Interleukin-6 signaling regulates hematopoietic stem cell emergence

Hematopoietic stem cells (HSCs) produce all lineages of mature blood cells for the lifetime of an organism. In vertebrates, HSCs derive from the transition of the hemogenic endothelium (HE) in the floor of the embryonic dorsal aorta. Most recently, a series of proinflammatory factors, such as tumor necrosis factor-α, interferon-γ, and Toll-like receptor 4, have been confirmed to play a key role in HSC specification. However, the full complement of necessary signaling inputs remains unknown to date. Here, we show that interleukin-6R (IL6R) via IL6 is required and sufficient for HSC generation. We found that Notch activates IL6R by regulating its expression in the HE and in HSCs. The secretion of IL6 mainly originates from HSC-independent myeloid cells, but not from HSCs and their adjacent vascular endothelial cells. In addition, blocking IL6 signaling does not affect vascular development or the production of primitive erythrocytes. Taken together, our results uncover a previously obscure relationship between IL6 signaling and HSC production and provide new insights into HSC regeneration using proinflammatory factors in vitro. A molecule that triggers inflammation, interleukin-6 (IL6), is crucial for development of blood stem cells, known as hematopoetic stem cells (HSCs). HSCs can differentiate into any type of blood or immune cell, and have enormous therapeutic potential. Although some of the signaling molecules that trigger their development are known, HSCs have yet to be grown under laboratory conditions, so knowledge gaps remain. Based on clues that IL6 might be one of the missing signals, He Huang at the Zhejiang University School of Medicine, Hangzhou, China, and coworkers investigated how IL6 affects HSC development in zebrafish, a common model of development. Zebrafish embryos lacking IL6 were deficient in HSCs, but showed normal blood vessel growth. Treating with IL6 restored HSC production. These results represent another step toward being able to grow HSCs for transplantation and therapy.