Modeling elastin-associated vasculopathy with patient induced pluripotent stem cells and tissue engineering

Abstract

Elastin-associated vasculopathies are life-threatening conditions of blood vessel dysfunction. The extracellular matrix protein elastin endows the recoil and compliance required for physiologic arterial function, while disruption of function can lead to aberrant vascular smooth muscle cell proliferation manifesting through stenosis, aneurysm, or vessel dissection. Although research efforts have been informative, they remain incomplete as no viable therapies exist outside of a heart transplant. Induced pluripotent stem cell technology may be uniquely suited to address current obstacles as these present a replenishable supply of patient-specific material with which to study disease. The following review will cover the cutting edge in vascular smooth muscle cell modeling of elastin-associated vasculopathy, and aid in the development of human disease modeling and drug screening approaches to identify potential treatments. Vascular proliferative disease can affect up to 50% of the population throughout the world, making this a relevant and critical area of research for therapeutic development.

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Abbreviations

VSMC:

Vascular smooth muscle cell

References

  1. 1.

    Christiano AM, Uitto J (1994) Molecular pathology of the elastic fibers. J Investig Dermatol 103(5, Supplement):S53–S57

    Article  Google Scholar 

  2. 2.

    Holst J et al (2010) Substrate elasticity provides mechanical signals for the expansion of hemopoietic stem and progenitor cells. Nat Biotechnol 28:1123

    PubMed  CAS  Article  Google Scholar 

  3. 3.

    Liu S-L et al (2015) Matrix metalloproteinase-12 is an essential mediator of acute and chronic arterial stiffening. Sci Rep 5:17189

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  4. 4.

    Parks WC et al (1988) Developmental regulation of tropoelastin isoforms. J Biol Chem 263(9):4416–4423

    PubMed  CAS  Google Scholar 

  5. 5.

    Swee MH, Parks WC, Pierce RA (1995) Developmental regulation of elastin production: expression of tropoelastin pre-mRNA persists after down-regulation of steady-state mRNA levels. J Biol Chem 270(25):14899–14906

    PubMed  CAS  Article  Google Scholar 

  6. 6.

    Sakai LY, Keene DR, Engvall E (1986) Fibrillin, a new 350-kD glycoprotein, is a component of extracellular microfibrils. J Cell Biol 103(6):2499

    PubMed  CAS  Article  Google Scholar 

  7. 7.

    Trask TM et al (2000) Interaction of tropoelastin with the amino-terminal domains of fibrillin-1 and fibrillin-2 suggests a role for the fibrillins in elastic fiber assembly. J Biol Chem 275(32):24400–24406

    PubMed  CAS  Article  Google Scholar 

  8. 8.

    Pfaff M et al (1996) Cell adhesion and integrin binding to recombinant human fibrillin-1. FEBS Lett 384(3):247–250

    PubMed  CAS  Article  Google Scholar 

  9. 9.

    Tiedemann K et al (2001) Interactions of fibrillin-1 with heparin/heparan sulfate, implications for microfibrillar assembly. J Biol Chem 276(38):36035–36042

    PubMed  CAS  Article  Google Scholar 

  10. 10.

    Yanagisawa H et al (2002) Fibulin-5 is an elastin-binding protein essential for elastic fibre development in vivo. Nature 415:168

    PubMed  Article  Google Scholar 

  11. 11.

    Ge X et al (2012) Modeling supravalvular aortic stenosis syndrome using human induced pluripotent stem cells. Circulation 126(14):1695–1704

    PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    Karnik SK et al (2003) A critical role for elastin signaling in vascular morphogenesis and disease. Development 130(2):411

    PubMed  CAS  Article  Google Scholar 

  13. 13.

    Karnik SK et al (2003) Elastin induces myofibrillogenesis via a specific domain, VGVAPG. Matrix Biol 22(5):409–425

    PubMed  CAS  Article  Google Scholar 

  14. 14.

    Lee P et al (2014) A novel cell adhesion region in tropoelastin mediates attachment to integrin αVβ5. J Biol Chem 289(3):1467–1477

    PubMed  CAS  Article  Google Scholar 

  15. 15.

    Misra A et al (2016) Integrin β3 inhibition is a therapeutic strategy for supravalvular aortic stenosis. J Exp Med 213(3):451–463

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  16. 16.

    Wilson BD et al (2011) Novel approach for endothelializing vascular devices: understanding and exploiting elastin-endothelial interactions. Ann Biomed Eng 39(1):337–346

    PubMed  Article  Google Scholar 

  17. 17.

