Abstract
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.
Highlights
Adult hematopoietic stem cells (HSCs) have the ability to self-renew and differentiate into all blood and immune cells throughout life
The transcript il6r was enriched in HSCs compared to endothelial cells (ECs), while the expression differences in the other two transcripts were not observed between the two groups[28]
Using Whole-mount in situ hybridization (WISH), we found that the expression of cmyb in or near the floor of the dorsal aorta (DA) region at 36 hpf was dramatically reduced in Il6and Il6r-deficient embryos compared with their wild-type siblings (Fig. 1a, b), indicating that the action of Il6 through Il6r is required in HSC development
Summary
Adult hematopoietic stem cells (HSCs) have the ability to self-renew and differentiate into all blood and immune cells throughout life. Under stress-induced hematopoiesis, adult short-term HSCs and multipotent progenitor cells (MPPs) can directly sense bacterial and viral components and systematically elevate cytokine expression through Toll-like receptors (TLRs)[9,10,11]. Several studies have demonstrated that proinflammatory signaling factors, including granulocyte-CSF(G-CSF), TNF-α, IFN-γ, and TLR4, can positively specify embryonic HSC fate[12,13,14,15,16]. All of these proinflammatory factors are functionally associated with Notch signaling. The targeted disruption of GP130 leads to embryonic lethality, presenting hypoplastic ventricular
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