Human Engineered Cardiac Tissues (hECTs)

Human engineered cardiac tissues (hECTs) are derived by experimental manipulation of pluripotent stem cells, such as human embryonic stem cells (hESCs) and, more recently, human induced pluripotent stem cells (hiPSCs) to differentiate into human cardiomyocytes.[1][2][3][4][5] Interest in these bioengineered cardiac tissues has risen due to their potential use in cardiovascular research and clinical therapies. These tissues provide a unique in vitro model to study cardiac physiology with a species-specific advantage over cultured animal cells in experimental studies.[1] hECTs also have therapeutic potential for in vivo regeneration of heart muscle.[2][3] hECTs provide a valuable resource to reproduce the normal development of human heart tissue, understand the development of human cardiovascular disease (CVD), and may lead to engineered tissue-based therapies for CVD patients.[3]

Generation of hECTs

hESCs and hiPSCs are the primary cells used to generate hECTs.[2][3][4][5] Human pluripotent stem cells are differentiated into cardiomyocytes (hPSC-CMs) in culture through a milieu containing small-molecule mediators (e.g. cytokines, growth and transcription factors).[1][6][7] Transforming hPSC-CMs into hECTs incorporates the use of 3-dimensional (3D) tissue scaffolds to mimic the natural physiological environment of the heart.[1][2][3][8] This 3D scaffold, along with collagen – a major component of the cardiac extracellular matrix[9] – provides the appropriate conditions to promote cardiomyocyte organization, growth and differentiation.[1][2][3][7][8]

hECT Characteristics

At the intracellular level, hECTs exhibit several essential structural features of cardiomyocytes, including organized sarcomeres, gap-junctions, and sarcoplasmic reticulum structures;[1] however, the distribution and organization of many of these structures is characteristic of neonatal heart tissue rather than adult human heart muscle.[1][3][4][8] hECTs also express key cardiac genes (α-MHC, SERCA2a and ACTC1) nearing the levels seen in the adult heart.[1] Analogous to the characteristics of ECTs from animal models,[10][11] hECTs beat spontaneously [1] and reconstitute many fundamental physiological responses of normal heart muscle, such as the Frank-Starling mechanism [1][7] and sensitivity to calcium.[1] hECTs show dose-dependent responses to certain drugs, such as morphological changes in action potentials due to ion channel blockers [4][12] and modulation of contractile properties by inotropic and lusitropic agents.[1][7]

