title: Engineering vascular tissue with functional smooth muscle cells derived from human iPS cells and nanofibrous scaffolds.
abstract: Tissue-engineered blood vessels (TEBVs) are promising in the replacement of diseased vascular tissues. However, it remains a great challenge to obtain a sufficient number of functional smooth muscle cells (SMCs) in a clinical setting to construct patient-specific TEBVs. In addition, it is critical to develop a scaffold to accommodate these cells and retain their functional phenotype for the regeneration of TEBVs. In this study, human induced pluripotent stem cells (iPSCs) were established from primary human aortic fibroblasts, and characterized with the pluripotency markers expression and cells' capabilities to differentiate into all three germ layer cells. A highly efficient method was then developed to induce these human iPSCs into proliferative SMCs. After multiple times of expansion, the expanded SMCs retained the potential to be induced into the functional contractile phenotype of mature SMCs, which was characterized by the contractile response to carbachol treatment, up-regulation of specific collagen genes under transforming growth factor β1 treatment, and up-regulation of specific matrix metalloproteinase genes under cytokine stimulation. We also developed an advanced macroporous and nanofibrous (NF) poly(l-lactic acid) (PLLA) scaffold with suitable pore size and interpore connectivity to seed these human iPSC-derived SMCs and maintain their differentiated phenotype. Subcutaneous implantation of the SMC-scaffold construct in nude mice demonstrated vascular tissue formation, with robust collagenous matrix deposition inside the scaffold and the maintenance of differentiated SMC phenotype. Taken together, this study established an exciting approach towards the construction of patient-specific TEBVs. We established patient-specific human iPSCs, derived proliferative SMCs for expansion, turned on their mature contractile SMC phenotype, and developed an advanced scaffold for these cells to regenerate vascular tissue in vivo.
authors.affiliation: Department of Cardiac Surgery, Cardiovascular Center, The University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Yongyu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Biologic and Materials Sciences, The University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Cardiac Surgery, Cardiovascular Center, The University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Jiao
authors.initials: J
authors.lastname: Jiao
authors.affiliation: Department of Biologic and Materials Sciences, The University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Zhongning
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Cardiac Surgery, Cardiovascular Center, The University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Department of Biologic and Materials Sciences, The University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Department of Molecular Genetics & Microbiology, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Lung-Ji
authors.initials: LJ
authors.lastname: Chang
authors.affiliation: Department of Cardiac Surgery, Cardiovascular Center, The University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: echenum@umich.edu.
authors.forename: Y Eugene
authors.initials: YE
authors.lastname: Chen
authors.affiliation: Department of Biologic and Materials Sciences, The University of Michigan, Ann Arbor, MI 48109, USA; Department of Biomedical Engineering, The University of Michigan, Ann Arbor, MI 48109, USA; Macromolecular Science and Engineering Center, The University of Michigan, Ann Arbor, MI 48109, USA; Department of Materials Science and Engineering, The University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: mapx@umich.edu.
authors.forename: Peter X
authors.initials: PX
authors.lastname: Ma
authors.affiliation: Department of Cardiac Surgery, Cardiovascular Center, The University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: boya@umich.edu.
authors.forename: Bo
authors.initials: B
authors.lastname: Yang
mesh_terms: D001808:Blood Vessels / Q000737:chemistry / Q000166:cytology; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D019344:Lactic Acid / Q000737:chemistry; D008855:Microscopy, Electron, Scanning; D009119:Muscle Contraction; D032389:Myocytes, Smooth Muscle / Q000166:cytology*; D057139:Nanofibers / Q000737:chemistry*; D010641:Phenotype; D011091:Polyesters; D011108:Polymers / Q000737:chemistry; D012038:Regeneration; D023822:Tissue Engineering / Q000379:methods*; D054457:Tissue Scaffolds / Q000737:chemistry*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D011091:Polyesters; D011108:Polymers; D053773:Transforming Growth Factor beta1; D019344:Lactic Acid; C033616:poly(lactide)
keywords: Human induced pluripotent stem cell; Nanofibrous scaffold; Smooth muscle cell; Tissue-engineered vascular tissue
references.citation: Biomaterials. 2011 Jul;32(19):4369-75
references.pmid: 21439638
references.citation: Biomaterials. 2009 Mar;30(8):1542-50
references.pmid: 19111338
references.citation: Circ Res. 2006 Jan 6;98(1):25-35
references.pmid: 16397155
references.citation: Yale J Biol Med. 2008 Dec;81(4):161-6
references.pmid: 19099046
references.citation: Tissue Eng. 2002 Apr;8(2):225-34
references.pmid: 12031112
references.citation: Curr Gene Ther. 2001 Sep;1(3):237-51
references.pmid: 12109139
references.citation: Tissue Eng Part B Rev. 2012 Oct;18(5):405-25
references.pmid: 22571595
references.citation: Circ Res. 2013 Feb 1;112(3):523-33
references.pmid: 23371901
references.citation: Biomaterials. 2010 Nov;31(31):7971-7
references.pmid: 20673997
references.citation: PLoS One. 2012;7(4):e35580
references.pmid: 22545119
references.citation: Circulation. 2003 Apr 29;107(16):2078-81
references.pmid: 12707231
references.citation: Sci Transl Med. 2011 Feb 2;3(68):68ra9
references.pmid: 21289273
references.citation: J Am Coll Cardiol. 2012 Dec 25;60(25 Suppl):S1-49
references.pmid: 23257320
references.citation: Stem Cells Transl Med. 2012 Jul;1(7):566-71
references.pmid: 23197861
references.citation: Proc Natl Acad Sci U S A. 2011 Feb 15;108(7):2705-10
references.pmid: 21282618
references.citation: Arterioscler Thromb Vasc Biol. 2007 Dec;27(12):e311-2
references.pmid: 18029907
references.citation: J Vasc Surg. 1993 Mar;17(3):499-509
references.pmid: 8445745
references.citation: Biomaterials. 2000 Nov;21(22):2215-31
references.pmid: 11026628
references.citation: Proc Natl Acad Sci U S A. 2006 Aug 8;103(32):12167-72
references.pmid: 16880387
references.citation: Science. 1999 Apr 16;284(5413):489-93
references.pmid: 10205057
references.citation: J Clin Invest. 2005 Jan;115(1):118-27
references.pmid: 15630451
references.citation: Blood. 1993 Jul 1;82(1):66-76
references.pmid: 8324235
references.citation: Ann Vasc Surg. 2005 May;19(3):448-56
references.pmid: 15864472
references.citation: Nat Med. 2003 Jun;9(6):685-93
references.pmid: 12778167