Browse > Article
http://dx.doi.org/10.14348/molcells.2018.0143

Maturation of Cardiomyocytes Derived from Human Pluripotent Stem Cells: Current Strategies and Limitations  

Jiang, Yanqing (University of Toronto, Hospital of Sick Children)
Park, Peter (Emory University, Department of Biology)
Hong, Sang-Min (Department of Physical Education, Dongguk University Seoul)
Ban, Kiwon (Department of Biomedical Sciences, City University of Hong Kong)
Abstract
The capacity of differentiation of human pluripotent stem cells (hPSCs), which include both embryonic stem cells and induced pluripotent stem cells, into cardiomyocytes (CMs) in vitro provides an unlimited resource for human CMs for a wide range of applications such as cell based cardiac repair, cardiac drug toxicology screening, and human cardiac disease modeling. However, their applicability is significantly limited by immature phenotypes. It has been well known that currently available CMs derived from hPSCs (hPSC-CMs) represent immature embryonic or fetal stage CMs and are functionally and structurally different from mature human CMs. To overcome this critical issue, several new approaches aiming to generate more mature hPSC-CMs have been developed. This review describes recent approaches to generate more mature hPSC-CMs including their scientific principles, advantages, and limitations.
Keywords
cardiomyocytes; human pluripotent stem cells; immaturity; maturation;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Gao, L., Gregorich, Z.R., Zhu, W., Mattapally, S., Oduk, Y., Lou, X., Kannappan, R., Borovjagin, A.V., Walcott, G.P., Pollard, A.E., et al. (2018). Large cardiac muscle patches engineered from human induced-pluripotent stem cell-derived cardiac cells improve recovery from myocardial infarction in swine. Circulation 137, 1712-1730.   DOI
2 Shigeru, M., Fukushima, S., Imanishi, Y., Kawamura, T., Mochizuki-Oda, N., Masuda, S., and Sawa, Y. (2016). Building a new treatment for heart failure-transplantation of induced pluripotent stem cellderived cells into the heart. Curr. Gene Ther. 16, 5-13.   DOI
3 Shimko, V.F., and Claycomb, W.C. (2008). Effect of mechanical loading on three-dimensional cultures of embryonic stem cell-derived cardiomyocytes. Tissue Eng. Part A 14, 49-58.
4 Snir, M., Kehat, I., Gepstein, A., Coleman, R., Itskovitz-Eldor, J., Livne, E., and Gepstein, L. (2003). Assessment of the ultrastructural and proliferative properties of human embryonic stem cell-derived cardiomyocytes. Am. J. Physiol. Heart Circ. Physiol. 285, H2355-H2363.   DOI
5 Gherghiceanu, M., Barad, L., Novak, A., Reiter, I., Itskovitz-Eldor, J., Binah, O., and Popescu, L.M. (2011). Cardiomyocytes derived from human embryonic and induced pluripotent stem cells: comparative ultrastructure. J. Cell. Mol. Med 15, 2539-2551.   DOI
6 Hazeltine, L.B., Simmons, C.S., Salick, M.R., Lian, X., Badur, M.G., Han, W., Delgado, S.M., Wakatsuki, T., Crone, W.C., Pruitt, B.L., et al. (2012). Effects of substrate mechanics on contractility of cardiomyocytes generated from human pluripotent stem cells. Int. J. Cell Biol. 2012, 508294.
