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词条 Human Engineered Cardiac Tissues (hECTs)
释义

  1. Generation of hECTs

  2. hECT Characteristics

  3. Experimental and Clinical Applications

  4. References

{{orphan|date=March 2014}}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 {{cite journal | vauthors = 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 | title = Advancing functional engineered cardiac tissues toward a preclinical model of human myocardium | journal = FASEB Journal | volume = 28 | issue = 2 | pages = 644–54 | date = Feb 2014 | pmid = 24174427 | doi = 10.1096/fj.13-228007 | pmc=3898643}}
2. ^1 2 3 4 5 {{cite journal | vauthors = Tiburcy M, Zimmermann WH | title = Modeling myocardial growth and hypertrophy in engineered heart muscle | journal = Trends in Cardiovascular Medicine | volume = 24 | issue = 1 | pages = 7–13 | date = Jan 2014 | pmid = 23953977 | doi = 10.1016/j.tcm.2013.05.003 }}
3. ^1 2 3 4 5 6 7 8 {{cite journal | vauthors = Tulloch NL, Murry CE | title = Trends in cardiovascular engineering: organizing the human heart | journal = Trends in Cardiovascular Medicine | volume = 23 | issue = 8 | pages = 282–6 | date = Nov 2013 | pmid = 23722092 | doi = 10.1016/j.tcm.2013.04.001 | pmc=3791174}}
4. ^1 2 3 4 {{cite journal | vauthors = Zhang D, Shadrin IY, Lam J, Xian HQ, Snodgrass HR, Bursac N | title = Tissue-engineered cardiac patch for advanced functional maturation of human ESC-derived cardiomyocytes | journal = Biomaterials | volume = 34 | issue = 23 | pages = 5813–20 | date = Jul 2013 | pmid = 23642535 | pmc = 3660435 | doi = 10.1016/j.biomaterials.2013.04.026 }}
5. ^1 2 {{cite journal | vauthors = Mummery CL, Zhang J, Ng ES, Elliott DA, Elefanty AG, Kamp TJ | title = Differentiation of human embryonic stem cells and induced pluripotent stem cells to cardiomyocytes: a methods overview | journal = Circulation Research | volume = 111 | issue = 3 | pages = 344–58 | date = Jul 2012 | pmid = 22821908 | pmc = 3578601 | doi = 10.1161/CIRCRESAHA.110.227512 }}
6. ^{{cite journal | vauthors = Wang H, Cao N, Spencer CI, Nie B, Ma T, Xu T, Zhang Y, Wang X, Srivastava D, Ding S | title = Small molecules enable cardiac reprogramming of mouse fibroblasts with a single factor, Oct4 | journal = Cell Reports | volume = 6 | issue = 5 | pages = 951–60 | date = Mar 2014 | pmid = 24561253 | pmc = 4004339 | doi = 10.1016/j.celrep.2014.01.038 }}
7. ^1 2 3 {{cite journal | vauthors = Soong PL, Tiburcy M, Zimmermann WH | title = Cardiac differentiation of human embryonic stem cells and their assembly into engineered heart muscle | journal = Current Protocols in Cell Biology | volume = Chapter 23 | issue = | pages = Unit23.8 | date = Jun 2012 | pmid = 23129117 | doi = 10.1002/0471143030.cb2308s55 }}
8. ^1 2 3 {{cite journal | vauthors = Tulloch NL, Muskheli V, Razumova MV, Korte FS, Regnier M, Hauch KD, Pabon L, Reinecke H, Murry CE | title = Growth of engineered human myocardium with mechanical loading and vascular coculture | journal = Circulation Research | volume = 109 | issue = 1 | pages = 47–59 | date = Jun 2011 | pmid = 21597009 | pmc = 3140796 | doi = 10.1161/CIRCRESAHA.110.237206 }}
9. ^{{cite journal | vauthors = Weber KT, Janicki JS, Shroff SG, Pick R, Chen RM, Bashey RI | title = Collagen remodeling of the pressure-overloaded, hypertrophied nonhuman primate myocardium | journal = Circulation Research | volume = 62 | issue = 4 | pages = 757–65 | date = Apr 1988 | pmid = 2964945 | doi = 10.1161/01.res.62.4.757 | url = http://circres.ahajournals.org/cgi/pmidlookup?view=long&pmid=2964945 }}
