BMP signaling in the establishment of the circulatory system

Kyunghee Choi

Dept of Pathology, Washington University Medical School

The in vitro differentiation model of embryonic stem (ES) cells is ideal for generating different types of somatic cells. The ability to produce many different cell types serves as a vital tool for studying cell lineage specification as well as for potentially utilizing these in vitro derived cells for therapies for human diseases for which there are currently no effective treatments. By utilizing the in vitro differentiation model of ES cells and conditional knockout mouse strategies, we show that hematopoietic and endothelial cells develop from murine ES cells by sequentially generated Flk-1 and Scl expressing cells. Specifically, we show that Scl expressing hematopoietic cells are generated from Flk-1 expressing mesoderm. Flk-1 expressing mesoderm has been shown to generate cells of hematopoietic, endothelial, smooth muscle, and skeletal muscle lineage as well as cardiomyocytes. We show that BMP signaling is a critical inductive signal for the specification of Flk-1-expressing mesoderm from Brachyury-expressing mesoderm. Moreover, we show that BMP signaling is continuously required within Flk-1 expressing mesoderm for endothelial cell remodeling and vessel maturation as well as for atrio-ventricular cushion formation in the heart. Collectively, these studies indicate the importance of BMP signaling in the establishment of the circulation system.