Abstract
In vitro disease modeling can provide compelling insights into the molecular underpinnings of various pathological conditions. Traditionally, researchers have used two-dimensional (2D) cell culture methods to elucidate the molecular mechanisms that drive diseases. However, this method of cell culture fails to recapitulate the complex, three-dimensional (3D) microenvironment that is present in vivo. Recently, tissue-engineered models have been generated to create culture systems that better recapitulate the complex 3D microenvironments found in living tissue. By using these engineered models, more relevant data may be produced to unravel the molecular underpinnings of disease states and potentially translate into new therapeutic strategies.
Keywords
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Works Cited
Thomson J, et al. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282:1145–7.
Itskovitz-Eldor J, et al. Differentiation of human embryonic stem cells into embryoid bodies compromising the three embryonic germ layers. Mol Med. 2000;6:88–95.
Mclaren A. Ethical and social considerations of stem cell research. Nature. 2001;414:129–31.
Takahashi K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131:861–72. https://doi.org/10.1016/j.cell.2007.11.019.
Später D, Hansson EM, Zangi L, Chien KR. How to make a cardiomyocyte. Development. 2014;141:4418–31.
Lee TM, et al. Pediatric cardiomyopathies. Circ Res. 2017;121:855–73.
Hansen A, et al. Development of a drug screening platform based on engineered heart tissue. Circ Res. 2010;107:35–44.
Schwan J, et al. Anisotropic engineered heart tissue made from laser-cut decellularized myocardium. Sci Rep. 2016;6:32068.
Haraguchi Y, et al. Fabrication of functional three-dimensional tissues by stacking cell sheets in vitro. Nat Protoc. 2012;7:850–8.
Jackman CP, Carlson AL, Bursac N. Dynamic culture yields engineered myocardium with near-adult functional output. Biomaterials. 2016;111:66–79.
Bian W, Badie N, Himel HD, Bursac N. Robust T-tubulation and maturation of cardiomyocytes using tissue-engineered epicardial mimetics. Biomaterials. 2014;35:3819–28.
Tiburcy M, et al. Defined engineered human myocardium with advanced maturation for applications in heart failure modelling and repair. Circulation. 2017;116:024145. https://doi.org/10.1161/CIRCULATIONAHA.116.024145.
MacQueen LA, et al. A tissue-engineered scale model of the heart ventricle. Nat Biomed Eng. 2018;2:930.
Wu B, et al. Developmental mechanisms of aortic valve malformation and disease. Annu Rev Physiol. 2017;79:21–41.
Arevalos CA, et al. Valve interstitial cells act in a Pericyte manner promoting angiogensis and invasion by valve endothelial cells. Ann Biomed Eng. 2016;44:1–17.
Varzideh F, et al. Human cardiomyocytes undergo enhanced maturation in embryonic stem cell-derived organoid transplants. Biomaterials. 2018;192:537–50.
Voges HK, et al. Development of a human cardiac organoid injury model reveals innate regenerative potential. Development. 2017;144:1118–27.
Mills RJ, et al. Functional screening in human cardiac organoids reveals a metabolic mechanism for cardiomyocyte cell cycle arrest. Proc Natl Acad Sci. 2017;114:E8372. https://doi.org/10.1073/pnas.1707316114.
Feric NT, Radisic M. Maturing human pluripotent stem cell-derived cardiomyocytes in human engineered cardiac tissues. Adv Drug Deliv Rev. 2016;96:110–34.
Robertson C, Tran D, George S. Concise review: maturation phases of human pluripotent stem cell-derived cardiomyocytes. Stem Cells. 2013;31:1–17.
French A, et al. Enabling consistency in pluripotent stem cell-derived products for research and development and clinical applications through material standards. Stem Cells Transl Med. 2015;4:217–23.
McMullen JR, Jennings GL. Differences between pathological and physiological cardiac hypertrophy: novel therapeutic strategies to treat heart failure. Clin Exp Pharmacol Physiol. 2007;34:255–62.
Feinberg AW, et al. Controlling the contractile strength of engineered cardiac muscle by hierarchal tissue architecture. Biomaterials. 2012;33:5732–41.
Ruan J-L, et al. Mechanical stress conditioning and electrical stimulation promote contractility and force maturation of induced pluripotent stem cell-derived human cardiac tissue clinical perspective. Circulation. 2016;134:1557–67.
Schwan J, Campbell SG. Prospects for in vitro myofilament maturation in stem cell-derived cardiac myocytes. Biomark Insights. 2015;2015:91–103.
Chong JJH, et al. Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts. Nature. 2014;510:273–7.
Hirt MN, et al. Functional improvement and maturation of rat and human engineered heart tissue by chronic electrical stimulation. J Mol Cell Cardiol. 2014;74:151–61.
Mihic A, et al. The effect of cyclic stretch on maturation and 3D tissue formation of human embryonic stem cell-derived cardiomyocytes. Biomaterials. 2014;35:2798–808.