Experimental and Clinical Applications

Even with current technologies, hECT structure and function is more at the level of newborn heart muscle than adult myocardium.[1][2][3][4][5][8] Nonetheless, important advances have led to the generation of hECT patches for myocardial repair in animal models[13][14] and use in in vitro models of drug screening.[1][3][12] hECTs can also be used to experimentally model CVD using genetic manipulation and adenoviral-mediated gene transfer.[1][15] In animal models of myocardial infarction (MI), hECT injection into the hearts of rats[16] and mice[17] reduces infarct size and improves heart function and contractility. As a proof of principle, grafts of engineered heart tissues have been implanted in rats following MI with beneficial effects on left ventricular function.[18] The use of hECTs in generating tissue engineered heart valves is also being explored to improve current heart valve constructs in in vivo animal studies.[19] As tissue engineering technology advances to overcome current limitations, hECTs are a promising avenue for experimental drug discovery, screening and disease modelling and in vivo repair.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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 (Feb 2014). "Advancing functional engineered cardiac tissues toward a preclinical model of human myocardium". FASEB Journal. 28 (2): 644–54. doi:10.1096/fj.13-228007. PMID 24174427.
  2. 1 2 3 4 5 6 Tiburcy M, Zimmermann WH (Jan 2014). "Modeling myocardial growth and hypertrophy in engineered heart muscle". Trends in Cardiovascular Medicine. 24 (1): 7–13. doi:10.1016/j.tcm.2013.05.003. PMID 23953977.
  3. 1 2 3 4 5 6 7 8 9 Tulloch NL, Murry CE (Nov 2013). "Trends in cardiovascular engineering: organizing the human heart". Trends in Cardiovascular Medicine. 23 (8): 282–6. doi:10.1016/j.tcm.2013.04.001. PMID 23722092.
  4. 1 2 3 4 5 Zhang D, Shadrin IY, Lam J, Xian HQ, Snodgrass HR, Bursac N (Jul 2013). "Tissue-engineered cardiac patch for advanced functional maturation of human ESC-derived cardiomyocytes". Biomaterials. 34 (23): 5813–20. doi:10.1016/j.biomaterials.2013.04.026. PMC 3660435Freely accessible. PMID 23642535.
  5. 1 2 3 Mummery CL, Zhang J, Ng ES, Elliott DA, Elefanty AG, Kamp TJ (Jul 2012). "Differentiation of human embryonic stem cells and induced pluripotent stem cells to cardiomyocytes: a methods overview". Circulation Research. 111 (3): 344–58. doi:10.1161/CIRCRESAHA.110.227512. PMC 3578601Freely accessible. PMID 22821908.
  6. ↑ Wang H, Cao N, Spencer CI, Nie B, Ma T, Xu T, Zhang Y, Wang X, Srivastava D, Ding S (Mar 2014). "Small molecules enable cardiac reprogramming of mouse fibroblasts with a single factor, Oct4". Cell Reports. 6 (5): 951–60. doi:10.1016/j.celrep.2014.01.038. PMC 4004339Freely accessible. PMID 24561253.
  7. 1 2 3 4 Soong PL, Tiburcy M, Zimmermann WH (Jun 2012). "Cardiac differentiation of human embryonic stem cells and their assembly into engineered heart muscle". Current Protocols in Cell Biology. Chapter 23: Unit23.8. doi:10.1002/0471143030.cb2308s55. PMID 23129117.
  8. 1 2 3 4 Tulloch NL, Muskheli V, Razumova MV, Korte FS, Regnier M, Hauch KD, Pabon L, Reinecke H, Murry CE (Jun 2011). "Growth of engineered human myocardium with mechanical loading and vascular coculture". Circulation Research. 109 (1): 47–59. doi:10.1161/CIRCRESAHA.110.237206. PMC 3140796Freely accessible. PMID 21597009.
  9. ↑ Weber KT, Janicki JS, Shroff SG, Pick R, Chen RM, Bashey RI (Apr 1988). "Collagen remodeling of the pressure-overloaded, hypertrophied nonhuman primate myocardium". Circulation Research. 62 (4): 757–65. doi:10.1161/01.res.62.4.757. PMID 2964945.
  10. ↑ Zimmermann WH, Fink C, Kralisch D, Remmers U, Weil J, Eschenhagen T (Apr 2000). "Three-dimensional engineered heart tissue from neonatal rat cardiac myocytes". Biotechnology and Bioengineering. 68 (1): 106–14. doi:10.1002/(SICI)1097-0290(20000405)68:1<106::AID-BIT13>3.0.CO;2-3. PMID 10699878.
  11. ↑ Zimmermann WH, Schneiderbanger K, Schubert P, Didié M, Münzel F, Heubach JF, Kostin S, Neuhuber WL, Eschenhagen T (Feb 2002). "Tissue engineering of a differentiated cardiac muscle construct". Circulation Research. 90 (2): 223–30. doi:10.1161/hh0202.103644. PMID 11834716.
  12. 1 2 Schaaf S, Shibamiya A, Mewe M, Eder A, Stöhr A, Hirt MN, Rau T, Zimmermann WH, Conradi L, Eschenhagen T, Hansen A (2011). "Human engineered heart tissue as a versatile tool in basic research and preclinical toxicology". PLOS ONE. 6 (10): e26397. doi:10.1371/journal.pone.0026397. PMC 3197640Freely accessible. PMID 22028871.
  13. ↑ Stevens KR, Kreutziger KL, Dupras SK, Korte FS, Regnier M, Muskheli V, Nourse MB, Bendixen K, Reinecke H, Murry CE (Sep 2009). "Physiological function and transplantation of scaffold-free and vascularized human cardiac muscle tissue". Proceedings of the National Academy of Sciences of the United States of America. 106 (39): 16568–73. doi:10.1073/pnas.0908381106. PMC 2746126Freely accessible. PMID 19805339.
  14. ↑ Lesman A, Habib M, Caspi O, Gepstein A, Arbel G, Levenberg S, Gepstein L (Jan 2010). "Transplantation of a tissue-engineered human vascularized cardiac muscle". Tissue Engineering. Part A. 16 (1): 115–25. doi:10.1089/ten.TEA.2009.0130. PMID 19642856.
  15. ↑ de Lange WJ, Hegge LF, Grimes AC, Tong CW, Brost TM, Moss RL, Ralphe JC (Jun 2011). "Neonatal mouse-derived engineered cardiac tissue: a novel model system for studying genetic heart disease". Circulation Research. 109 (1): 8–19. doi:10.1161/CIRCRESAHA.111.242354. PMC 3123426Freely accessible. PMID 21566213.
  16. ↑ Min JY, Yang Y, Converso KL, Liu L, Huang Q, Morgan JP, Xiao YF (Jan 2002). "Transplantation of embryonic stem cells improves cardiac function in postinfarcted rats". Journal of Applied Physiology. 92 (1): 288–96. PMID 11744672.
  17. ↑ Kolossov E, Bostani T, Roell W, Breitbach M, Pillekamp F, Nygren JM, Sasse P, Rubenchik O, Fries JW, Wenzel D, Geisen C, Xia Y, Lu Z, Duan Y, Kettenhofen R, Jovinge S, Bloch W, Bohlen H, Welz A, Hescheler J, Jacobsen SE, Fleischmann BK (Oct 2006). "Engraftment of engineered ES cell-derived cardiomyocytes but not BM cells restores contractile function to the infarcted myocardium". The Journal of Experimental Medicine. 203 (10): 2315–27. doi:10.1084/jem.20061469. PMC 2118112Freely accessible. PMID 16954371.
  18. ↑ Zimmermann WH, Melnychenko I, Wasmeier G, Didié M, Naito H, Nixdorff U, Hess A, Budinsky L, Brune K, Michaelis B, Dhein S, Schwoerer A, Ehmke H, Eschenhagen T (Apr 2006). "Engineered heart tissue grafts improve systolic and diastolic function in infarcted rat hearts". Nature Medicine. 12 (4): 452–8. doi:10.1038/nm1394. PMID 16582915.
  19. ↑ Pucéat M (Apr 2013). "Embryological origin of the endocardium and derived valve progenitor cells: from developmental biology to stem cell-based valve repair". Biochimica et Biophysica Acta. 1833 (4): 917–22. doi:10.1016/j.bbamcr.2012.09.013. PMID 23078978.
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