7 Hirt, M.N., Hansen, A., and Eschenhagen, T. (2014). Cardiac Tissue Engineering. Circ. Res. 114, 354.   DOI
8 Jacot, J.G., McCulloch, A.D., and Omens, J.H. (2008). Substrate stiffness affects the functional maturation of neonatal rat ventricular myocytes. Biophys. J. 95, 3479-3487.   DOI
9 Kamakura, T., Makiyama, T., Sasaki, K., Yoshida, Y., Wuriyanghai, Y., Chen, J., Hattori, T., Ohno, S., Kita, T., Horie, M., et al. (2013). Ultrastructural maturation of human-induced pluripotent stem cell-derived cardiomyocytes in a long-term culture. Circ. J. 77, 1307-1314.   DOI
10 Takahashi, K., Kakimoto,Y., Toda, K., and Naruse, K. (2013). Mechanobiology in cardiac physiology and diseases. J. Cell Mol. Med. 17, 225-232.   DOI
11 Tulloch, N. L., Muskheli, V., Razumova, M.V., Korte, F.S., Regnier, M., Hauch, K.D., Pabon, L., Reinecke, H., and Murry, C.E. (2011). Growth of engineered human myocardium with mechanical loading and vascular coculture. Circ. Res. 109, 47-59.   DOI
12 Vanwinkle, W.B., Snuggs, M.B., and Buja, L.M. (1996). Cardiogel: A biosynthetic extracellular matrix for cardiomyocyte culture. In Vitro Cell. Dev. Biol. Anim. 32, 478-485.   DOI
13 Veerman, C.C., Kosmidis, G., Mummery, C.L., Casini, S., Verkerk, A.O., and Bellin, M. (2015). Immaturity of human stem-cell-derived cardiomyocytes in culture: fatal flaw or soluble problem? Stem Cells Dev. 24, 1035-1052.   DOI
14 Vreeker, A., van Stuijvenberg, L., Hund, T.J., Mohler, P.J., Nikkels, P.G., and van Veen, T.A.. (2014). Assembly of the cardiac intercalated disk during pre- and postnatal development of the human heart. PLoS One 9, e94722.   DOI
15 Kim, H.D., Kim, D.J., Lee, I.J., Rah, B.J., Sawa, Y., and Schaper, J. (1992). Human fetal heart development after mid-term: morphometry and ultrastructural study. J. Mol. Cell Cardiol. 24, 949-965.   DOI
16 Kim, C., Majdi, M., Xia, P., Wei, K.A., Talantova, M., Spiering, S., Nelson, B., Mercola, M., Chen, H.S. (2010). Non-cardiomyocytes influence the electrophysiological maturation of human embryonic stem cell-derived cardiomyocytes during differentiation. Stem Cells Dev. 19, 783-795.   DOI
17 Kohl, P., and Ravens, U. (2003). Cardiac mechano-electric feedback: past, present, and prospect. Prog. Biophys. Mol. Biol. 82, 3-9.   DOI
18 Wang, Y., Xu, H., Kumar, R., Tipparaju, S.M., Wagner, M.B., and Joyner, R.W. (2003). Differences in transient outward current properties between neonatal and adult human atrial myocytes. J. Mol. Cell Cardiol. 35, 1083-1092.   DOI
19 Yang, X., Pabon, L., and Murry, C.E. (2014a). Engineering adolescence: maturation of human pluripotent stem cell-derived cardiomyocytes. Circ. Res. 114, 511-523.   DOI
20 Yang, X., Rodriguez, M., Pabon, L., Fischer, K.A., Reinecke, H., Regnier, M., Sniadecki, N.J., Ruohola-Baker, H., and Murry, C.E. (2014b). Tri-iodo-l-thyronine promotes the maturation of human cardiomyocytes-derived from induced pluripotent stem cells. J. Mol. Cell Cardiol. 72, 296-304.   DOI
21 Taber, L.A. (2001). Biomechanics of cardiovascular development. Annu. Rev. Biomed. Eng. 3, 1-25.   DOI
22 Kruger, M., Sachse, C., Zimmermann, W.H., Eschenhagen, T., Klede, S., and Linke, W.A. (2008). Thyroid hormone regulates developmental titin isoform transitions via the phosphatidylinositol-3-kinase/ AKT pathway. Circ. Res. 102, 439.   DOI
23 Laflamme, M.A., and Murry, C.E. (2011). Heart regeneration. Nature 473, 326-335.   DOI
24 Laflamme, M.A., Chen, K.Y., Naumova, A.V., Muskheli, V., Fugate, J.A., Dupras, S.K., Reinecke, H., Xu, C., Hassanipour, M., Police, S., et al. (2007). Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts. Nat. Biotechnol. 25, 1015-1024.   DOI
25 You, J.O., Rafat, M., Ye, G.J.C., and Auguste, D.T. (2011). Nanoengineering the heart: Conductive scaffolds enhance connexin 43 expression. Nano Lett. 11, 3643-3648.   DOI
26 Zhang, J., Klos, M., Wilson, G.F., Herman, A.M., Lian, X., Raval, K.K., Barron, M.R., Hou, L., Soerens, A.G., Yu, J., et al. (2012). Extracellular matrix promotes highly efficient cardiac differentiation of human pluripotent stem cells: the matrix sandwich method. Circ. Res. 111, 1125-1136.   DOI
27 Zhang, J., Wilson, G.F., Soerens, A.G., Koonce, C.H., Yu, J., Palecek, S.P., Thomson, J.A., and Kamp, T.J. (2009). Functional cardiomyocytes derived from human induced pluripotent stem cells. Circ. Res. 104, e30-41.
