A sustainable source of cardiocytes for cell therapy

Development of heart cells is initiated and regulated by a complex network of signals emanating from all germ layers. We demonstrated that extra-embryonic endoderm secretes several growth factors ambivalently influencing cardiomyogenesis and identified SPARC and S100A4 as two new factors promoting cardiomyogenesis. Here we suggest to investigate their signalling pathway(s) in cardiomyocytes, and to employ these factors for the identification and isolation of cardioblast-like stem cells both from embryonic stem cell derived embryoid bodies and from murine and human heart tissue. Expected results will foster the understanding of molecular mechanisms regulating cardiomyogenesis at the cellular level, and by improvement of in vitro cardiomyogenesis, will contribute to the development of a renewable and sustainable source of cardiomyocytes for cell therapy of the heart.

Development and life long function of our heart is influenced by a vast number of molecular factors and cellular processes. We were first to succeed in the generation of clonal cardiac stem cells from murine hearts which self- renew and divide indefinitely, and demonstrated that they develop exclusively to cardiomyocytes and blood vessel cells. Self-renewal in culture is sustained by the growth factor LIF and development to cardiomyocytes is increased by SPARC. SPARC, a versatile secreted protein activates the Glycogensynthase-Kinase-3, a mediator of the Wnt- signaling pathway, and activates SMAD-2, a mediator of the TGFß-signaling pathway. SPARC expression is enhanced by Desmin and leads to the upregulated expression of Nkx2.5, which in turn pushes undifferentiated mesodermal cells to become cardiomyocytes. By isolating clonal stem cells of the heart we generated for the first time an exhaustless source for heart cells which will contribute to our understanding of the cell therapy of the heart. As a fundamental contribution to the understanding of our heart function, we could demonstrate for the first time that molecular processes influencing heart development during embryogenesis also play fundamental roles in self- renewal and differentiation of somatic stem cells from adult hearts.