Cardiac Differentiation of Embryonic Stem Cells by Patterning Culture

Abstract

Although heart transplantation has been established as an ultimate therapy for severe heart failure, it is not a universal therapy because of the lack of donor hearts. As the alternative to heart transplantation, regenerative medicine based on cell transplantation attracts increasing attention. Recent studies revealed that bone marrow-derived cells (Messina et al., 2004; Wollert et al., 2004), endothelial progenitor cells (Kawamoto et al., 2001), adipose-derived cells (Wang et al., 2009), and myoblasts (Memon et al., 2005; Hata et al., 2006; Kondoh et al., 2006) have the potential to improve cardiac function when they are transplanted into a failing heart. Because these somatic cells can be harvested from the patients themselves, their clinical applications have already started. It is considered that the therapeutic potential of these cells depends on the paracrine effects such as the promotion of angiogenesis, suppression of fibrosis, suppression of apoptosis, and attraction of stem cells, and/or the direct contribution to angiogenesis by the differentiation into vascular cells. It was also reported that bone marrow-derived cells and adipose-derived cells have the potential to differentiate into cardiomyocytes (Makino et al., 1999; Planat-Benard et al., 2004). However, the efficiency is too low to directly contribute to the cardiac contractility. Therefore, although the above cells are significantly useful for cardiac regeneration, they cannot replace the dysfunctional cardiomyocytes in a failing heart, and thus their therapeutic potential is limited. Cardiac contractility mainly depends on the cardiomyocytes which account for one third of the total cell content of a heart (Brutsaert, 2003). Therefore, for the better recovery of cardiac contractility, supplementation of functional cardiomyocytes must be necessary. The representative diseases requiring heart transplantation are dilated cardiomyopathy (DCM) and dilated form of hypertrophic cardiomyopathy (D-HCM). Actually, in Japan, approximately 90% of the patients undergoing heart transplantation so far were DCM or DHCM. In both DCM and D-HCM, cardiac contractility is decreased by the dysfunction and loss of cardiomyocytes. In approximately 20% of DCM and 60% of HCM, the responsible gene mutations were identified. One of the destinations in cardiac regenerative therapy is to transplant enough amounts of functional cardiomyocytes to mechanically support the cardiac contractility, replacing the dysfunctional and lost cardiomyocytes in a failing heart of such cardiomyopathies. A human left ventricle contains several billions of cardiomyocytes (Olivetti et al., 1991). Therefore, more than a billion is the desired number of cardiomyocytes to be transplanted for the recovery of cardiac contractility. It is impossible