10. ^{{cite journal | vauthors = Zimmermann WH, Fink C, Kralisch D, Remmers U, Weil J, Eschenhagen T | title = Three-dimensional engineered heart tissue from neonatal rat cardiac myocytes | journal = Biotechnology and Bioengineering | volume = 68 | issue = 1 | pages = 106–14 | date = Apr 2000 | pmid = 10699878 | doi = 10.1002/(SICI)1097-0290(20000405)68:1<106::AID-BIT13>3.0.CO;2-3 }}
11. ^{{cite journal | vauthors = Zimmermann WH, Schneiderbanger K, Schubert P, Didié M, Münzel F, Heubach JF, Kostin S, Neuhuber WL, Eschenhagen T | title = Tissue engineering of a differentiated cardiac muscle construct | journal = Circulation Research | volume = 90 | issue = 2 | pages = 223–30 | date = Feb 2002 | pmid = 11834716 | doi = 10.1161/hh0202.103644 | url = http://circres.ahajournals.org/cgi/pmidlookup?view=long&pmid=11834716 }}
12. ^1 {{cite journal | vauthors = Schaaf S, Shibamiya A, Mewe M, Eder A, Stöhr A, Hirt MN, Rau T, Zimmermann WH, Conradi L, Eschenhagen T, Hansen A | title = Human engineered heart tissue as a versatile tool in basic research and preclinical toxicology | journal = PLOS ONE | volume = 6 | issue = 10 | pages = e26397 | year = 2011 | pmid = 22028871 | pmc = 3197640 | doi = 10.1371/journal.pone.0026397 }}
13. ^{{cite journal | vauthors = Stevens KR, Kreutziger KL, Dupras SK, Korte FS, Regnier M, Muskheli V, Nourse MB, Bendixen K, Reinecke H, Murry CE | title = Physiological function and transplantation of scaffold-free and vascularized human cardiac muscle tissue | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 39 | pages = 16568–73 | date = Sep 2009 | pmid = 19805339 | pmc = 2746126 | doi = 10.1073/pnas.0908381106 }}
14. ^{{cite journal | vauthors = Lesman A, Habib M, Caspi O, Gepstein A, Arbel G, Levenberg S, Gepstein L | title = Transplantation of a tissue-engineered human vascularized cardiac muscle | journal = Tissue Engineering. Part A | volume = 16 | issue = 1 | pages = 115–25 | date = Jan 2010 | pmid = 19642856 | doi = 10.1089/ten.TEA.2009.0130 }}
15. ^{{cite journal | vauthors = de Lange WJ, Hegge LF, Grimes AC, Tong CW, Brost TM, Moss RL, Ralphe JC | title = Neonatal mouse-derived engineered cardiac tissue: a novel model system for studying genetic heart disease | journal = Circulation Research | volume = 109 | issue = 1 | pages = 8–19 | date = Jun 2011 | pmid = 21566213 | pmc = 3123426 | doi = 10.1161/CIRCRESAHA.111.242354 }}
16. ^{{cite journal | vauthors = Min JY, Yang Y, Converso KL, Liu L, Huang Q, Morgan JP, Xiao YF | title = Transplantation of embryonic stem cells improves cardiac function in postinfarcted rats | journal = Journal of Applied Physiology | volume = 92 | issue = 1 | pages = 288–96 | date = Jan 2002 | pmid = 11744672 | url = http://jap.physiology.org/cgi/pmidlookup?view=long&pmid=11744672 }}
17. ^{{cite journal | vauthors = 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 | title = Engraftment of engineered ES cell-derived cardiomyocytes but not BM cells restores contractile function to the infarcted myocardium | journal = The Journal of Experimental Medicine | volume = 203 | issue = 10 | pages = 2315–27 | date = Oct 2006 | pmid = 16954371 | pmc = 2118112 | doi = 10.1084/jem.20061469 }}
18. ^{{cite journal | vauthors = 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 | title = Engineered heart tissue grafts improve systolic and diastolic function in infarcted rat hearts | journal = Nature Medicine | volume = 12 | issue = 4 | pages = 452–8 | date = Apr 2006 | pmid = 16582915 | doi = 10.1038/nm1394 }}
19. ^{{cite journal | vauthors = Pucéat M | title = Embryological origin of the endocardium and derived valve progenitor cells: from developmental biology to stem cell-based valve repair | journal = Biochimica et Biophysica Acta | volume = 1833 | issue = 4 | pages = 917–22 | date = Apr 2013 | pmid = 23078978 | doi = 10.1016/j.bbamcr.2012.09.013 }}

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