Cardiac Tissue Engineering Models of Inherited and Acquired Cardiomyopathies
The lack of biomimetic in vitro models of the human heart has posed a critical barrier to progress in the field of modeling cardiac disease. Human engineered cardiac tissues (hECTs)—autonomous, beating structures that recapitulate key aspects of native cardiac muscle physiology—offer an attractive alternative to traditional in vitro models. Here we describe the use of hECTs to advance our understanding and modeling of cardiac diseases in order to test therapeutic interventions, with a focus on contractile dysfunction in the setting of inherited and acquired forms of cardiomyopathies. Four major procedures are discussed in this chapter: (1) preparation of hECTs from human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) on single-tissue and multitissue bioreactors; (2) data acquisition of hECT contractile function on both of these platforms; (3) hECT modeling of hereditary phospholamban-R14 deletion-dilated cardiomyopathy; and (4) cryo-injury and doxorubicin-induced hECT models of acquired cardiomyopathy.
Key wordsTissue engineering Genetic cardiomyopathy Acquired cardiomyopathy Contractility Models of disease Stem cells
This work was supported by NIH/NHLBI K01HL133424 (ICT), NIH/NHLBI 1F30HL134283-01A1 (JM), American Heart Association 15POST25090116 (DKC), and NIH/NHLBI R01HL132226 (KDC).
- 1.Towbin JA, Lowe AM, Colan SD, Sleeper LA, Orav EJ, Clunie S, Messere J, Cox GF, Lurie PR, Hsu D, Canter C, Wilkinson JD, Lipshultz SE (2006) Incidence, causes, and outcomes of dilated cardiomyopathy in children. JAMA 296(15):1867–1876. https://doi.org/10.1001/jama.296.15.1867CrossRefPubMedGoogle Scholar
- 2.Mushtaq M, DiFede DL, Golpanian S, Khan A, Gomes SA, Mendizabal A, Heldman AW, Hare JM (2014) Rationale and design of the percutaneous stem cell injection delivery effects on neomyogenesis in dilated cardiomyopathy (the POSEIDON-DCM study): a phase I/II, randomized pilot study of the comparative safety and efficacy of transendocardial injection of autologous mesenchymal stem cell vs. allogeneic mesenchymal stem cells in patients with non-ischemic dilated cardiomyopathy. J Cardiovasc Transl Res 7(9):769–780. https://doi.org/10.1007/s12265-014-9594-0CrossRefPubMedPubMedCentralGoogle Scholar
- 3.Turnbull IC, Karakikes I, Serrao GW, Backeris P, Lee JJ, Xie C, Senyei G, Gordon RE, Li RA, Akar FG, Hajjar RJ, Hulot JS, Costa KD (2014) Advancing functional engineered cardiac tissues toward a preclinical model of human myocardium. FASEB J 28(2):644–654. https://doi.org/10.1096/fj.13-228007CrossRefPubMedPubMedCentralGoogle Scholar
- 5.Mayourian J, Cashman TJ, Ceholski DK, Johnson BV, Sachs D, Kaji DA, Sahoo S, Hare JM, Hajjar RJ, Sobie EA, Costa KD (2017) Experimental and computational insight into human mesenchymal stem cell paracrine signaling and heterocellular coupling effects on cardiac contractility and arrhythmogenicity. Circ Res 121(4):411–423. https://doi.org/10.1161/CIRCRESAHA.117.310796CrossRefPubMedPubMedCentralGoogle Scholar
- 6.Serrao GW, Turnbull IC, Ancukiewicz D, Kim DE, Kao E, Cashman TJ, Hadri L, Hajjar RJ, Costa KD (2012) Myocyte-depleted engineered cardiac tissues support therapeutic potential of mesenchymal stem cells. Tissue Eng Part A 18(13–14):1322–1333. https://doi.org/10.1089/ten.TEA.2011.0278CrossRefPubMedPubMedCentralGoogle Scholar
- 10.Karakikes I, Senyei GD, Hansen J, Kong CW, Azeloglu EU, Stillitano F, Lieu DK, Wang J, Ren L, Hulot JS, Iyengar R, Li RA, Hajjar RJ (2014) Small molecule-mediated directed differentiation of human embryonic stem cells toward ventricular cardiomyocytes. Stem Cells Transl Med 3(1):18–31. https://doi.org/10.5966/sctm.2013-0110CrossRefPubMedGoogle Scholar