Glandular Stem Cells: A New Source for Myocardial Repair?

1. Introduction For more than 95% of the patients with end-stage heart failure there is no definitive treatment option up to now (AHA, 2009). This fact is caused by a severe shortage in donor hearts on the one hand and on the other hand by technical and economic limitations of cardiac assist devices and artificial hearts. Thus there is a big need for alternative treatement options. Basically heart failure is due to the inability of adult cardiomyocytes to divide and repair damaged heart muscle. For myocardial regenerative medicine stem cells which show the ability to differentiate into functional cardiomyocytes might be a promising source. Although human embryonic stem cells can differentiate into beating cardiomyocytes (Xu et al, 2002), however the therapeutic use of these cells is not without legal and ethical problems. Previous studies in animal models have demonstrated the therapeutical potential of intra-myocardial injection of adult murine stem cells. In a cell-cell contact dependent manner in mammals, mesenchymal stem cells aquired a cardiomyocyte phenotype (Orlic & Kocher 2001, Kawamoto & Yeh 2003, Wang et. al., 2006). Furthermore spontaneously beating cardiomyocytes were derived from isolated cardiomyogenic cell lines of murine bone marrow stromal cells (Makino et al., 1999) adipose tissue stroma cells (Planat-Bernard et. al., 2004) and from spermatogonial stem cells from the adult mouse testis (Guan et. al., 2006). In human myocardium however, adult stem cells from different origins applied intramyocardially did not show a differentiation into cardiomyocytes (Yoon & Wollert 2005). Thus, the search for an appropriate source of cells being able to differentiate into functional cardiomyocytes in human or to contribute to a contractile myocardial patch is still continuing. From adult rat pancreatic tissue multipotential stem cells were isolated and differentiated into the endodermal pancreatic and hepatic cells (Zulewski, 2001). Human pancreatic stem cells showed also a differentiation into mesodermal structures, like adipocytes, chondrocytes and osteocytes (Seeberger et. al., 2006). Furthermore rat and human pancreatic stem cells gave rise to cellular aggregates containing cell types of all three germ layers (Kruse et.al, 2004) including ectodermal lineages also shown in further recent publications (Seaberg et. al., 2004; Choi et. al., 2004). But up to now neither in animals nor in humans cardiomyocytes were generated from pancreatic stem cells. Due to the clinical need of cardiomyocytes, we investigated the differentiation of human pancreatic stem cell cultures into cardiomyocytes, a process potentially promoted by co-culture with human myocardial biopsies. Myocardial regeneration with artificially applied cardiomyocytes is emerging to a promising issue of significant scientific and clinical impact. Nevertheless the source of cells for human cardiomyocyte differentiation especially from adult tissue is still unclear. We hypothesized that human pancreatic stem cells may differentiate into cardiomyocyte-like cells enhanced when co- cultured with myocardial tissue.