Abstract
The discovery that the definitive hematopoietic stem cells (HSCs) derive from specialized regions of the endothelium, known as the hemogenic endothelium (HE), shed a good deal of light on HSC embryonic developmental processes. This knowledge opened up new possibilities for the design of new strategies to obtain HSCs in vitro from pluripotent stem cells (PSCs). Previous advances in this field have shown that the Wnt/β-catenin signaling pathway plays a crucial role in PSC-derived HSC formation. In this work, we identified lithium, a GSK3 inhibitor, as an element capable of stabilizing β-catenin and inducing ESCs differentiation in the mesodermal lineage and subsequently in the HE precursors, highly consistent with the role of Wnt agonists on ESC differentiation. ESCs treated with 10 mM lithium express CD31+, SCA-1+, Nkx2-5+, CD34+ and FLK1+ cells characteristic of the hemangioblast cells that precede HE development. However, 10 mM Li treated cells remained arrested in a hemangioblast-like phase, which switched into the expression of HE markers after stimulation with maturation medium. The ability of lithium-treated ESCs to further derive into HE was confirmed after defined maturation, resulting in a rapid increase in cells positive for the HE markers RUNX1 and SOX17. Our results represent a novel strategy for generating HSC precursors in vitro as a multipotent source of stem cells for blood disease therapies.
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