ABSTRACT
How many cardiomyocytes are required to artificially create cardiac tissue that can mechanically support the deteriorated cardiac contractility of a failing heart? The human left ventricle contains several billions of cardiomyocytes [1], and it is estimated that about a billion cardiomyocytes are lost in a typical myocardial infarction [2]. In the case of cardiomyopathy, the contractility of cardiomyocytes becomes deteriorated and many cells result in the apoptosis. From these facts, it seems that preferably more than a billion cardiomyocytes are necessary to substantially support the contractility of a failing heart. Then, how can such a large number of cardiomyocytes be prepared? Among human cell types, it has been
reported that various types of stem cells, including bone marrowderived stem cells [3], adipose-derived stem cells [4], resident cardiac stem cells [5], human embryonic stem cells (hESCs) [6], and human induced pluripotent stem cells (hiPSCs) [7], have the ability to differentiate into cardiomyocytes. Among these cell types, bone marrow-derived stem cells, adipose-derived stem cells, and resident cardiac stem cells have only limited ability of proliferation and cardiac differentiation. On the other hand, hESCs and hiPSCs (ESCs/ iPSCs) have unlimited self-renewal ability and satisfactory cardiac differentiation potential [8]. Therefore, currently ESCs/iPSCs might be the most promising cell sources to prepare such a large number of cardiomyocytes. Many investigations in preparing ESC-/iPSC-derived cardiomyocytes pursue the issue of how to enhance the efficiency of cardiac differentiation. Such investigations are of course essential and indispensable. However, for the purpose of clinical application, the following two aspects are required, in addition to mere the efficiency of cardiac differentiation. The first is whether the culture methods are scalable for preparing the necessary number of cardiomyocytes with approapriate cost-and labor-effectiveness. The second aspect is the safety of prepared cells for clinical use. Coculture with animal cells and the use of animal-derived materials are the possible factors of infection and should be avoided as much as possible. The process of preparing cardiomyocytes from ESCs/iPSCs consists of three steps: (1) the expansion of undifferentiated ESCs/iPSCs, (2) the induction of cardiac differentiation, and (3) the enrichment of ESC-/iPSC-derived cardiomyocytes. In this chapter, recent technologies in these three steps are reviewed, particularly in terms of the cost-effectiveness and safety of prepared cells.
