Pulmonary-arterial-hypertension (PAH)-on-a-chip: fabrication, validation and application

被引:21
作者
Al-Hilal, Taslim A. [1 ,9 ]
Keshavarz, Ali [1 ]
Kadry, Hossam [1 ]
Lahooti, Behnaz [1 ]
Al-Obaida, Ahmed [1 ]
Ding, Zhenya [2 ]
Li, Wei [2 ]
Kamm, Roger [3 ,4 ]
McMurtry, Ivan F. [5 ]
Lahm, Tim [6 ,7 ]
Nozik-Grayck, Eva [8 ]
Stenmark, Kurt R. [8 ]
Ahsan, Fakhrul [1 ]
机构
[1] Texas Tech Univ, Jerry H Hodge Sch Pharm, Dept Pharmaceut Sci, Hlth Sci Ctr, 1300 Coulter Dr, Amarillo, TX 79119 USA
[2] Texas Tech Univ, Dept Chem Engn, Lubbock, TX 79409 USA
[3] MIT, Dept Mech Engn, Cambridge, MA 02139 USA
[4] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA
[5] Univ S Alabama, Ctr Lung Biol, Dept Pharmacol, Mobile, AL 36688 USA
[6] Indiana Univ Sch Med, Dept Pulm & Crit Care, Dept Med, Indianapolis, IN 46202 USA
[7] Richard L Roudebush Vet Affairs Med Ctr, 1481 W 10th St, Indianapolis, IN 46202 USA
[8] Univ Colorado Denver, Dept Pediat & Med, Cardiovasc Pulm Res Labs, Anschutz Med Campus, Aurora, CO 80045 USA
[9] Univ Texas El Paso, Dept Pharmaceut Sci, El Paso, TX 79968 USA
关键词
TO-MESENCHYMAL TRANSITION; PATHOGENESIS; DISEASE; FASUDIL; MODELS; TARGET; CELLS;
D O I
10.1039/d0lc00605j
中图分类号
Q5 [生物化学];
学科分类号
071010 ; 081704 ;
摘要
Currently used animal and cellular models for pulmonary arterial hypertension (PAH) only partially recapitulate its pathophysiology in humans and are thus inadequate in reproducing the hallmarks of the disease, inconsistent in portraying the sex-disparity, and unyielding to combinatorial study designs. Here we sought to deploy the ingenuity of microengineering in developing and validating a tissue chip model for human PAH. We designed and fabricated a microfluidic device to emulate the luminal, intimal, medial, adventitial, and perivascular layers of a pulmonary artery. By growing three types of pulmonary arterial cells (PACs)-endothelial, smooth muscle, and adventitial cells, we recreated the PAH pathophysiology on the device. Diseased (PAH) PACs, when grown on the chips, moved of out their designated layers and created phenomena similar to the major pathologies of human PAH: intimal thickening, muscularization, and arterial remodeling and show an endothelial to mesenchymal transition. Flow-induced stress caused control cells, grown on the chips, to undergo morphological changes and elicit arterial remodeling. Our data also suggest that the newly developed chips can be used to elucidate the sex disparity in PAH and to study the therapeutic efficacy of existing and investigational anti-PAH drugs. We believe this miniaturized device can be deployed for testing various prevailing and new hypotheses regarding the pathobiology and drug therapy in human PAH.
引用
收藏
页码:3334 / 3345
页数:12
相关论文
共 40 条
  • [1] Fibrotic microtissue array to predict anti-fibrosis drug efficacy
    Asmani, Mohammadnabi
    Velumani, Sanjana
    Li, Yan
    Wawrzyniak, Nicole
    Hsia, Isaac
    Chen, Zhaowei
    Hinz, Boris
    Zhao, Ruogang
    [J]. NATURE COMMUNICATIONS, 2018, 9
  • [2] Endothelial fluid shear stress sensing in vasculr health and disease
    Baeyens, Nicolas
    Bandyopadhyay, Chirosree
    Coon, Brian G.
    Yun, Sanguk
    Schwartz, Martin A.
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 2016, 126 (03) : 821 - 828
  • [3] Microfluidic organs-on-chips
    Bhatia, Sangeeta N.
    Ingber, Donald E.
    [J]. NATURE BIOTECHNOLOGY, 2014, 32 (08) : 760 - 772
  • [4] Translating Research into Improved Patient Care in Pulmonary Arterial Hypertension
    Bonnet, Sebastien
    Provencher, Steeve
    Guignabert, Christophe
    Perros, Frederic
    Boucherat, Olivier
    Schermuly, Ralph Theo
    Hassoun, Paul M.
    Rabinovitch, Marlene
    Nicolls, Mark R.
    Humbert, Marc
    [J]. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2017, 195 (05) : 583 - 595
  • [5] Bonnet S, 2016, AM J RESP CRIT CARE, V193, P1331, DOI 10.1164/rccm.201601-0113ED
  • [6] ASK1 Inhibition Halts Disease Progression in Preclinical Models of Pulmonary Arterial Hypertension
    Budas, Grant R.
    Boehm, Mario
    Kojonazarov, Baktybek
    Viswanathan, Gayathri
    Tian, Xia
    Veeroju, Swathi
    Novoyatleva, Tatyana
    Grimminger, Friedrich
    Hinojosa-Kirschenbaum, Ford
    Ghofrani, Hossein A.
    Weissmann, Norbert
    Seeger, Werner
    Liles, John T.
    Schermuly, Ralph T.
    [J]. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2018, 197 (03) : 373 - 385
  • [7] SURFACTANT DISPOSITION IN RATS WITH MONOCROTALINE-INDUCED PNEUMOTOXICITY
    BUMMER, PM
    BAUGHN, JA
    SANDERS, LP
    ABSHER, KR
    OCONNOR, WN
    OLSON, JW
    GILLESPIE, MN
    [J]. TOXICOLOGY, 1994, 90 (1-2) : 53 - 62
  • [8] Colvin Kelley L, 2014, J Pulm Respir Med, V4
  • [9] Human Primary Lung Endothelial Cells in Culture
    Comhair, Suzy A. A.
    Xu, Weiling
    Mavrakis, Lori
    Aldred, Micheala A.
    Asosingh, Kewal
    Erzurum, Serpil C.
    [J]. AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 2012, 46 (06) : 723 - 730
  • [10] Development of pulmonary arterial hypertension in mice over-expressing S100A4/Mts1 is specific to females
    Dempsie, Yvonne
    Nilsen, Margaret
    White, Kevin
    Mair, Kirsty M.
    Loughlin, Lynn
    Ambartsumian, Noona
    Rabinovitch, Marlene
    MacLean, Margaret R.
    [J]. RESPIRATORY RESEARCH, 2011, 12