Nanopatterned Human iPSC-Based Model of a Dystrophin-Null Cardiomyopathic Phenotype

Springer Science and Business Media LLC - Tập 8 Số 3 - Trang 320-332 - 2015
Macadangdang, Jesse1,2, Guan, Xuan3,4,2, Smith, Alec S. T.1, Lucero, Rachel1, Czerniecki, Stefan4,2, Childers, Martin K.4,2, Mack, David L.4,2, Kim, Deok-Ho1,2,5
1Department of Bioengineering, University of Washington, Seattle, USA
2Institute of Stem Cell and Regenerative Medicine, University of Washington, Seattle, USA
3Department of Physiology and Pharmacology, School of Medicine, Wake Forest University Health Sciences, Winston-Salem, USA
4Department of Rehabilitation Medicine, University of Washington, Seattle USA
5Center for Cardiovascular Biology, University of Washington, Seattle, USA

Tóm tắt

Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) offer unprecedented opportunities to study inherited heart conditions in vitro, but are phenotypically immature, limiting their ability to effectively model adult-onset diseases. Cardiomyopathy is becoming the leading cause of death in patients with Duchenne muscular dystrophy (DMD), but the pathogenesis of this disease phenotype is not fully understood. Therefore, we aimed to test whether biomimetic nanotopography could further stratify the disease phenotype of DMD hiPSC-CMs to create more translationally relevant cardiomyocytes for disease modeling applications. We found that anisotropic nanotopography was necessary to distinguish structural differences between normal and DMD hiPSC-CMs, as these differences were masked on conventional flat substrates. DMD hiPSC-CMs exhibited a diminished structural and functional response to the underlying nanotopography compared to normal cardiomyocytes at both the macroscopic and subcellular levels. This blunted response may be due to a lower level of actin cytoskeleton turnover as measured by fluorescence recovery after photobleaching. Taken together these data suggest that DMD hiPSC-CMs are less adaptable to changes in their extracellular environment, and highlight the utility of nanotopographic substrates for effectively stratifying normal and structural cardiac disease phenotypes in vitro.

