Cell Sheet Tissue Engineering for Heart Failure
In recent years, regenerative medicine using cells for treating tissue defects has been in the spotlight as a new treatment for severe heart failure. Direct injection of bone marrow-derived cells and isolated skeletal myoblasts has already been used clinically as a method to improve cardiac function by regenerating cardiac muscle cells and blood vessels. The research on reconstructing functional three-dimensional (3D) cardiac grafts using tissue engineering methods has also now been addressed as a treatment for the next generation. Our laboratory has proposed an original tissue engineering technology called “cell sheet engineering” that stacks cell sheets to reconstruct functional 3D tissues. Transplantation of cell sheets has already shown it can cure damaged hearts, and it seems clear that the field of cell sheet tissue engineering can offer realistic treatment for patients with severe cardiac disorders.
KeywordsCardiac tissue engineering Cell sheet Regenerative medicine
Heart transplantation is the last hope for treatment of patients with severe heart failure due to ischemia-related disease and dilated cardiomyopathy. However, the lack of donor organs for transplantation continues to be a serious problem around the world. Although there have been many developments in artificial heart systems such as mechanical temporary assist devices or left ventricular assist devices (LVADs), there are also problems in conjunction with thromboembolism, infection, and finite durability. Given these challenges with current technologies, regenerative therapies are being investigated as an alternative approach and present new possibilities for the repair of a damaged heart. Recently, the direct injection of either autologous skeletal myoblasts or bone marrow-derived cells has been examined in clinical studies as an alternative cell source to cardiac muscle cells [1, 2, 3]. The direct injection of the dissociated cells has shown to be slightly effective, but it is often difficult to control the form, dimensions, or the position of implanted cells. In an attempt to solve these problems, research on advanced therapies using functional tissue produced by engineered cardiac grafts has started. Over the past decade, several studies have proved that bioengineered cardiac tissues could improve cardiac function in animal models of impaired heart . In this review, we discuss the progress of research on myocardial regeneration with a focus on our own original approach using cell sheet engineering.
3.2 Cell Sheet Engineering
3.3 Cardiac Tissue Reconstruction
Harvested cell sheets consist of only confluently cultured cells with their biological ECM on the basal side of the cell sheets, which acts as an adhesive agent for promoting an intimate attachment between each layered cardiac cell sheet. Within layered cardiac constructs, gap junctions are formed which rapidly establish an electrical connection between the cell sheets, leading to 3D cardiac tissues that synchronously pulsatile . Additionally, when these tissues were transplanted onto the subcutaneous tissue of nude rats, the grafts were macroscopically observed to beat synchronously . Importantly, these implanted tissues also showed long-term survival up to 1 year and 8 months, and the grafts also contained elongated sarcomeres, gap junctions, and well-organized vascular networks within the bioengineered cardiac tissues .
3.4 Cell Sheet Transplantation in Small Animal Models
3.5 Cell Sheet Transplantation in Preclinical and Clinical Studies
Our latest work has been to transplant engineered tissue in clinically relevant large- animal models. In a pacing-induced canine dilated cardiomyopathy model, transplantation of skeletal myoblast grafts has shown improved cardiac function with reduction of fibrosis and apoptosis . In a porcine cardiac infarction model, skeletal myoblast graft transplantation provided improvement of cardiac function with attenuation of cardiac remodeling . Transplantation of skeletal myoblast grafts has also demonstrated that it is an appropriate and safe treatment for chronic myocardial infarction without increasing the risk of ventricular arrhythmias. Most recently, the transplantation of cardiac progenitor cell grafts derived from embryonic stem cells improved cardiac function without teratoma formation and induced cardiomyogenic differentiation in a simian impaired heart model. Our latest work provides evidence of the safety and efficacy of using embryonic stem cells for myocardial regeneration .
Based on the promising results in various animal models, there is a clinical study using cell sheet transplantation currently underway. Autologous skeletal myoblast sheet therapy has demonstrated that it is possible to improve cardiac function to such a degree that LVADs are no longer required for patients with dilated cardiomyopathy .
The field of tissue engineering presents an exciting approach to regenerative therapies. The future solutions scaling up give more powerful construct creation, resulting in the developments of remarkable tissue-engineered cardiac assist devices or organ replacement. Overall, cell sheet tissue engineering is a novel approach for cardiac treatment that promises efficient and effective alternative therapies in regenerative medicine.
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