Abstract
Aims: Our recent work demonstrated that common cardiovascular progenitor cells are characterized and induced by the expression of the transcription factor MesP1 in vertebrate embryos and murine embryonic stem cells. As the proliferative potential of stem cell derived cardiomyocytes is limited, it is crucial to understand how MesP1 expression is mediated, in order to achieve reasonable and reliable yields for novel stem cell based therapeutic options. As potential upstream regulators of MesP1 we therefore analysed Eomes and Brachyury(T), which had been controversely discussed to be crucial for cardiovasculogenic lineage formation. Methods and results: Wild-type and transgenic murine embryonic stem cell lines, mRNA-analyses, embryoid body formation, and cell sorting revealed that the MesP1 positive population emerges from the Brachyury(T) positive fraction. In situ hybridizations using wild-type mouse embryos confirmed that Brachyury(T) colocalises with MesP1 in vivo . Likewise, shRNA based loss of Brachyury(T) causes a dramatic decrease of MesP1 expression accompanied by reduced cardiac markers in differentiating embryonic stem cells, which is reflected in vivo via in situs using Brachyury(T) knock-out embryos where MesP1 mRNA is greatly abolished. We finally defined a 3.4 kb proximal MesP1-promoter fragment which is directly bound and activated by Brachyury(T) via a T responsive element as shown via Bandshift, Chromatin Immuneprecipitation and Reporter Assays. Conclusion: Our work contributes to the understanding of the earliest cardiovasculogenic events and may become an important prerequisite for cell therapy, tissue engineering and pharmacological testing in the culture dish using pluripotent stem cell derived as well as directly reprogrammed cardiovascular cell types.
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