Tài liệu tham khảo

citation_journal_title=Proc. Natl. Acad. Sci.; citation_title=Sildenafil reverses cardiac dysfunction in the mdx mouse model of Duchenne muscular dystrophy; citation_author=CM Adamo; citation_volume=107; citation_publication_date=2010; citation_pages=19079-19083; citation_doi=10.1073/pnas.1013077107; citation_id=CR1 citation_journal_title=Science; citation_title=Multiplex genome engineering using CRISPR/Cas systems; citation_author=L Cong; citation_volume=339; citation_publication_date=2013; citation_pages=819-823; citation_doi=10.1126/science.1231143; citation_id=CR2 citation_journal_title=Pediatr. Neurol.; citation_title=Pathophysiology of duchenne muscular dystrophy: current hypotheses; citation_author=N Deconinck, B Dan; citation_volume=36; citation_publication_date=2007; citation_pages=1-7; citation_doi=10.1016/j.pediatrneurol.2006.09.016; citation_id=CR3 citation_journal_title=Circ. Res.; citation_title=Knock-in mouse model of dilated cardiomyopathy caused by troponin mutation; citation_author=C-K Du; citation_volume=101; citation_publication_date=2007; citation_pages=185-194; citation_doi=10.1161/CIRCRESAHA.106.146670; citation_id=CR4 citation_journal_title=Cardiovasc. Res.; citation_title=Disease characterization using LQTS-specific induced pluripotent stem cells; citation_author=T Egashira; citation_volume=95; citation_publication_date=2012; citation_pages=419-429; citation_doi=10.1093/cvr/cvs206; citation_id=CR5 citation_journal_title=Biochimica et Biophysica Acta (BBA)—Molecular Basis of Disease; citation_title=Dystrophin, its interactions with other proteins, and implications for muscular dystrophy; citation_author=J Ervasti; citation_volume=1772; citation_publication_date=2007; citation_pages=108-117; citation_doi=10.1016/j.bbadis.2006.05.010; citation_id=CR6 citation_journal_title=Biomaterials; citation_title=Controlling the contractile strength of engineered cardiac muscle by hierarchal tissue architecture; citation_author=AW Feinberg; citation_volume=33; citation_publication_date=2012; citation_pages=5732-5741; citation_doi=10.1016/j.biomaterials.2012.04.043; citation_id=CR7 citation_journal_title=Nat. Rev. Cardiol.; citation_title=Treatment of dystrophin cardiomyopathies; citation_author=J Finsterer, L Cripe; citation_volume=11; citation_publication_date=2014; citation_pages=168-179; citation_doi=10.1038/nrcardio.2013.213; citation_id=CR8 citation_journal_title=Muscle Nerve; citation_title=Exercise increases utrophin protein expression in the mdxmouse model of Duchenne muscular dystrophy; citation_author=BS Gordon, DA Lowe, MC Kostek; citation_volume=49; citation_publication_date=2014; citation_pages=915-918; citation_doi=10.1002/mus.24151; citation_id=CR9 citation_journal_title=Stem Cell Res.; citation_title=Dystrophin-deficient cardiomyocytes derived from human urine: new biologic reagents for drug discovery; citation_author=X Guan; citation_volume=12; citation_publication_date=2014; citation_pages=467-480; citation_doi=10.1016/j.scr.2013.12.004; citation_id=CR10 citation_journal_title=Circ. Res.; citation_title=Development of a drug screening platform based on engineered heart tissue; citation_author=A Hansen; citation_volume=107; citation_publication_date=2010; citation_pages=35-44; citation_doi=10.1161/CIRCRESAHA.109.211458; citation_id=CR11 citation_journal_title=Circ. Res.; citation_title=Cardiac tissue engineering: state of the art; citation_author=MN Hirt, A Hansen, T Eschenhagen; citation_volume=114; citation_publication_date=2014; citation_pages=354-367; citation_doi=10.1161/CIRCRESAHA.114.300522; citation_id=CR12 citation_journal_title=Nature Nature Publishing Group; citation_title=Modelling the long QT syndrome with induced pluripotent stem cells; citation_author=I Itzhaki; citation_volume=471; citation_publication_date=2011; citation_pages=225-229; citation_id=CR13 citation_journal_title=Proc. Natl. Acad. Sci.; citation_title=Nanoscale cues regulate the structure and function of macroscopic cardiac tissue constructs; citation_author=D-H Kim; citation_volume=107; citation_publication_date=2010; citation_pages=565-570; citation_doi=10.1073/pnas.0906504107; citation_id=CR14 citation_journal_title=Integr Biol; citation_title=Nanopatterned cardiac cell patches promote stem cell niche formation and myocardial regeneration; citation_author=D-H Kim; citation_volume=4; citation_publication_date=2012; citation_pages=1019; citation_doi=10.1039/c2ib20067h; citation_id=CR15 citation_journal_title=J. Hum. Genet. Nat. Publ. Group; citation_title=Molecular basis of hereditary cardiomyopathy: abnormalities in calcium sensitivity, stretch response, stress response and beyond; citation_author=A Kimura; citation_volume=55; citation_publication_date=2010; citation_pages=81-90; citation_id=CR16 Kshitiz, et al. Control of stem cell fate and function by engineering physical microenvironments. Integr. Biol. 4:1–20, 2012. citation_journal_title=Dis. Models Mech.; citation_title=Model for long QT syndrome type 2 using human iPS cells demonstrates arrhythmogenic characteristics in cell culture; citation_author=AL Lahti; citation_volume=5; citation_publication_date=2012; citation_pages=220-230; citation_doi=10.1242/dmm.008409; citation_id=CR18 Lee, J., M.E. Razu, X. Wang, C. Lacerda, and J. Kim. Biomimetic cardiac microsystems for pathophysiological studies and drug screens. J. Lab. Autom. 