Fate restriction of multipotent cardiovascular progenitor populations

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Heart failure is one of the leading causes for mortality in the western world. Partially, this can be attributed to the limited regenerative potential of the human heart after injury. In contrast to other species, like the zebrafish or salamanders, dead cardiomyocytes in the human heart cannot be replaced by new cells. Instead, scarring occurs limiting cardiac function. Human cardiovascular progenitor cells, which occur during embryogenesis and can be differentiated in vitro from human embryonic stem cells, harbor great potential as a therapeutic cell source for regenerative medicine. They can differentiate into cells of all cardiac lineages and are known drivers for cardiac regeneration in other species. However, the cellular mechanisms governing fundamental processes like self-renewal and fate-decision of these cells are still largely elusive hampering successful clinical translation of this promising approach. The hypothesis of this proposal is that the multipotent cardiovascular progenitor populations which arise during in vitro differentiation of human embryonic stem cells are not homogeneous populations but consist of multiple subpopulations. These subpopulations differ in their differentiation capacities, are governed by distinct transcriptional networks and respond differently to exogenous signaling cues. The main objective of the project is to develop strategies for identifying, isolating and amplifying the different cardiovascular progenitor subpopulations. To achieve this, advanced single cell technologies (transcriptomics and epigenomics) will be combined with virus-based lineage tracing. The knowledge generated will be further exploited to establish new tools to temporally and spatially control amplification and differentiation of these cells in a novel 3D cell-culture system mimicking the in vivo situation. This targeted approach will provide first results on the therapeutic potential of cardiovascular progenitor subpopulations as a novel cell source for regenerative therapies.