Abstract
Recent studies have reported that the injection of isolated cells can improve cardiac function in models of myocardial infarction. However, the loss of transplanted cells from the target site due to local hypoxia and cell washout remains a major problem. To overcome these limitations, we have developed cell sheet-based tissue engineering that allows the generation of confluent cultured cells, stacked cell sheets, and three-dimensional (3D) cell-dense tissues. Cell sheet-based patches can improve the function of damaged hearts in animal models. Stacked cardiac cell sheets beat synchronously both in vitro and in vivo and have the characteristic structure of native heart tissue. Upscaling of this technology through multistep transplantation of triple-layered cell sheets allowed the construction of functional cardiac tissue about 1 mm thick. Furthermore, we succeeded in bioengineering 3D cardiac tissue containing a vascular network by in vitro perfusion culture of cell sheets stacked sequentially on a vascular bed obtained from resected tissue. Since the vascular bed was excised with its artery and vein intact, the bioengineered tissue could be transplanted by anastomosis of its vessels with those of the host animal. Following the creation of cardiac patches for direct implantation onto a damaged heart, the next challenge will be to engineer organs with tubular or spherical structures that can function as pumps to provide circulatory support. The goal for the future is to develop this technology to create functional organ-like tissues with vascular networks that can be used in patients as an alternative to conventional organ transplantation.
Similar content being viewed by others
References
Birla RK, Dow DE, Huang YC, Migneco F, Khait L, Borschel GH, Dhawan V, Brown DL (2008) Methodology for the formation of functional, cell-based cardiac pressure generation constructs in vitro. In Vitro Cell Dev Biol Anim 44(8–9):340–350
Bursac N, Papadaki M, Cohen RJ, Schoen FJ, Eisenberg SR, Carrier R, Vunjak-Novakovic G, Freed LE (1999) Cardiac muscle tissue engineering: toward an in vitro model for electrophysiological studies. Am J Physiol 277(2):H433–H444
Caspi O, Huber I, Kehat I, Habib M, Arbel G, Gepstein A, Yankelson L, Aronson D, Beyar R, Gepstein L (2007) Transplantation of human embryonic stem cell-derived cardiomyocytes improves myocardial performance in infarcted rat hearts. J Am Coll Cardiol 50(19):1884–1893
Chouinard JA, Gagnon S, Couture MG, Levesque A, Vermette P (2009) Design and validation of a pulsatile perfusion bioreactor for 3D high cell density cultures. Biotechnol Bioeng 104(6): 1215–1223
Christman KL, Lee RJ (2006) Biomaterials for the treatment of myocardial infarction. J Am Coll Cardiol 48(5):907–913
Evans HJ, Sweet JK, Price RL, Yost M, Goodwin RL (2003) Novel 3D culture system for study of cardiac myocyte development. Am J Physiol Heart Circ Physiol 285(2):H570–H578
Franchini JL, Propst JT, Comer GR, Yost MJ (2007) Novel tissue engineered tubular heart tissue for in vitro pharmaceutical toxicity testing. Microsc Microanal 13(4):267–271
Haraguchi Y, Shimizu T, Yamato M, Kikuchi A, Okano T (2006) Electrical coupling of cardiomyocyte sheets occurs rapidly via functional gap junction formation. Biomaterials 27(27):4765–4774
Hata H, Matsumiya G, Miyagawa S, Kondoh H, Kawaguchi N, Matsuura N, Shimizu T, Okano T, Matsuda H, Sawa Y (2006) Grafted skeletal myoblast sheets attenuate myocardial remodeling in pacing-induced canine heart failure model. J Thorac Cardiovasc Surg 132(4):918–924
Hofmann M, Wollert KC, Meyer GP, Menke A, Arseniev L, Hertenstein B, Ganser A, Knapp WH, Drexler H (2005) Monitoring of bone marrow cell homing into the infarcted human myocardium. Circulation 111(17):2198–2202
