(5):446-8. (PMID: 15115879)
      Circ Cardiovasc Genet. 2012 Jun;5(3):336-43. (PMID: 22474227)
      J Clin Invest. 2012 Dec;122(12):4306-13. (PMID: 23202738)
      J Med Genet. 2003 Dec;40(12 ):865-71. (PMID: 14684682)
      Nat Genet. 2008 Feb;40(2):243-8. (PMID: 18176565)
      Am J Physiol Cell Physiol. 2011 May;300(5):C968-9. (PMID: 21389280)
      Cell Metab. 2015 Apr 7;21(4):596-608. (PMID: 25863249)
      Proc Natl Acad Sci U S A. 2014 Dec 2;111(48):17224-9. (PMID: 25413365)
      Nat Protoc. 2007;2(2):329-33. (PMID: 17406593)
      Circulation. 2016 May 3;133(18):1783-94. (PMID: 27045138)
      Int J Biochem Cell Biol. 2014 Oct;55:109-18. (PMID: 25161149)
      J Cell Biol. 1989 Nov;109(5):2455-62. (PMID: 2530239)
      J Cell Sci. 2005 Aug 1;118(Pt 15):3471-85. (PMID: 16079289)
      Am J Respir Cell Mol Biol. 2013 Sep;49(3):403-9. (PMID: 23590310)
      Biol Reprod. 2013 Oct 24;89(4):97. (PMID: 23966325)
      BMC Med Genomics. 2008 Sep 29;1:45. (PMID: 18823550)
      Circulation. 1993 Apr;87(4):1264-74. (PMID: 8384938)
      J Cell Biol. 2009 Jan 12;184(1):83-99. (PMID: 19139264)
      Am J Pathol. 2006 Jan;168(1):331-9. (PMID: 16400034)
      Exp Physiol. 2014 Oct;99(10):1427-38. (PMID: 25037566)
      Cell. 2015 Mar 12;160(6):1072-86. (PMID: 25768904)
      Br J Pharmacol. 2003 Feb;138(4):594-601. (PMID: 12598413)
      J Biol Chem. 2012 Jan 20;287(4):2632-42. (PMID: 22139847)
      Circulation. 2012 Oct 9;126(15):1907-16. (PMID: 22923426)
      Circulation. 2012 Feb 21;125(7):920-30. (PMID: 22247494)
      J Clin Invest. 2013 Aug;123(8):3600-13. (PMID: 23867624)
      Circulation. 2004 Jan 20;109(2):159-65. (PMID: 14734504)
      Br J Pharmacol. 2009 Feb;156(4):545-62. (PMID: 19187341)
      J Biol Chem. 2004 Mar 12;279(11):10005-12. (PMID: 14699139)
    • Grant Information:
      R01 HL102020 United States HL NHLBI NIH HHS; U01 HG007674 United States HG NHGRI NIH HHS; K99 HL135258 United States HL NHLBI NIH HHS; U01 HL107393 United States HL NHLBI NIH HHS; K12 HL120001 United States HL NHLBI NIH HHS; R01 HL122887 United States HL NHLBI NIH HHS
    • Contributed Indexing:
      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
    • Accession Number:
      0 (Bone Morphogenetic Protein 4)
      0 (Smad Proteins)
      EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
      EC 2.7.11.30 (BMPR2 protein, human)
      EC 2.7.11.30 (Bone Morphogenetic Protein Receptors, Type II)
    • Publication Date:
      Date Created: 20161227 Date Completed: 20170731 Latest Revision: 20230207
    • Publication Date:
      20250114
    • Accession Number:
      PMC5500296
    • Accession Number:
      10.1016/j.stem.2016.08.019
    • Accession Number:
      28017794