ISL1+ CARDIOBLASTS · The LIM-homeodomain transcription factor islet-1 is a genetic marker for isolation and generation of cardiovascular progenitor cells

Final Activity Report Summary - ISL1+ CARDIOBLASTS (The LIM-homeodomain transcription factor islet-1 is a genetic marker for isolation and generation of cardiovascular progenitor cells)

Taking advantage of the developmental lineage marker Isl1 for undifferentiated cardiogenic precursor cells, our group has previously reported the identification of a novel cardiac cell type in the post-natal heart, which is capable of self-renewal with the maintenance of spontaneous and triggered differentiation into fully mature cardiomyocytes. We were able to demonstrate that Isl1+/Nkx2.5+/flk1+ clones of ES cell derived mesodermal precursors represent multipotent master cardiovascular stem cells capable to differentiate in vitro into all three major cell lineages of the heart, cardiac muscle, smooth muscle and endothelium (Laugwitz et al., Nature 2005; Moretti et al., Cell 2006; Laugwitz et al., Development 2008). The ability to derive multipotent cardiovascular progenitors from ES cells and to amplify them in a selective and clonal manner on cardiac mesenchyme feeder layers may allow an alternative way for the regeneration of specific heart structures without the dangers of teratomas that are known to arise from other ES systems. In collaboration with of Dr. Kenneth Chien and Dr. Sylvia Evans we could demonstrate that the Wnt/beta-catenin pathway is a major component of the cardiac mesenchymal environment controlling self-renewal and specification of Isl1+ cardiovascular precursors from mouse ES cells, embryos and postnatal hearts (Qyang et al., Cell Stem Cell 2007). Moreover this work has shown that chemical inhibitors of the glycogen synthase kinase 3 (GSK3-beta) can markedly promote the in vitro proliferation of Isl1+ cells from human neonatal hearts, representing a key advance towards the eventual cloning of human Isl1+ cardiac progenitors. The recent landmark discovery that mouse and human somatic cells can be reprogrammed to ground state of pluripotency by ectopic expression of only a few defined transcription factors offers a novel fascinating route to patient-specific pluripotent cells, without the technical and ethical limitations of somatic cell nuclear transfer. However, for iPSCs to fulfill their potential for in vitro disease modelling and regenerative medicine, efficient differentiation protocols to derive specific cell lineages need to be established. We have demonstrate, in collaboration with the group of Dr. Austin Smith, that mouse and human iPS cells could be a source of Isl1+ cardiovascular progenitors which display multipotency into all three cardiovascular lineages in vitro and in vivo. (Moretti et al., FASEB J 2010). These results represent a first step towards the generation of patient-specific iPSC-based ISL1+ cardiovascular precursors, which would be extremely valuable in designing disease-specific assays for screening of drug-cardiotoxicity, in identifying and validating therapeutic targets, and in studying mechanisms of both congenital and acquired forms of cardiovascular disorders. Submitted work has in fact proven that patient-specific iPSC-derived cardiomyocytes can be used to model the specific pathology seen in a genetically inherited cardiac disease (LQT1 syndrome) and to validate established therapeutical treatments. Furthermore, the accessibility of patient-specific iPSC-derived cardiac progenitors and may represent a significant advantage over differentiated cells or pluripotent stem cells to achieve large-scale production of multipotent, tumor-free cardiac cells for clinical and translational applications in the future (Laugwitz et al., Development 2008).

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