In recent years, numerous groups provided compelling evidence for the existence of somatic stem cells in the heart of different mammalian species.  Stem cells and progenitor cells are supposed to exist in niches, where they remain in an undifferentiated and quasi-dormant state until external signals stimulate commitment and differentiation to specific somatic cells which may contribute to the repair or maintenance of homeostasis of an organ. Mimicking a stem cell niche of the heart in vitro, we succeeded in the isolation of somatic stem cells from postnatal murine hearts and could maintain these cells as monoclonal self-renewing cells lines expressing Oct4, Sox2 and Nanog for several years (Fig. 1). These cells obviously committed to the mesodermal lineage and expressing early myocardial transcription factors Brachyury, Nkx2.5, GATA4, and Isl1 exclusively differentiate to cardiomyocytes, smooth muscle cells, and vascular endothelial cells and thus were named cardiovascular progenitor cells (CVPCs). Cardiomyogenic progenitors further differentiate to equal numbers of functional pacemakers, atrial and ventricular cardiomyocytes with a near-adult action potential. Stimulation of CVPCs with Activin A and Retinoic Acid did not yield any cell types of the endodermal and ectodermal lineage, respectively. Addition of BMP2 and SPARC promoted cardiomyogenesis and led to the upregulation of genes for the mesoderm specific transcription factor Brachyury and the early myocardial transcription factor Nkx2.5.

In our ongoing research, we try to reveal the molecular pathways which allow SPARC, BMP2 and Nodal to activate Brachyury and Nkx2.5 expression in CVPCs and how Brachyury, Nanog and Nkx2.5 interact on the transcriptional level in undifferentiated and differentiating CVPCs. Our long term scientific goal is to understand early cardiomyogenesis and how somatic stem cells may contribute to homeostasis of the heart. Understanding the molecular and cellular interplay regulating stem cell self-renewal and differentiation may contribute to future targeted therapies utilizing growth factors or small molecules for the temporal endogenous activation of the stem cell pool.