Homma J, Sekine H, Matsuura K, Yamato M, Shimizu T (2017) Myoblast cell sheet transplantation enhances the endogenous regenerative abilities of infant hearts in rats with myocardial infarction. J Tissue Eng Regen Med 11(6):1897–1906
Hudson W, Collins MC, deFreitas D, Sun YS, Muller-Borer B, Kypson AP (2007) Beating and arrested intramyocardial injections are associated with significant mechanical loss: implications for cardiac cell transplantation. J Surg Res 142(2):263–267
Kondoh H, Sawa Y, Miyagawa S, Sakakida-Kitagawa S, Memon IA, Kawaguchi N, Matsuura N, Shimizu T, Okano T, Matsuda H (2006) Longer preservation of cardiac performance by sheet-shaped myoblast implantation in dilated cardiomyopathic hamsters. Cardiovasc Res 69(2): 466–475
Kubo H, Shimizu T, Yamato M, Fujimoto T, Okano T (2007) Creation of myocardial tubes using cardiomyocyte sheets and an in vitro cell sheet-wrapping device. Biomaterials 28(24): 3508–3516
Kushida A, Yamato M, Konno C, Kikuchi A, Sakurai Y, Okano T (1999) Decrease in culture temperature releases monolayer endothelial cell sheets together with deposited fibronectin matrix from temperature-responsive culture surfaces. J Biomed Mater Res 45(4):355–362
Kutschka I, Chen IY, Kofidis T, von Degenfeld G, Sheikh AY, Hendry SL, Hoyt G, Pearl J, Blau HM, Gambhir SS, Robbins RC (2007) In vivo optical bioluminescence imaging of collagen-supported cardiac cell grafts. J Heart Lung Transplant 26(3):273–280
Laflamme MA, Murry CE (2005) Regenerating the heart. Nat Biotechnol 23(7):845–856
Langer R, Vacanti JP (1993) Tissue engineering. Science 260(5110):920–926
Lee EJ, Kim DE, Azeloglu EU, Costa KD (2008) Engineered cardiac organoid chambers: toward a functional biological model ventricle. Tissue Eng Part A 14(2):215–225
Leor J, Aboulafia-Etzion S, Dar A, Shapiro L, Barbash IM, Battler A, Granot Y, Cohen S (2000) Bioengineered cardiac grafts: a new approach to repair the infarcted myocardium? Circulation 102(19 Suppl 3):III56–III61
Li RK, Jia ZQ, Weisel RD, Mickle DA, Choi A, Yau TM (1999) Survival and function of bioengineered cardiac grafts. Circulation 100(19 Suppl):II63–II69
Memon IA, Sawa Y, Fukushima N, Matsumiya G, Miyagawa S, Taketani S, Sakakida SK, Kondoh H, Aleshin AN, Shimizu T, Okano T, Matsuda H (2005) Repair of impaired myocardium by means of implantation of engineered autologous myoblast sheets. J Thorac Cardiovasc Surg 130(5):1333–1341
Menasche P, Hagege AA, Vilquin JT, Desnos M, Abergel E, Pouzet B, Bel A, Sarateanu S, Scorsin M, Schwartz K, Bruneval P, Benbunan M, Marolleau JP, Duboc D (2003) Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction. J Am Coll Cardiol 41(7):1078–1083
Menasche P, Alfieri O, Janssens S, McKenna W, Reichenspurner H, Trinquart L, Vilquin JT, Marolleau JP, Seymour B, Larghero J, Lake S, Chatellier G, Solomon S, Desnos M, Hagege AA (2008) The Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC) trial: first randomized placebo-controlled study of myoblast transplantation. Circulation 117(9):1189–1200
Michel JB (2003) Anoikis in the cardiovascular system: known and unknown extracellular mediators. Arterioscler Thromb Vasc Biol 23(12):2146–2154
Miyagawa S, Sawa Y, Sakakida S, Taketani S, Kondoh H, Memon IA, Imanishi Y, Shimizu T, Okano T, Matsuda H (2005) Tissue cardiomyoplasty using bioengineered contractile cardiomyocyte sheets to repair damaged myocardium: their integration with recipient myocardium. Transplantation 80(11):1586–1595
Miyagawa S, Saito A, Sakaguchi T, Yoshikawa Y, Yamauchi T, Imanishi Y, Kawaguchi N, Teramoto N, Matsuura N, Iida H, Shimizu T, Okano T, Sawa Y (2010) Impaired myocardium regeneration with skeletal cell sheets – a preclinical trial for tissue-engineered regeneration therapy. Transplantation 90(4):364–372
