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

Youmna S Kfoury; Fei Ji; Michael Mazzola; David B Sykes; Allison K Scherer; Anthony Anselmo; Yasutoshi Akiyama; Francois Mercier; Nicolas Severe; Konstantinos D Kokkaliaris; Ting Zhao; Thomas Brouse; Borja Saez; Jefferson Seidl; Ani Papazian; Pavel Ivanov; Michael K Mansour; Ruslan I Sadreyev; David T Scadden

doi:10.1016/j.stem.2021.08.014

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

Cell Stem Cell. 2021 Dec 2;28(12):2090-2103.e9. doi: 10.1016/j.stem.2021.08.014. Epub 2021 Sep 21.

Authors

Youmna S Kfoury¹, Fei Ji², Michael Mazzola³, David B Sykes³, Allison K Scherer⁴, Anthony Anselmo², Yasutoshi Akiyama⁵, Francois Mercier³, Nicolas Severe³, Konstantinos D Kokkaliaris³, Ting Zhao³, Thomas Brouse³, Borja Saez³, Jefferson Seidl³, Ani Papazian³, Pavel Ivanov⁶, Michael K Mansour⁷, Ruslan I Sadreyev⁸, David T Scadden⁹

Affiliations

¹ Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA; Harvard Stem Cell Institute, 7 Divinity Avenue, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA. Electronic address: [email protected].
² Department of Molecular Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
³ Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA; Harvard Stem Cell Institute, 7 Divinity Avenue, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
⁴ Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA 02114, USA.
⁵ Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
⁶ Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Harvard Initiative for RNA Medicine, Boston, MA 02115, USA.
⁷ Harvard Stem Cell Institute, 7 Divinity Avenue, Cambridge, MA 02138, USA; Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
⁸ Department of Molecular Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
⁹ Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA; Harvard Stem Cell Institute, 7 Divinity Avenue, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA. Electronic address: [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Bone Marrow
Bone Marrow Cells
Extracellular Vesicles*
Hematopoiesis
Hematopoietic Stem Cells*

Abstract

Publication types

MeSH terms

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