@article{d362a07d70634c36ad881106c47002d1,
title = "Mesenchymal stromal cell-derived extracellular vesicles promote myeloid-biased multipotent hematopoietic progenitor expansion via toll-like receptor engagement",
abstract = "Mesenchymal stromal cells (MSCs) present in the bone marrow microenvironment secrete cytokines and angiogenic factors that support the maintenance and regenerative expansion of hematopoietic stem and progenitor cells (HSPCs). Here, we tested the hypothesis that extracellular vesicles (EVs) released by MSCs contribute to the paracrine crosstalk that shapes hematopoietic function. We systematically characterized EV release by murine stromal cells and demonstrate that MSC-derived EVs prompt a loss of HSPC quiescence with concomitant expansion of murine myeloid progenitors. Our studies reveal that HSPC expansion by MSC EVs is mediated via the MyD88 adapter protein and is partially blocked by treatment with a TLR4 inhibitor. Imaging of fluorescence protein-tagged MSC EVs corroborated their cellular co-localization with TLR4 and endosomal Rab5 compartments in HSPCs. The dissection of downstream responses to TLR4 activation reveals that the mechanism by which MSC EVs impact HSPCs involves canonical NF-κB signaling and downstream activation of Hif-1α and CCL2 target genes. Our aggregate data identify a previously unknown role for MSC-derived EVs in the regulation of hematopoiesis through innate immune mechanisms and illustrate the expansive cell-cell crosstalk in the bone marrow microenvironment.",
author = "Goloviznina, {Natalya A.} and Verghese, {Santhosh Chakkaramakkil} and Yoon, {Young Me} and Oleh Taratula and Marks, {Daniel L.} and Peter Kurre",
note = "Funding Information: Preliminary accounts of this work were presented at the annual meeting of the International Society for Extracellular Vesicles, Bethesda, MD on April 23-26, 2015, in Washington, D. C. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.1Present address: Molecular, Cellular, Developmental Biology and Genetics Program, University of Minnesota, Minneapolis, MN 55108. Some of the materials employed in this work were provided by the Tulane Center for Gene Therapy through the National Center for Research Resources (NCRR) Grant P40RR017447. We gratefully acknowledge the assistance of Dr. Stephanie Krasnow, Dr. Xinxia Zhu, Pete Levasseur, Dr. Claudia Lopez, John Butler, Dr. Shelton Viola, Ben Doron, and Merna Labib with select experiments. We also thank Dr. David W. Erikson at The Endocrine Technologies Support Core (ETSC) at the Oregon National Primate Research Center (ONPRC) for help with the Luminex experiment. The ETSC at the ONPRC is supported by National Institutes of Health Grant P51 OD011092 awarded to ONPRC. Publisher Copyright: {\textcopyright} 2016 by The American Society for Biochemistry and Molecular Biology, Inc.",
year = "2016",
month = nov,
day = "18",
doi = "10.1074/jbc.M116.745653",
language = "English (US)",
volume = "291",
pages = "24607--24617",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "47",
}