Miyahara Y, Nagaya N, Kataoka M, Yanagawa B, Tanaka K, Hao H, Ishino K, Ishida H, Shimizu T, Kangawa K, Sano S, Okano T, Kitamura S, Mori H (2006) Monolayered mesenchymal stem cells repair scarred myocardium after myocardial infarction. Nat Med 12(4):459–465
Nelson TJ, Martinez-Fernandez A, Yamada S, Perez-Terzic C, Ikeda Y, Terzic A (2009) Repair of acute myocardial infarction by human stemness factors induced pluripotent stem cells. Circulation 120(5):408–416
Okano T, Yamada N, Sakai H, Sakurai Y (1993) A novel recovery system for cultured cells using plasma-treated polystyrene dishes grafted with poly(N-isopropylacrylamide). J Biomed Mater Res 27(10):1243–1251
Ott HC, Matthiesen TS, Goh SK, Black LD, Kren SM, Netoff TI, Taylor DA (2008) Perfusion-decellularized matrix: using nature’s platform to engineer a bioartificial heart. Nat Med 14(2):213–221
Ren X, Moser PT, Gilpin SE, Okamoto T, Wu T, Tapias LF, Mercier FE, Xiong L, Ghawi R, Scadden DT, Mathisen DJ, Ott HC (2015) Engineering pulmonary vasculature in decellularized rat and human lungs. Nat Biotechnol 33(10):1097–1102
Richardson TP, Peters MC, Ennett AB, Mooney DJ (2001) Polymeric system for dual growth factor delivery. Nat Biotechnol 19(11):1029–1034
Sakaguchi K, Shimizu T, Horaguchi S, Sekine H, Yamato M, Umezu M, Okano T (2013) In vitro engineering of vascularized tissue surrogates. Sci Rep 3:1316
Sawa Y, Miyagawa S, Sakaguchi T, Fujita T, Matsuyama A, Saito A, Shimizu T, Okano T (2012) Tissue engineered myoblast sheets improved cardiac function sufficiently to discontinue LVAS in a patient with DCM: report of a case. Surg Today 42(2):181–184
Sekine H, Shimizu T, Kosaka S, Kobayashi E, Okano T (2006a) Cardiomyocyte bridging between hearts and bioengineered myocardial tissues with mesenchymal transition of mesothelial cells. J Heart Lung Transplant 25(3):324–332
Sekine H, Shimizu T, Yang J, Kobayashi E, Okano T (2006b) Pulsatile myocardial tubes fabricated with cell sheet engineering. Circulation 114(1 Suppl):I87–I93
Sekine H, Shimizu T, Hobo K, Sekiya S, Yang J, Yamato M, Kurosawa H, Kobayashi E, Okano T (2008) Endothelial cell coculture within tissue-engineered cardiomyocyte sheets enhances neovascularization and improves cardiac function of ischemic hearts. Circulation 118(14 Suppl):S145–S152
Sekine H, Shimizu T, Dobashi I, Matsuura K, Hagiwara N, Takahashi M, Kobayashi E, Yamato M, Okano T (2011) Cardiac cell sheet transplantation improves damaged heart function via superior cell survival in comparison with dissociated cell injection. Tissue Eng Part A 17(23–24): 2973–2980
Sekine H, Shimizu T, Sakaguchi K, Dobashi I, Wada M, Yamato M, Kobayashi E, Umezu M, Okano T (2013) In vitro fabrication of functional three-dimensional tissues with perfusable blood vessels. Nat Commun 4:1399
Sekiya S, Shimizu T, Yamato M, Kikuchi A, Okano T (2006) Bioengineered cardiac cell sheet grafts have intrinsic angiogenic potential. Biochem Biophys Res Commun 341(2):573–582
Seta H, Matsuura K, Sekine H, Yamazaki K, Shimizu T (2017) Tubular cardiac tissues derived from human induced pluripotent stem cells generate pulse pressure in vivo. Sci Rep 7:45499
Shiba Y, Gomibuchi T, Seto T, Wada Y, Ichimura H, Tanaka Y, Ogasawara T, Okada K, Shiba N, Sakamoto K, Ido D, Shiina T, Ohkura M, Nakai J, Uno N, Kazuki Y, Oshimura M, Minami I, Ikeda U (2016) Allogeneic transplantation of iPS cell-derived cardiomyocytes regenerates primate hearts. Nature 538(7625):388–391
Shimizu T, Yamato M, Isoi Y, Akutsu T, Setomaru T, Abe K, Kikuchi A, Umezu M, Okano T (2002) Fabrication of pulsatile cardiac tissue grafts using a novel 3-dimensional cell sheet manipulation technique and temperature-responsive cell culture surfaces. Circ Res 90(3):e40