    Broekelmann TJ et al (2005) Tropoelastin interacts with cell-surface glycosaminoglycans via its COOH-terminal domain. J Biol Chem 280(49):40939–40947

    PubMed  CAS  Article  Google Scholar 

  18. 18.

    Mochizuki S, Brassart B, Hinek A (2002) Signaling pathways transduced through the elastin receptor facilitate proliferation of arterial smooth muscle cells. J Biol Chem 277(47):44854–44863

    PubMed  CAS  Article  Google Scholar 

  19. 19.

    Cordes KR et al (2009) miR-145 and miR-143 regulate smooth muscle cell fate decisions. Nature 460(7256):705–710

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  20. 20.

    Xie W-B et al (2013) Smad2 and MRTFB cooperatively regulate vascular smooth muscle differentiation from neural crest cells. Circ Res 113(8):p. https://doi.org/10.1161/CIRCRESAHA.113.301921

    CAS  Article  Google Scholar 

  21. 21.

    Carta L et al (2009) p38 MAPK is an early determinant of promiscuous Smad2/3 signaling in the aortas of fibrillin-1 (Fbn1)-null mice. J Biol Chem 284(9):5630–5636

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  22. 22.

    Thyberg J (1996) Differentiated properties and proliferation of arterial smooth muscle cells in culture. In: Jeon KW (ed) International review of cytology. Academic Press, Cambridge, pp 183–265

    Google Scholar 

  23. 23.

    Ferruzzi J et al (2011) Mechanical assessment of elastin integrity in fibrillin-1-deficient carotid arteries: implications for Marfan syndrome. Cardiovasc Res 92(2):287–295

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  24. 24.

    Li DY et al (1998) Elastin is an essential determinant of arterial morphogenesis. Nature 393:276

    PubMed  CAS  Article  Google Scholar 

  25. 25.

    Nakamura T et al (2002) Fibulin-5/DANCE is essential for elastogenesis in vivo. Nature 415:171

    PubMed  CAS  Article  Google Scholar 

  26. 26.

    Spencer JA et al (2005) Altered vascular remodeling in fibulin-5-deficient mice reveals a role of fibulin-5 in smooth muscle cell proliferation and migration. Proc Natl Acad Sci USA 102(8):2946

    PubMed  CAS  Article  Google Scholar 

  27. 27.

    Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4):663–676

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  28. 28.

    Huang H et al (2006) Differentiation of human embryonic stem cells into smooth muscle cells in adherent monolayer culture. Biochem Biophys Res Commun 351(2):321–327

    PubMed  CAS  Article  Google Scholar 

  29. 29.

    Cheung C et al (2014) Modeling cerebrovascular pathophysiology in amyloid-β metabolism using neural-crest-derived smooth muscle cells. Cell Rep 9(1):391–401

    PubMed  CAS  Article  Google Scholar 

  30. 30.

    Granata A et al (2016) An iPSC-derived vascular model of Marfan syndrome identifies key mediators of smooth muscle cell death. Nat Genet 49:97

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Dash Biraja C et al (2016) Tissue-engineered vascular rings from human iPSC-derived smooth muscle cells. Stem Cell Rep 7(1):19–28

    CAS  Article  Google Scholar 

  32. 32.

    Fernandez CE et al (2016) Human vascular microphysiological system for in vitro drug screening. Sci Rep 6:21579

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  33. 33.

    Niklason LE et al (1999) Functional arteries grown in vitro. Science 284(5413):489

    PubMed  CAS  Article  Google Scholar 

  34. 34.

    Quint C et al (2011) Decellularized tissue-engineered blood vessel as an arterial conduit. Proc Natl Acad Sci USA 108(22):9214–9219

    PubMed  CAS  Article  Google Scholar 

  35. 35.

    Gui L et al (2014) Construction of tissue-engineered small-diameter vascular grafts in fibrin scaffolds in 30 days. Tissue Eng Part A 20(9–10):1499–1507

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  36. 36.

    Sundaram S et al (2014) Tissue-engineered vascular grafts created from human induced pluripotent stem cells. Stem Cells Transl Med 3(12):1535–1543

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  37. 37.

    Atchison L et al (2017) A tissue engineered blood vessel model of Hutchinson–Gilford progeria syndrome using human iPSC-derived smooth muscle cells. Sci Rep 7(1):8168

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  38. 38.

    Zhang P et al (2012) Inhibition of microRNA 29 enhances elastin levels in cells haploinsufficient for elastin and in bioengineered vessels. Arterioscler Thromb Vasc Biol 32(3):756–759

    PubMed  CAS  Article  Google Scholar 

  39. 39.

