Conversion of Danger Signals into Cytokine Signals by Hematopoietic Stem and Progenitor Cells for Regulation of Stress-Induced Hematopoiesis

• Undifferentiated HSPCs produce a wide range of cytokines upon stimulation
• The cytokine production function of HSPCs is regulated by the TLR/NF-κB axis
• HSPCs are significantly more potent cytokine secretors than mature immune cells
• Cytokines produced by HSPCs allow efficient myelopoiesis in vitro and in vivo

SummaryDuring an infection, the body increases the output of mature immune cells in order to fight off the pathogen. Despite convincing evidence that hematopoietic stem and progenitor cells (HSPCs) can sense pathogens directly, how this contributes to hematopoietic cell output remains unknown. Here, we have combined mouse models with a single-cell proteomics platform to show that, in response to Toll-like receptor stimulation, short-term HSCs and multipotent progenitor cells produce copious amounts of diverse cytokines through nuclear factor κB (NF-κB) signaling. Interestingly, the cytokine production ability of HSPCs trumps mature immune cells in both magnitude and breadth. Among cytokines produced by HSPCs, IL-6 is a particularly important regulator of myeloid differentiation and HSPC proliferation in a paracrine manner and in mediating rapid myeloid cell recovery during neutropenia. This study has uncovered an important property of HSPCs that enables them to convert danger signals into versatile cytokine signals for the regulation of stress hematopoiesis.

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