tiRNA signaling occurs via stress-regulated vesicle transfer in the hematopoietic niche

Extracellular vesicles (EV) transfer complex biologic material between cells. However the role of this process in in-vivo organismal physiology is poorly defined. Here, we demonstrate that osteoblastic cells in the bone marrow elaborate extracellular vesicles that are taken up by hematopoietic progenitor cells in vivo . Genotoxic or infectious stress rapidly increased stromal-derived extracellular vesicle transfer to granulocyte-monocyte progenitors. Stimulating osteoblastic cells with parathyroid hormone or activating the parathyroid hormone receptor enhanced extracellular vesicle transfer, myeloid recovery post radiation and improved animal survival from Candida sepsis. The extracellular vesicles contained tiRNAs known to modulate protein translation. 5’-ti-Pro-CGG-1 was preferentially abundant in osteoblast-derived extracellular vesicles and when transferred to granulocyte- monocyte progenitors, increased protein translation, cell proliferation and myeloid differentiation. Therefore, EV-mediated tiRNA transfer provides a stress modulated signaling axis distinct from conventional cytokine-driven stress responses. Kfoury, Scadden et al., demonstrate stress-regulated transfer of tiRNA loaded extracellular vesicles (EVs) from specific stromal cells to myeloid progenitors in the bone marrow as a cytokine-independent means of enhancing myeloid cell production and host defense. Stress regulated tiRNA transfer alters hematopoiesis