Myocardial cell sheet therapy and cardiac function

Abstract

Heart failure (HF) is the leading cause of death in developed countries. Regenerative medicine has the potential to drastically improve treatment for advanced HF. Stem cell-based medicine has received attention as a promising candidate therapy over the past decade; however, it has not yet realized this potential in terms of reliability. The cell sheet is an innovative technology for constructing aligned graft cells, and several cell sources have been investigated for making a feasible cell sheet. The most representative thus far is skeletal myoblast, although such cells raise the issue of arrhythmogenicity. Regenerative cardiomyocytes (CMs) derived from pluripotent stem cells (PSCs), such as embryonic stem cells or induced PSCs, are the most promising, because a myocardial cell sheet (MCS) constructed with regenerative CMs can potentially enable contraction recovery and electromechanical coupling with host CMs. The functional outcomes of experimental MCS are reduction of ventricular wall stress and paracrine effects rather than contraction recovery. Several technical obstacles still hamper the clinical application of MCSs, with graft survival the most pivotal issue. Ischemia, apoptosis, inflammation, and immune response can all cause graft cell death, and a stable blood supply to the MCS is critical for successful engraftment. Ventricular tachycardia must also be considered in any myocardial cell therapy, and multiple layering of MCS (>3 layers) is necessary to reconstruct human myocardium. Innervation is also a potential issue. The future application of myocardial cell therapy with MCS for advanced HF depends on resolving these difficulties.

Engineered Cardiac Tissues Generated from Immature Cardiac and Stem Cell-Derived Cells: Multiple Approaches and Outcomes

“…The constructs used for cardiac tissue repair include the implantation of multicellular cardiospheres [18], various formulations of 2D cellular sheets [19][20][21][22], and various formulations of 3D tissues [5][6][7][8]13]. The composition of the noncellular constituents varies from minimal constituents for cardiosphere clusters to a range of ECM components [23,24] and growth factors [25][26][27] selected for their ability to facilitate CM survival and functional maturation.…”

Future Prospects for Regenerated Heart Using Induced Pluripotent Stem Cells

“…It is also well known that myoblasts induced arrhythmia in the Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC) trial for severe HF patients (4). Even though myoblasts were transplanted as cell sheets, they still provoked arrhythmia because myoblasts do not express connexin43 or N-cadherin, and have their own automaticity (5). On the other hand, CMs can connect with a host heart, inducing less risk of arrhythmia with transplanted CMs.…”

“…Several cell sources are potentially available for such therapy including bone marrow stem cells, myoblasts, and cardiac progenitor cells, while BMSCs and CPCs were shown to be safe in transplanted patients (2 -4). However, while all of these cell sources are functionally successful in small animal experiments, none has produced a marked improvement of cardiac function in large clinical studies (5). Thus, transplantation of purified cardiomyocytes (CMs) is eagerly awaited to achieve feasible and solid strategies for regenerative cardiac medicine.…”

Report of the American Heart Association (AHA) Scientific Sessions 2012, Los Angeles

“…Some clinical trials in this area are ongoing; however, in general, large clinical trials have failed to show a marked improvement in cardiac function, despite most of the basic studies using small-animal models, such as mice or rats, showed a prominently significant improvement in cardiac function (>10% increase in LVEF) with cell therapies. 17 The valley of death between basic and clinical research in stem cell therapy demands the necessity for preclinical studies with large-animal models. The "Tissue-Engineered Heart Repair" session focused on how to achieve functional repair following the loss of large numbers of cardiomyocytes.…”