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

Mammals respond to infection by rapid production of innate immune cells. Hematopoietic stem and progenitor cells (HSPCs) have the ability to respond to pathogens directly through toll-like receptors. However, how the pathogen sensing ability of HSPCs may contribute to immune cell output remains unknown. Using a novel single-cell proteomic platform and mouse genetic models, we have shown that in response to toll-like receptor stimulation, short-term HSCs and multipotent progenitor cells produce copious amounts of diverse cytokines through 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. This is especially important in mediating rapid early myeloid cell recovery during neutropenia after chemotherapy or HSC transplant. 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-induced hematopoiesis. To translate these findings into human hematopoietic system, we have recently developed a human cytokine chip and our preliminary analysis suggests that purified human bone marrow HSCs also have the capacity to secrete cytokines.