Ronaldson-Bouchard K, et al. Advanced maturation of human cardiac tissue grown from pluripotent stem cells. Nature. 2018;556:239–43.
van Mil A, et al. Modelling inherited cardiac disease using human induced pluripotent stem cell-derived cardiomyocytes: progress, pitfalls, and potential. Cardiovasc Res. 2018;114(14):1828–42. https://doi.org/10.1093/cvr/cvy208.
Eschenhagen T, Carrier L. Cardiomyopathy phenotypes in human-induced pluripotent stem cell-derived cardiomyocytes—a systematic review. Pflugers Arch. 2018; https://doi.org/10.1093/cvr/cvy208.
Mestroni L, Brun F, Spezzacatene A, Sinagra G, MRG T. Genetic causes of dilated cardiomyopathy. Prog Pediatr Cardiol. 2015;37:13–8.
Hinson JT, et al. Titin mutations in iPS cells define sarcomere insufficiency as a cause of dilated cardiomyopathy. Science. 2015;349:982–6.
Boudou T, et al. A microfabricated platform to measure and manipulate the mechanics of engineered cardiac microtissues. Tissue Eng Part A. 2012;18:910–9.
Tiburcy M, Meyer T, Soong PL, Zimmermann W-H. Collagen-based engineered heart muscle. Methods Mol Biol. 2014;1181:167–76.
Streckfuss-Bömeke K, et al. Severe DCM phenotype of patient harboring RBM20 mutation S635A can be modeled by patient-specific induced pluripotent stem cell-derived cardiomyocytes. J Mol Cell Cardiol. 2017;113:9–21.
Marian AJ, Braunwald E. Hypertrophic cardiomyopathy: genetics, pathogenesis, clinical manifestations, diagnosis, and therapy. Circ Res. 2017;121:749–70.
Mosqueira D, et al. CRISPR/Cas9 editing in human pluripotent stem cell-cardiomyocytes highlights arrhythmias, hypocontractility, and energy depletion as potential therapeutic targets for hypertrophic cardiomyopathy. Eur Heart J. 2018;39:3879–92.
Smith JGW, et al. Isogenic pairs of hiPSC-CMs with hypertrophic cardiomyopathy/LVNC-associated ACTC1 E99K mutation unveil differential functional deficits. Stem Cell Reports. 2018;11:1226–43.
Daw EW, et al. Genome-wide mapping of modifier chromosomal loci for human hypertrophic cardiomyopathy. Hum Mol Genet. 2007;16:2463–71.
Hinson JT, et al. Integrative analysis of PRKAG2 cardiomyopathy iPS and microtissue models identifies AMPK as a regulator of metabolism, survival, and fibrosis. Cell Rep. 2016;17:3292–304.
Marcelo KL, Goldie LC, Hirschi KK. Regulation of endothelial cell differentiation and specification. Circ Res. 2013;112:1272–87.
Masumura T, Yamamoto K, Shimizu N, Obi S, Ando J. Shear stress increases expression of the arterial endothelial marker ephrinB2 in murine ES cells via the VEGF-notch signaling pathways. Arterioscler Thromb Vasc Biol. 2009;29:2125–31.
Sivarapatna A, et al. Arterial specification of endothelial cells derived from human induced pluripotent stem cells in a biomimetic flow bioreactor. Biomaterials. 2015;53:621–33.
Yoder MC. Endothelial stem and progenitor cells (stem cells): (2017 Grover Conference Series). Pulm Circ. 2018;8 https://doi.org/10.1177/2045893217743950.
Lee SJ, Kim KH, Yoon YS. Generation of human pluripotent stem cell-derived endothelial cells and their therapeutic utility. Curr Cardiol Rep. 2018;20(45):45.
Lian X, et al. Efficient differentiation of human pluripotent stem cells to endothelial progenitors via small-molecule activation of WNT signaling. Stem Cell Reports. 2014;3:804–16.
Patsch C, et al. Generation of vascular endothelial and smooth muscle cells from human pluripotent stem cells. Nat Cell Biol. 2015;17:994–1003.
Prasain N, et al. Differentiation of human pluripotent stem cells to cells similar to cord-blood endothelial colony-forming cells. Nat Biotechnol. 2014;32:1151–7.
Ellis MW, Luo J, Qyang Y. Modeling elastin-associated vasculopathy with patient induced pluripotent stem cells and tissue engineering. Cell Mol Life Sci. 2018. https://doi.org/10.1007/s00018-018-2969-7 [pii].
Majesky MW, Mummery CL. Smooth muscle diversity from human pluripotent cells. Nat Biotechnol. 2012;30:152–4.
Cheung C, Bernardo AS, Trotter MW, Pedersen RA, Sinha S. Generation of human vascular smooth muscle subtypes provides insight into embryological origin-dependent disease susceptibility. Nat Biotechnol. 2012;30:165–73.