    Topouzis S, Majesky MW (1996) Smooth muscle lineage diversity in the chick embryo: two types of aortic smooth muscle cell differ in growth and receptor-mediated transcriptional responses to transforming growth factor-β. Dev Biol 178(2):430–445

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Jaalouk DE, Lammerding J (2009) Mechanotransduction gone awry. Nat Rev Mol Cell Biol 10(1):63–73

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  41. 41.

    Geiger B, Spatz JP, Bershadsky AD (2009) Environmental sensing through focal adhesions. Nat Rev Mol Cell Biol 10:21

    PubMed  CAS  Article  Google Scholar 

  42. 42.

    DuFort CC, Paszek MJ, Weaver VM (2011) Balancing forces: architectural control of mechanotransduction. Nat Rev Mol Cell Biol 12(5):308–319

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  43. 43.

    Humphrey JD et al (2014) Dysfunctional mechanosensing in aneurysms. Science 344(6183):477

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  44. 44.

    Guo D-C et al (2007) Mutations in smooth muscle α-actin (ACTA2) lead to thoracic aortic aneurysms and dissections. Nat Genet 39:1488

    PubMed  CAS  Article  Google Scholar 

  45. 45.

    Wang L et al (2010) Mutations in myosin light chain kinase cause familial aortic dissections. Am J Hum Genet 87(5):701–707

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  46. 46.

    Zhu L et al (2006) Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus. Nat Genet 38:343

    PubMed  CAS  Article  Google Scholar 

  47. 47.

    Jiao Y et al (2017) Deficient circumferential growth is the primary determinant of aortic obstruction attributable to partial elastin deficiency. Arterioscler Thromb Vasc Biol 37(5):930–941

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  48. 48.

    Pober BR, Johnson M, Urban Z (2008) Mechanisms and treatment of cardiovascular disease in Williams–Beuren syndrome. J Clin Investig 118(5):1606–1615

    PubMed  CAS  Article  Google Scholar 

  49. 49.

    Urbán Z et al (2002) Connection between elastin haploinsufficiency and increased cell proliferation in patients with supravalvular aortic stenosis and Williams–Beuren Syndrome. Am J Hum Genet 71(1):30–44

    PubMed  PubMed Central  Article  Google Scholar 

  50. 50.

    Kumar A et al (2016) Talin tension sensor reveals novel features of focal adhesion force transmission and mechanosensitivity. J Cell Biol 213(3):371

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  51. 51.

    Jiang G et al (2006) Rigidity sensing at the leading edge through α(v)β(3) integrins and RPTPα. Biophys J 90(5):1804–1809

    PubMed  CAS  Article  Google Scholar 

  52. 52.

    Jiao Y et al (2017) mTOR (mechanistic target of rapamycin) inhibition decreases mechanosignaling, collagen accumulation, and stiffening of the thoracic aorta in elastin-deficient mice. Arterioscler Thromb Vasc Biol 37(9):1657–1666

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  53. 53.

    Gui L et al (2016) Implantable tissue-engineered blood vessels from human induced pluripotent stem cells. Biomaterials 102:120–129

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  54. 54.

    Huang AH et al (2016) Biaxial stretch improves elastic fiber maturation, collagen arrangement, and mechanical properties in engineered arteries. Tissue engineering. Part C. Methods 22(6):524–533

    CAS  Google Scholar 

  55. 55.

    Wanjare M, Agarwal N, Gerecht S (2015) Biomechanical strain induces elastin and collagen production in human pluripotent stem cell-derived vascular smooth muscle cells. Am J Physiol Cell Physiol 309(4):C271–C281

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  56. 56.

    Tojais NF et al (2017) Co-dependence of BMPR2 and TGFβ in elastic fiber assembly and its perturbation in pulmonary arterial hypertension. Arterioscler Thromb Vasc Biol 37(8):1559–1569

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  57. 57.

    Huang R et al (2006) Inhibition of versican synthesis by antisense alters smooth muscle cell phenotype and induces elastic fiber formation in vitro and in neointima after vessel injury. Circ Res 98(3):370

    PubMed  CAS  Article  Google Scholar 

  58. 58.

    Jimenez F et al (2006) Ellagic and tannic acids protect newly synthesized elastic fibers from premature enzymatic degradation in dermal fibroblast cultures. J Investig Dermatol 126(6):1272–1280

    PubMed  CAS  Article  Google Scholar 

  59. 59.

    Wu W, Allen RA, Wang Y (2012) Fast degrading elastomer enables rapid remodeling of a cell-free synthetic graft into a neo-artery. Nat Med 18(7):1148–1153

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  60. 60.

    Luo J et al (2017) Vascular smooth muscle cells derived from inbred swine induced pluripotent stem cells for vascular tissue engineering. Biomaterials 147:116–132

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  61. 61.

