| Summary: | Summary: Exogenous cues involved in the regulation of the initial steps of lymphatic endothelial development remain largely unknown. We have used an in vitro model based on the co-culture of vascular precursors derived from mouse embryonic stem cell (ESC) differentiation and OP9 stromal cells to examine the first steps of lymphatic specification and expansion. We found that bone morphogenetic protein 9 (BMP9) induced a dose-dependent biphasic effect on ESC-derived vascular precursors. At low concentrations, below 1 ng/mL, BMP9 expands the LYVE-1-positive lymphatic progeny and activates the calcineurin phosphatase/NFATc1 signaling pathway. In contrast, higher BMP9 concentrations preferentially enhance the formation of LYVE-1-negative endothelial cells. This effect results from an OP9 stromal cell-mediated VEGF-A secretion. RNA-silencing experiments indicate specific involvement of ALK1 and ALK2 receptors in these different BMP9 responses. BMP9 at low concentrations may be a useful tool to generate lymphatic endothelial cells from stem cells for cell-replacement strategies. : In this article, Vittet and colleagues analyze the initial events governing the expansion of the lymphatic endothelial lineage during mouse embryonic stem cell differentiation. They report that BMP9, at low doses, increases the formation of LYVE-1-positive endothelial cells, whereas at high doses it induces LYVE-1-negative endothelial cell formation. These differential BMP9 responses result from differential involvement of type I receptors. Keywords: embryonic stem cell, lymphatic development, lymphatic endothelial cell, endothelial cell, lymphangiogenesis, BMP9 protein, NFATc1 signaling
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