@article{34d144774bae4e38bd420ddf9db99ab3,
title = "tiRNA signaling via stress-regulated vesicle transfer in the hematopoietic niche",
abstract = "Extracellular vesicles (EVs) transfer complex biologic material between cells. However, the role of this process in vivo is poorly defined. Here, we demonstrate that osteoblastic cells in the bone marrow (BM) niche 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. The extracellular vesicles contained processed tRNAs (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. Upregulating EV transfer improved hematopoietic recovery from genotoxic injury and survival from fungal sepsis. Therefore, EV-mediated tiRNA transfer provides a stress-modulated signaling axis in the BM niche distinct from conventional cytokine-driven stress responses.",
keywords = "bone marrow, extracellular vesicles, hematopoiesis, myeloid progenitors, niche, protein translation, signaling, tiRNAs",
author = "Kfoury, {Youmna S.} and Fei Ji and Michael Mazzola and Sykes, {David B.} and Scherer, {Allison K.} and Anthony Anselmo and Yasutoshi Akiyama and Francois Mercier and Nicolas Severe and Kokkaliaris, {Konstantinos D.} and Ting Zhao and Thomas Brouse and Borja Saez and Jefferson Seidl and Ani Papazian and Pavel Ivanov and Mansour, {Michael K.} and Sadreyev, {Ruslan I.} and Scadden, {David T.}",
note = "Funding Information: The authors would like to thank Phillip Chea at Massachusetts General Hospital for his technical help; Adalis Maisonet and Ulandt Kim from the MGH next-generation sequencing core ( NIH P30 DK040561 ) for helping in library constructions and Illumina sequencing; and Scott Mordecai at the Department of Pathology Flow, Image and Mass Cytometry Core ( 1S10OD012027-01A1 ) at MGH for his help in imaging flow cytometry. We would also like to acknowledge the HSCI-CRM flow cytometry facility for their help in flow cytometry analysis and sorting, Center for Skeletal Research Core ( NIH P30 AR066261 ) for their help in microcomputed tomography, and Microscopy Core of the Center for Systems Biology/Program in Membrane Biology ( DK043351 and BADERC award DK057521 ). Y.S.K. was supported by grants from the Dubai Harvard Foundation for Medical Research and the Aplastic Anemia and MDS International Foundation . D.T.S. was supported by the National Institute of Diabetes, Digestive and Kidney Diseases ( DK107784 ), the Harvard Stem Cell Institute , and the Gerald and Darlene Jordan Chair of Medicine at Harvard University . Funding Information: The authors would like to thank Phillip Chea at Massachusetts General Hospital for his technical help; Adalis Maisonet and Ulandt Kim from the MGH next-generation sequencing core (NIH P30 DK040561) for helping in library constructions and Illumina sequencing; and Scott Mordecai at the Department of Pathology Flow, Image and Mass Cytometry Core (1S10OD012027-01A1) at MGH for his help in imaging flow cytometry. We would also like to acknowledge the HSCI-CRM flow cytometry facility for their help in flow cytometry analysis and sorting, Center for Skeletal Research Core (NIH P30 AR066261) for their help in microcomputed tomography, and Microscopy Core of the Center for Systems Biology/Program in Membrane Biology (DK043351 and BADERC award DK057521). Y.S.K. was supported by grants from the Dubai Harvard Foundation for Medical Research and the Aplastic Anemia and MDS International Foundation. D.T.S. was supported by the National Institute of Diabetes, Digestive and Kidney Diseases (DK107784), the Harvard Stem Cell Institute, and the Gerald and Darlene Jordan Chair of Medicine at Harvard University. Y.S.K. initiated the project, designed and performed experiments, and wrote the manuscript. F.J. A.A. and R.I.S. performed bioinformatics analyses. M.M. and Y.A. performed the northern blots. D.B.S. helped establish the HA9 cell line and provided thoughtful advice. A.P. J.S. T.B. F.M. N.S. K.D.K. A.K.S. T.Z. and B.S. helped perform experiments. M.K.M. and P.I. provided thoughtful advice. D.T.S. initiated the project, provided supervision, and wrote the manuscript. All authors read and helped edit the manuscript. D.T.S. is a director, co-founder, and shareholder of Magenta Therapeutics, Clear Creek Bio, and LifeVaultBio; a director and shareholder of Agios Pharmaceuticals and Editas Medicines; and a co-founder and a shareholder of Fate Therapeutics. D.B.S. is a scientific founder and shareholder in Clear Creek Bio. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = dec,
day = "2",
doi = "10.1016/j.stem.2021.08.014",
language = "English",
volume = "28",
pages = "2090--2103.e9",
journal = "Cell Stem Cell",
issn = "1934-5909",
publisher = "Cell Press",
number = "12",
}