    Del Monaco M et al (1997) Identification of novel glucocorticoid-response elements in human elastin promoter and demonstration of nucleotide sequence specificity of the receptor binding. J Investig Dermatol 108(6):938–942

    PubMed  Article  Google Scholar 

  62. 62.

    Kähäri VM et al (1990) Deletion analyses of 5′-flanking region of the human elastin gene. Delineation of functional promoter and regulatory cis-elements. J Biol Chem 265(16):9485–9490

    PubMed  Google Scholar 

  63. 63.

    Sugitani H et al (2001) Nitric oxide stimulates elastin expression in chick aortic smooth muscle cells. Biol Pharm Bull 24(5):461–464

    PubMed  CAS  Article  Google Scholar 

  64. 64.

    Wachi H et al (1995) Cell cycle-dependent regulation of elastin gene in cultured chick vascular smooth-muscle cells. Biochem J 309(2):575

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  65. 65.

    Kucich U et al (2002) Transforming growth factor-β stabilizes elastin mRNA by a pathway requiring active Smads, protein kinase C-δ, and p38. Am J Respir Cell Mol Biol 26(2):183–188

    PubMed  CAS  Article  Google Scholar 

  66. 66.

    Marigo V et al (1994) Identification of a TGF-β responsive element in the human elastin promoter. Biochem Biophys Res Commun 199(2):1049–1056

    PubMed  CAS  Article  Google Scholar 

  67. 67.

    Pierce RA, Kolodziej ME, Parks WC (1992) 1,25-Dihydroxyvitamin D3 represses tropoelastin expression by a posttranscriptional mechanism. J Biol Chem 267(16):11593–11599

    PubMed  CAS  Google Scholar 

  68. 68.

    Trapnell C et al (2010) Transcript assembly and abundance estimation from RNA-Seq reveals thousands of new transcripts and switching among isoforms. Nat Biotechnol 28(5):511–515

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  69. 69.

    Chen F, Chisholm AD, Jin Y (2017) Tissue-specific regulation of alternative polyadenylation represses expression of a neuronal ankyrin isoform in C. elegans epidermal development. Development (Camb, Engl) 144(4):698–707

    CAS  Article  Google Scholar 

  70. 70.

    Xia Z et al (2014) Dynamic analyses of alternative polyadenylation from RNA-seq reveal a 3′-UTR landscape across seven tumour types. Nat Commun 5:5274

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  71. 71.

    Raz V et al (2018) The distinct transcriptomes of slow and fast adult muscles are delineated by noncoding RNAs. FASEB J 32(3):1579–1590

    PubMed  CAS  Article  Google Scholar 

  72. 72.

    Ahmad Y et al (2012) Systematic analysis of protein pools, isoforms, and modifications affecting turnover and subcellular localization. Mol Cell Proteom 11(3):p. M111.013680

    Article  CAS  Google Scholar 

  73. 73.

    Dapas M et al (2017) Comparative evaluation of isoform-level gene expression estimation algorithms for RNA-seq and exon-array platforms. Brief Bioinform 18(2):260–269

    PubMed  CAS  Google Scholar 

  74. 74.

    Katz Y et al (2010) Analysis and design of RNA sequencing experiments for identifying isoform regulation. Nat Methods 7(12):1009–1015

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  75. 75.

    Liu Y et al (2017) Impact of alternative splicing on the human proteome. Cell Rep 20(5):1229–1241

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  76. 76.

    Cheung C et al (2012) Generation of human vascular smooth muscle subtypes provides insight into embryological origin-dependent disease susceptibility. Nat Biotechnol 30(2):165–173

    PubMed  PubMed Central  CAS  Article  Google Scholar 

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Acknowledgements

We appreciate the support from Muhammad Riaz (Ph.D.) and Luke Batty (M.S.). This work was supported by NIH 1K02HL101990-01, 1R01HL116705-01, and Connecticut’s Regenerative Medicine Research Fund (CRMRF) 12-SCB-YALE-06 and 15-RMB-YALE-08 (all to Y.Q.). Work was also supported by an NIH Institutional Pre-Doctoral Pharmacology Training Program Fellowship T32-GM0007324 (M.E.) directed by Dr. Anton Bennett at Yale.

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Correspondence to Yibing Qyang.

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Ellis, M.W., Luo, J. & Qyang, Y. Modeling elastin-associated vasculopathy with patient induced pluripotent stem cells and tissue engineering. Cell. Mol. Life Sci. 76, 893–901 (2019). https://doi.org/10.1007/s00018-018-2969-7

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Keywords

  • Elastin
  • Disease modeling
  • Engineering
  • Induced pluripotent stem cells