28 Lee, P., Klos, M., Bollensdorff, C., Hou, L., Ewart, P., Kamp, T.J., Zhang, J., Bizy, A., Guerrero-Serna, G., Kohl, P., et al. (2012). Simultaneous voltage and calcium mapping of genetically purified human induced pluripotent stem cell-derived cardiac myocyte monolayers. Circ. Res. 110, 1556-1563.   DOI
29 Lieu, D.K., Liu, J., Siu, C.W., McNerney, G.P., Tse, H.F., Abu-Khalil, A., Huser, T., and Li, R.A. (2009). Absence of transverse tubules contributes to non-uniform $Ca^{2+}$ wavefronts in mouse and human embryonic stem cell-derived cardiomyocytes. Stem Cells Dev. 18, 1493-1500.   DOI
30 Liu, J., Laksman, Z., and Backx, P.H. (2016). The electrophysiological development of cardiomyocytes. Adv. Drug Deliv. Rev. 96, 253-273.   DOI
31 Lundy, S.D., Zhu, W.Z., Regnier, M., and Laflamme, M.A. (2013). Structural and functional maturation of cardiomyocytes derived from human pluripotent stem cells. Stem Cells Dev. 22, 1991-2002.   DOI
32 Ma, J., Guo, L., Fiene, S.J., Anson, B.D., Thomson, J.A., Kamp, T.J., Kolaja, K.L., Swanson, B.J., and January, C.T. (2011). High purity human-induced pluripotent stem cell-derived cardiomyocytes: electrophysiological properties of action potentials and ionic currents. Am. J. Physiol. Heart Circ. Physiol. 301, H2006-2017.   DOI
33 Ziman, A.P., Gomez-Viquez, N.L., Bloch, R.J., and Lederer, W.J. (2010). Excitation-contraction coupling changes during postnatal cardiac development. J. Mol. Cell Cardiol. 48, 379-386.   DOI
34 Zimmermann, W.H., Schneiderbanger, K., Schubert, P., Didie, M., Munzel, F., Heubach, J.F., Kostin, S., Neuhuber, W.L., and Eschenhagen, T. (2002). Tissue engineering of a differentiated cardiac muscle construct. Circ. Res. 90, 223-230.   DOI
35 Martherus, R.S., Vanherle, S.J., Timmer, E.D., Zeijlemaker, V.A., Broers, J.L., Smeets, H.J., Geraedts, J.P., and Ayoubi, T.A. (2010). Electrical signals affect the cardiomyocyte transcriptome independently of contraction. Physiol Genomics 42A, 283-289.   DOI
36 Mihic, A., Li, J., Miyagi, Y., Gagliardi, M., Li, S.H., Zu, J., Weisel, R.D., Keller, G., and Li, R.K. (2014). The effect of cyclic stretch on maturation and 3D tissue formation of human embryonic stem cellderived cardiomyocytes. Biomaterials 35, 2798-2808.   DOI
37 Mollova, M., Bersell, K., Walsh, S., Savla, J., Das, L.T., Park, S.Y., Silberstein, L.E., Dos Remedios, C.G., Graham, D., Colan, S., et al. (2013). Cardiomyocyte proliferation contributes to heart growth in young humans. Proc. Natl. Acad. Sci. USA 110, 1446-1451.   DOI
38 Mozaffarian, D., Benjamin, E.J., Go, A.S., Arnett, D.K., Blaha, M.J., Cushman, M., Das, S.R., de Ferranti, S., Despres, J.P., Fullerton, H.J., et al. (2016). Heart disease and stroke statistics-2016 update. A Report From the American Heart Association 133, e38-e360.
39 Nunes, S.S., Miklas, J.W., Liu, J., Aschar-Sobbi, R., Xiao, Y., Zhang, B., Jiang, J., Masse, S., Gagliardi, M., Hsieh, A., et al. (2013). Biowire: a platform for maturation of human pluripotent stem cell-derived cardiomyocytes. Nat. Methods 10, 781-787.   DOI
40 Oakley, R.H., and Cidlowski, J.A. (2015). Glucocorticoid signaling in the heart: A cardiomyocyte perspective. J. Steroid. Biochem. Mol. Biol. 153, 27-34.   DOI
41 Parikh, S.S., Blackwell, D.J., Gomez-Hurtado, N., Frisk, M., Wang, L., Kim, K., Dahl, C.P., Fiane, A., Tonnessen, T., Kryshtal, D.O., et al. (2017). Thyroid and glucocorticoid hormones promote functional T-tubule development in human-induced pluripotent stem cell-derived cardiomyocytes. Circ. Res. 121, 1323-1330.   DOI
42 Pasumarthi, K.B., and Field, L.J. (2002). Cardiomyocyte cell cycle regulation. Circ. Res. 90, 1044-1054.   DOI
43 Pedron, S., van Lierop, S., Horstman, P., Penterman, R., Broer, D.J., and Peeters, E. (2011). Stimuli responsive delivery vehicles for cardiac microtissue transplantation. Adv. Funct. Mater. 21, 1624-1630.   DOI