Shimizu T, Sekine H, Isoi Y, Yamato M, Kikuchi A, Okano T (2006a) Long-term survival and growth of pulsatile myocardial tissue grafts engineered by the layering of cardiomyocyte sheets. Tissue Eng 12(3):499–507
Shimizu T, Sekine H, Yang J, Isoi Y, Yamato M, Kikuchi A, Kobayashi E, Okano T (2006b) Polysurgery of cell sheet grafts overcomes diffusion limits to produce thick, vascularized myocardial tissues. FASEB J 20(6):708–710
Song JJ, Guyette JP, Gilpin SE, Gonzalez G, Vacanti JP, Ott HC (2013) Regeneration and experimental orthotopic transplantation of a bioengineered kidney. Nat Med 19(5):646–651
Soonpaa MH, Koh GY, Klug MG, Field LJ (1994) Formation of nascent intercalated disks between grafted fetal cardiomyocytes and host myocardium. Science 264(5155):98–101
Terrovitis J, Lautamaki R, Bonios M, Fox J, Engles JM, Yu J, Leppo MK, Pomper MG, Wahl RL, Seidel J, Tsui BM, Bengel FM, Abraham MR, Marban E (2009) Noninvasive quantification and optimization of acute cell retention by in vivo positron emission tomography after intramyocardial cardiac-derived stem cell delivery. J Am Coll Cardiol 54(17):1619–1626
Wilmut I, Leslie S, Martin NG, Peschanski M, Rao M, Trounson A, Turner D, Turner ML, Yamanaka S, Taylor CJ (2015) Development of a global network of induced pluripotent stem cell haplobanks. Regen Med 10(3):235–238
Yamada N, Okano T, Sakai H, Karikusa F, Sawasaki Y, Sakurai Y (1990) Thermo-responsive polymeric surfaces; control of attachment and detachment of cultured cells. Makromol Chem Rapid 11(11):571–576
Yang J, Yamato M, Kohno C, Nishimoto A, Sekine H, Fukai F, Okano T (2005) Cell sheet engineering: recreating tissues without biodegradable scaffolds. Biomaterials 26(33): 6415–6422
Yildirim Y, Naito H, Didie M, Karikkineth BC, Biermann D, Eschenhagen T, Zimmermann WH (2007) Development of a biological ventricular assist device: preliminary data from a small animal model. Circulation 116(11 Suppl):I16–I23
Yost MJ, Baicu CF, Stonerock CE, Goodwin RL, Price RL, Davis JM, Evans H, Watson PD, Gore CM, Sweet J, Creech L, Zile MR, Terracio L (2004) A novel tubular scaffold for cardiovascular tissue engineering. Tissue Eng 10(1–2):273–284
Zandonella C (2003) Tissue engineering: the beat goes on. Nature 421(6926):884–886
Zhang M, Methot D, Poppa V, Fujio Y, Walsh K, Murry CE (2001) Cardiomyocyte grafting for cardiac repair: graft cell death and anti-death strategies. J Mol Cell Cardiol 33(5):907–921
Zhang B, Montgomery M, Chamberlain MD, Ogawa S, Korolj A, Pahnke A, Wells LA, Masse S, Kim J, Reis L, Momen A, Nunes SS, Wheeler AR, Nanthakumar K, Keller G, Sefton MV, Radisic M (2016) Biodegradable scaffold with built-in vasculature for organ-on-a-chip engineering and direct surgical anastomosis. Nat Mater 15(6):669–678
Zimmermann WH, Melnychenko I, Wasmeier G, Didie M, Naito H, Nixdorff U, Hess A, Budinsky L, Brune K, Michaelis B, Dhein S, Schwoerer A, Ehmke H, Eschenhagen T (2006) Engineered heart tissue grafts improve systolic and diastolic function in infarcted rat hearts. Nat Med 12(4):452–458
Acknowledgments
This research was supported by JSPS KAKENHI grant number 19H04453. We thank OxMedComms (www.oxmedcomms.com) for writing assistance.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2020 Springer Nature Switzerland AG
About this entry
Cite this entry
Sekine, H., Homma, J., Shimizu, T. (2020). Cell Sheets for Cardiac Tissue Engineering. In: Eberli, D., Lee, S., Traweger, A. (eds) Organ Tissue Engineering. Reference Series in Biomedical Engineering(). Springer, Cham. https://doi.org/10.1007/978-3-030-18512-1_3-1
Download citation
DOI: https://doi.org/10.1007/978-3-030-18512-1_3-1
Received:
Accepted:
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-18512-1
Online ISBN: 978-3-030-18512-1
eBook Packages: Springer Reference EngineeringReference Module Computer Science and Engineering