1–24, 2014. citation_journal_title=Ann. Neurol.; citation_title=Sildenafil does not improve cardiomyopathy in Duchenne/Becker muscular dystrophy; citation_author=DG Leung; citation_volume=76; citation_publication_date=2014; citation_pages=541-549; citation_doi=10.1002/ana.24214; citation_id=CR20 citation_journal_title=Circulation; citation_title=Drug screening using a library of human induced pluripotent stem cell-derived cardiomyocytes reveals disease-specific patterns of cardiotoxicity; citation_author=P Liang; citation_volume=127; citation_publication_date=2013; citation_pages=1677-1691; citation_doi=10.1161/CIRCULATIONAHA.113.001883; citation_id=CR21 citation_journal_title=Lancet; citation_title=Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010; citation_author=R Lozano; citation_volume=380; citation_publication_date=2012; citation_pages=2095-2128; citation_doi=10.1016/S0140-6736(12)61728-0; citation_id=CR22 Macadangdang, J., et al. Capillary force lithography for cardiac tissue engineering. JoVE 88:e50039, 2014. citation_journal_title=Eur. Heart J.; citation_title=Drug evaluation in cardiomyocytes derived fromhuman induced pluripotent stem cells carrying along QT syndrome type 2 mutation; citation_author=E Matsa; citation_volume=32; citation_publication_date=2011; citation_pages=952-962; citation_doi=10.1093/eurheartj/ehr073; citation_id=CR24 citation_journal_title=Integr. Biol.; citation_title=Cell Image Velocimetry (CIV): boosting the automated quantification of cell migration in wound healing assays; citation_author=F Milde, D Franco, A Ferrari, V Kurtcuoglu, D Poulikakos, P Koumoutsakos; citation_volume=4; citation_publication_date=2012; citation_pages=1437; citation_doi=10.1039/c2ib20113e; citation_id=CR25 citation_journal_title=Nat Cell Biol.; citation_title=Role of telomere dysfunction in cardiac failure in Duchenne muscular dystrophy; citation_author=F Mourkioti; citation_volume=15; citation_publication_date=2013; citation_pages=895-904; citation_doi=10.1038/ncb2790; citation_id=CR26 citation_journal_title=Circulation; citation_title=Screening drug-induced arrhythmia events using human induced pluripotent stem cell-derived cardiomyocytes and low-impedance microelectrode arrays; citation_author=EG Navarrete; citation_volume=128; citation_publication_date=2013; citation_pages=S3-S13; citation_doi=10.1161/CIRCULATIONAHA.112.000570; citation_id=CR27 citation_journal_title=Sci. Adv.; citation_title=Screening system for drug-induced arrhythmogenic risk combining a patch clamp and heart simulator; citation_author=JI Okada; citation_volume=1; citation_publication_date=2015; citation_pages=e1400142-e1400142; citation_doi=10.1126/sciadv.1400142; citation_id=CR28 citation_journal_title=Circ. Res.; citation_title=Dilated cardiomyopathy mutant tropomyosin mice develop cardiac dysfunction with significantly decreased fractional shortening and myofilament calcium sensitivity; citation_author=S Rajan; citation_volume=101; citation_publication_date=2007; citation_pages=205-214; citation_doi=10.1161/CIRCRESAHA.107.148379; citation_id=CR29 citation_journal_title=Nat. Protoc.; citation_title=Genome engineering using the CRISPR-Cas9 system; citation_author=FA Ran, PD Hsu, J Wright, V Agarwala, DA Scott, F Zhang; citation_volume=8; citation_publication_date=2013; citation_pages=2281-2308; citation_doi=10.1038/nprot.2013.143; citation_id=CR30 citation_journal_title=Circulation; citation_title=Heart disease and stroke statistics—2012 update: a report from the american heart association; citation_author=VL Roger; citation_volume=125; citation_publication_date=2012; citation_pages=e2-e220; citation_doi=10.1161/CIR.0b013e31823ac046; citation_id=CR31 citation_journal_title=Eur. J. Cell Biol.; citation_title=Upregulation of paxillin and focal adhesion signaling follows Dystroglycan Complex deletions and promotes a hypertensive state of differentiation; citation_author=S Sen, M Tewari, A Zajac, E Barton, HL Sweeney, DE Discher; citation_volume=90; citation_publication_date=2010; citation_pages=249-260; citation_doi=10.1016/j.ejcb.2010.06.005; citation_id=CR32 Sipp, D. Challenges in the clinical application of induced pluripotent stem cells. Stem Cell Res. Ther. 1:1–3, 2010. citation_journal_title=Sci. Transl. Med.; citation_title=Patient-specific induced pluripotent stem cells as a model for familial dilated cardiomyopathy; citation_author=N Sun; citation_volume=4; citation_publication_date=2012; citation_pages=1-14; citation_doi=10.1126/scitranslmed.3003552; citation_id=CR34 citation_journal_title=Hum. Mol. Genet.; citation_title=Back to the future: how human induced pluripotent stem cells will transform regenerative medicine; citation_author=CN Svendsen; citation_volume=22; citation_publication_date=2013; citation_pages=R32-R38; citation_doi=10.1093/hmg/ddt379; citation_id=CR35 citation_journal_title=Cell; citation_title=Induction of pluripotent stem cells from adult human fibroblasts by defined factors; citation_author=K Takahashi; citation_volume=131; citation_publication_date=2007; citation_pages=861-872; citation_doi=10.1016/j.cell.2007.11.019; citation_id=CR36 Turnbull, I. C., D. K. Lieu, R. A. Li, and K. D. Costa. Cardiac tissue engineering using human stem cell-derived cardiomyocytes for disease modeling and drug discovery. Drug Discov. Today Dis. Models 9:e219–e227, 2012. citation_journal_title=Tissue Eng.; citation_title=Challenges in cardiac tissue engineering; citation_author=G Vunjak-Novakovic; citation_volume=16; citation_publication_date=2010; citation_pages=169-187; citation_doi=10.1089/ten.teb.2009.0352; citation_id=CR38 citation_journal_title=Nat. Med.; citation_title=Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced pluripotent stem cell and heart-on-chip technologies; citation_author=G Wang; citation_volume=20; citation_publication_date=2014; citation_pages=616-623; citation_doi=10.1038/nm.3545; citation_id=CR39 citation_journal_title=Mol. Ther.; citation_title=Lentiviral vector design and imaging approaches to visualize the early stages of cellular reprogramming; citation_author=E Warlich; citation_volume=19; citation_publication_date=2009; citation_pages=782-789; citation_doi=10.1038/mt.2010.314; citation_id=CR40 Yang, H. S., et al. Electroconductive nanopatterned substrates for enhanced myogenic differentiation and maturation. Adv. Healthcare Mater. 2015. doi: 10.1002/adhm.201500003 . citation_journal_title=Biomaterials; citation_title=Nanopatterned muscle cell patches for enhanced myogenesis and dystrophin expression in a mouse model of muscular dystrophy; citation_author=HS Yang; citation_volume=35; citation_publication_date=2014; citation_pages=1478-1486; citation_doi=10.1016/j.biomaterials.2013.10.067; citation_id=CR42 citation_journal_title=J. Urol.; citation_title=Urine derived cells are a potential source for urological tissue reconstruction; citation_author=Y Zhang; citation_volume=180; citation_publication_date=2008; citation_pages=2226-2233; citation_doi=10.1016/j.juro.2008.07.023; citation_id=CR43