44 Peters, N.S., Green, C.R., Poole-Wilson, P.A., and Severs, N.J. (1993). Reduced content of connexin43 gap junctions in ventricular myocardium from hypertrophied and ischemic human hearts. Circulation 88, 864-875.   DOI
45 Peters, N.S., Severs, N.J., Rothery, S.M., Lincoln, C., Yacoub, M.H., and Green, C.R. (1994). Spatiotemporal relation between gap junctions and fascia adherens junctions during postnatal development of human ventricular myocardium. Circulation 90, 713.   DOI
46 Prakash, Y.S., Cody, M.J., Housmans P.R., Hannon J.D., and Sieck, G.C. (1999). Comparison of cross-bridge cycling kinetics in neonatal vs. adult rat ventricular muscle. J. Muscle Res. Cell Motil 20, 717-723.   DOI
47 Robertson, C., Tran, D.D., and George, S.C. (2013). Concise review: maturation phases of human pluripotent stem cell-derived cardiomyocytes. Stem Cells 31, 829-837.   DOI
48 Rog-Zielinska, E.A., Craig, M.A,. Manning, J.R., Richardson, R.V., Gowans, G.J., Dunbar, D.R., Gharbi, K., Kenyon, C.J., Holmes, M.C., Hardie, D.G., et al. (2015). Glucocorticoids promote structural and functional maturation of foetal cardiomyocytes: a role for PGC-$1{\alpha}$. Cell Death Differ. 22, 1106-1116.   DOI
49 Ruan, J.L., Tulloch, N.L., Razumova, M.V., Saiget, M., Muskheli, V., Pabon, L., Reinecke, H., Regnier, M., and Murry, C.E. (2016). Mechanical stress conditioning and electrical stimulation promote contractility and force maturation of induced pluripotent stem cell-derived human cardiac tissue. Circulation 134, 1557-1567.   DOI
50 Amin, A.S., Tan, H.L., and Wilde, A.A. (2010). Cardiac ion channels in health and disease. Heart Rhythm. 7, 117-126.   DOI
51 Camci-Unal, G., Annabi, N., Dokmeci, M.R., Liao, R., and Khademhosseini, A. (2014). Hydrogels for cardiac tissue engineering. NPG Asia Mater 6, e99.   DOI
52 Chattergoon, N.N., Giraud, G.D., Louey, S., Stork, P., Fowden, A.L., and Thornburg, K.L. (2012). Thyroid hormone drives fetal cardiomyocyte maturation. FASEB J. 26, 397-408.   DOI
53 Davis, R.P., Casini, S., van den Berg, C.W., Hoekstra, M., Remme, C.A., Dambrot, C., Salvatori, D., Oostwaard, D.W., Wilde, A.A., Bezzina, C.R., et al. (2012). Cardiomyocytes derived from pluripotent stem cells recapitulate electrophysiological characteristics of an overlap syndrome of cardiac sodium channel disease. Circulation 125, 3079-3091.   DOI
54 DeForest, C.A., and Anseth, K.S. (2012). Advances in bioactive hydrogels to probe and direct cell fate. Annu. Rev. Chem. Biomol. Eng. 3, 421-444.   DOI
55 Feric, N.T., and Radisic, M. (2016). Maturing human pluripotent stem cell-derived cardiomyocytes in human engineered cardiac tissues. Adv. Drug Deliv. Rev. 96, 110-134.   DOI
56 Sankova, B., Benes, J. Jr., Krejci, E., Dupays, L., Theveniau-Ruissy, M., Miquerol, L., and Sedmera, D. (2012). The effect of connexin40 deficiency on ventricular conduction system function during development. Cardiovasc Res. 95, 469-479.   DOI
57 Sartiani, L., Bettiol, E., Stillitano, F., Mugelli, A., Cerbai, E., and Jaconi, M.E. (2007). Developmental changes in cardiomyocytes differentiated from human embryonic stem cells: a molecular and electrophysiological approach. Stem Cells 25, 1136-1144.   DOI
58 Scuderi, G.J. and Butcher, J. (2017). Naturally engineered maturation of cardiomyocytes. Front. Cell Dev. Biol. 5, 50.   DOI
59 Shadrin, I.Y., Allen, B.W., Qian, Y., Jackman, C.P., Carlson, A.L., Juhas, M.E., and Bursac, N. (2017). Cardiopatch platform enables maturation and scale-up of human pluripotent stem cell-derived engineered heart tissues. Nat. Commun. 8, 1825.   DOI
60 Shiba, Y., Fernandes, S., Zhu, W.Z., Filice, D., Muskheli, V., Kim, J., Palpant, N.J., Gantz, J., Moyes, K.W., Reinecke, H., et al. (2012). Human ES-cell-derived cardiomyocytes electrically couple and suppress arrhythmias in injured hearts. Nature 489, 322-325.   DOI