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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.
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Details
1 Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Institute of Hematology, Zhejiang University, Hangzhou, China; Zhejiang Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China; Stem Cell Institute, Zhejiang University, Hangzhou, China; Department of Hematology, the Second Clinical Medical College, Shanxi Medical University, Taiyuan, China
2 Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Institute of Hematology, Zhejiang University, Hangzhou, China
3 Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Institute of Hematology, Zhejiang University, Hangzhou, China; Zhejiang Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China; Stem Cell Institute, Zhejiang University, Hangzhou, China