Interleukin-6 signaling regulates hematopoietic stem cell emergence

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.

Hypoxia and Inflammation: Insights From High-Altitude Physiology

“…Inflammation impacts crucial sites of erythrocyte production to redistribute resources toward myeloid cell production and therefore reduces lymphoid and erythroid output. For example, expression of pro-inflammatory IL-1β, interferon gamma (IFNγ), and IL-6 skew multipotential hematopoietic progenitors toward myeloid cell development ( Tie et al, 2019 ). This is an adaptive response since myeloid cells are needed to fight infection; however, this comes at the cost of bone marrow erythropoiesis.…”

Macrophages Derived From Human Induced Pluripotent Stem Cells: The Diversity of Protocols, Future Prospects, and Outstanding Questions

“…In the context of inflammation, IL-6 induces emergency granulopoiesis, even in the absence of GM-CSF and G-CSF ( Ishihara and Hirano, 2002 ; Maeda et al, 2009 ). During zebrafish embryogenesis, IL-6 promoted the generation of hematopoietic cells and HSCs ( Tie et al, 2019 ). IL-6 has been used in some 2D-F protocols at the HP and MY stages ( Table 6 ).…”

Acute Intestinal Inflammation Depletes/Recruits Histamine-Expressing Myeloid Cells From the Bone Marrow Leading to Exhaustion of MB-HSCs

“…IL6 is a prominent proinflammatory cytokine that plays a critical role in modulating immunity and inflammation, 51 , 52 and also regulates the proliferation and differentiation of HSCs. 53 Interestingly, we found that H2R-agonist treatment reduced the level of IL6 in the circulation, spleen, and colon, and suppressed the activation of HSCs, leading to improved survival of mice with severe colitis. HSC differentiation is induced by the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF), which is thought to drive HSCs to differentiate into common myeloid progenitors.…”