Mesenchymal stromal cell-derived extracellular vesicles promote myeloid-biased multipotent hematopoietic progenitor expansion via toll-like receptor engagement

Natalya A. Goloviznina, Santhosh Chakkaramakkil Verghese, Young Me Yoon, Oleh Taratula, Daniel Marks, Peter Kurre

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)24607-24617
Number of pages11
JournalJournal of Biological Chemistry
Volume291
Issue number47
DOIs
StatePublished - Nov 18 2016

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Toll-Like Receptors
Hematopoietic Stem Cells
Mesenchymal Stromal Cells
Crosstalk
Bone
Chemical activation
Dissection
Angiogenesis Inducing Agents
Proteins
Genes
Fluorescence
Cytokines
Imaging techniques
Bone Marrow
Myeloid Differentiation Factor 88
Extracellular Vesicles
Optical Imaging
Hematopoiesis
Stromal Cells
Maintenance

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Mesenchymal stromal cell-derived extracellular vesicles promote myeloid-biased multipotent hematopoietic progenitor expansion via toll-like receptor engagement. / Goloviznina, Natalya A.; Verghese, Santhosh Chakkaramakkil; Yoon, Young Me; Taratula, Oleh; Marks, Daniel; Kurre, Peter.

In: Journal of Biological Chemistry, Vol. 291, No. 47, 18.11.2016, p. 24607-24617.

Research output: Contribution to journalArticle

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