Xie C, Ritchie RP, Huang H, Zhang J, Chen YE. Smooth muscle cell differentiation in vitro: models and underlying molecular mechanisms. Arterioscler Thromb Vasc Biol. 2011;31:1485–94.
Rensen SS, Doevendans PA, van Eys GJ. Regulation and characteristics of vascular smooth muscle cell phenotypic diversity. Neth Hear J. 2007;15:100–8.
Xie CQ, et al. A highly efficient method to differentiate smooth muscle cells from human embryonic stem cells. Arterioscler Thromb Vasc Biol. 2007;27:e311–2.
Wanjare M, Kuo F, Gerecht S. Derivation and maturation of synthetic and contractile vascular smooth muscle cells from human pluripotent stem cells. Cardiovasc Res. 2013;97:321–30.
Wanjare M, Kusuma S, Gerecht S. Defining differences among perivascular cells derived from human pluripotent stem cells. Stem Cell Reports. 2014;2:746.
Wanjare M, Agarwal N, Gerecht S. Biomechanical strain induces elastin and collagen production in human pluripotent stem cell-derived vascular smooth muscle cells. Am J Physiol Cell Physiol. 2015;309:C271–81.
Eoh JH, et al. Enhanced elastin synthesis and maturation in human vascular smooth muscle tissue derived from induced-pluripotent stem cells. Acta Biomater. 2017;52:49–59.
Niklason LE, et al. Functional arteries grown in vitro. Science. 1999;284:489–93.
Syedain ZH, et al. A completely biological ‘off-the-shelf’ arteriovenous graft that recellularizes in baboons. Sci Transl Med. 2017;9:pii: eaan4209.
Atchison L, Zhang H, Cao K, Truskey GA. A tissue engineered blood vessel model of Hutchinson-Gilford Progeria Syndrome using human iPSC-derived smooth muscle cells. Sci Rep. 2017;7(8168):8168.
Gui L, et al. Implantable tissue-engineered blood vessels from human induced pluripotent stem cells. Biomaterials. 2016;102:120–9.
Fernandez CE, et al. Human vascular microphysiological system for in vitro drug screening. Sci Rep. 2016;6:21579.
Strobel HA, Calamari EL, Alphonse B, Hookway TA, Rolle MW. Fabrication of custom agarose wells for cell seeding and tissue ring self-assembly using 3D-printed molds. J Vis Exp. 2018; https://doi.org/10.3791/56618.
Dash BC, et al. Tissue-engineered vascular rings from human iPSC-derived smooth muscle cells. Stem Cell Reports. 2016;7:19–28.
Ren Y, et al. Small molecule Wnt inhibitors enhance the efficiency of BMP-4-directed cardiac differentiation of human pluripotent stem cells. J Mol Cell Cardiol. 2011;51:280–7.
Gui L, et al. Biomaterials implantable tissue-engineered blood vessels from human induced pluripotent stem cells. Biomaterials. 2016;102:120–9.
Zhang D, et al. Tissue-engineered cardiac patch for advanced functional maturation of human ESC-derived cardiomyocytes. Biomaterials. 2013;34:5813–20.
Abilez OJ, et al. Passive stretch induces structural and functional maturation of engineered heart muscle as predicted by computational modeling. Stem Cells. 2018;36:265–77.
Khan M, et al. Evaluation of changes in morphology and function of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) cultured on an aligned-nanofiber cardiac patch. PLoS One. 2015;10:1–19.
Funding Acknowledgments
This work was supported by 1R01HL116705, 1R01HL131940, DOD 11959515, Connecticut’s Regenerative Medicine Research Fund (CRMRF) (all to YQ), P.D. Soros Fellowship for New Americans and a NIH/NIGMS Medical Scientist Training Program Grant (T32GM007205) (both to LRS), NIH 1F31HL143928-01 (to CWA), and 1R01HL136590 (to SC).
Competing Interests L.E.N. is a founder and shareholder in Humacyte, Inc., which is a regenerative medicine company. Humacyte produces engineered blood vessels from allogeneic smooth muscle cells for vascular surgery. L.E.N.’s spouse has equity in Humacyte, and L.E.N. serves on Humacyte’s Board of Directors. L.E.N. is an inventor on patents that are licensed to Humacyte and that produce royalties for L.E.N. L.E.N. has received an unrestricted research gift to support research in her laboratory at Yale. Humacyte did not fund this review, and Humacyte did not influence the writing of this review.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2019 Springer Nature Switzerland AG
About this chapter
Cite this chapter
Anderson, C.W. et al. (2019). Tissue-Engineered Stem Cell Models of Cardiovascular Diseases. In: Serpooshan, V., Wu, S. (eds) Cardiovascular Regenerative Medicine. Springer, Cham. https://doi.org/10.1007/978-3-030-20047-3_1
Download citation
DOI: https://doi.org/10.1007/978-3-030-20047-3_1
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-20046-6
Online ISBN: 978-3-030-20047-3
eBook Packages: MedicineMedicine (R0)