Cell sheet engineering for heart tissue repair☆
Introduction
Recently, cell-based therapies have emerged as alternative treatments to cardiac transplantation for the repair of damaged heart tissue, since the benefits of heart transplantation are restricted by donor shortages [1]. Although cell suspension transplantation is one of the promising treatments for impaired heart tissue, it is often difficult to control shape, size and location of the injected cells. Additionally, isolated cell transplantation may not be applicable in treating myocardial tissue defects. Therefore, research on methods of transplanting tissue-engineered functional heart grafts has been established over the past decade.
Tissue engineering has been developed as a basic technology for regenerative medicine. The popular components used in tissue engineering approaches have generally included isolated cells or cell substitutes, appropriate signaling molecules such as cytokines or growth factors, and extracellular matrix (ECM) proteins [2]. As alternatives for the extracellular matrix, 3-dimensional (3-D) biodegradable scaffolds have been used for the reconstruction of various tissues and organs including cartilage, bone, skin, blood vessels and heart valves.
By using the methods based on biodegradable polymers, the spaces occupied by the biodegradable polymers often become filled with large amounts of deposited ECM, with the number of cell-to-cell connections becoming reduced in the resultant tissues. In addition, scaffold biodegradation can result in inflammatory responses and pathological fibrotic states. To overcome these problems, we have developed a novel tissue engineering methodology termed “cell sheet engineering”, that constructs 3-D functional tissues by layering two-dimensional (2-D) confluent cell sheets without the use of any biodegradable ECM alternatives.
Section snippets
Cell sheet harvest using temperature-responsive culture dishes
Cell sheets are obtained by using specialized cell culture surfaces that are covalently grafted with the temperature-responsive polymer, poly (N-isopropylacrylamide) (PIPAAm) [3], [4]. The surfaces are slightly hydrophobic and cells adhere and proliferate under normal culture conditions at 37 °C. By lowering the temperature below 32 °C, the surfaces become highly hydrophilic and therefore non-adhesive to cells due to rapid hydration and swelling of the grafted PIPAAm. This unique surface change
Myocardial tissue engineering by layering cell sheets
In myocardial tissue engineering, various biomaterials such as poly (glycolic acid) (PGA), gelatin, alginate and collagen have been used as prefabricated biodegradable scaffolds [21]. For the repair of damaged cardiac muscle, two strategies have been applied to incorporate cells into the scaffolding materials. One method is to seed cells into prefabricated, highly porous scaffolds (Fig. 2A). The group of Papadaki and Vunjak-Novakovic reported the cultivation of neonatal rat cardiomyocytes on
Cell sources
Although it has been possible to reconstruct myocardial tissues using tissue engineering methods, several crucial problems remain unresolved for future clinical applications. One of the critical problems is the potential source of cardiac cells. Thus far, primary cells derived from fetal or neonatal hearts have been applied to regenerate myocardial tissues in animal studies, it is difficult to obtain human fetal or neonatal cardiomyocytes with regard to ethical and moral concepts. From these
Conclusions
Myocardial tissue engineering based on cell sheet engineering can provide new in vitro heart models and might be useful for cardiovascular tissue repair.
Acknowledgements
We would like to thank Joseph Yang for his helpful assistance. The present work was supported by grants for the High-Tech Research Center Program and the Center of Excellence Program for 21st Century from the Ministry of Education, Culture, Sports, Science and Technology in Japan.
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2020, Tissue and CellCitation Excerpt :Two models of 3D heart muscle have been developed using scaffold free methods. Temperature sensitive surfaces (Sekine et al., 2016; Shimizu, 2014; Matsuura et al., 2014; Haraguchi et al., 2014; Shimizu et al., 2009; Masuda et al., 2008) and changes in the concentration of surface adhesion proteins (Khait and Birla, 2008; Huang et al., 2008; Baar et al., 2005; Khait et al., 2009; Khait and Birla, 2009) have been used to modulate the culture environment, supporting 3D tissue formation. In both cases, the process results in a sheet of cohesive and contracting CMs with very high functional performance.
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This review is part of the Advanced Drug Delivery Reviews theme issue on “Emerging Trends in Cell-Based Therapeutics”.