Dendritic Cell-derived Extracellular Vesicles mediate Mesenchymal Stem/Stromal Cell recruitment

Abstract

Orchestration of bone repair processes requires crosstalk between different cell populations, including immune cells and mesenchymal stem/stromal cells (MSC). Extracellular vesicles (EV) as mediators of these interactions remain vastly unexplored. Here, we aimed to determine the mechanism of MSC recruitment by Dendritic Cells (DC), hypothesising that it would be mediated by EV. Primary human DC-secreted EV (DC-EV), isolated by ultracentrifugation, were characterized for their size, morphology and protein markers, indicating an enrichment in exosomes. DC-EV were readily internalized by human bone marrow-derived MSC, without impacting significantly their proliferation or influencing their osteogenic/chondrogenic differentiation. Importantly, DC-EV significantly and dose-dependently promoted MSC recruitment across a transwell system and enhanced MSC migration in a microfluidic chemotaxis assay. DC-EV content was analysed by chemokine array, indicating the presence of chemotactic mediators. Osteopontin and matrix metalloproteinase-9 were confirmed inside EV. In summary, DC-EV are naturally loaded with chemoattractants and can contribute to cell recruitment, thus inspiring the development of new tissue regeneration strategies.

Monocyte‐derived extracellular vesicles stimulate cytokine secretion and gene expression of matrix metalloproteinases by mesenchymal stem/stromal cells

“…). The same was previously found for BM‐MSCs that took up EVs from LPS‐activated MCs ) and dendritic cells , another mononuclear phagocytic cell type. These results suggest that many, if not all, mononuclear phagocytes interact with MSCs through their EVs.…”

“…EV derived from LPS-activated MCs were reported to stimulate osteogenic differentiation of MSCs [20] and similar results have been reported for dendritic-cell derived EVs [32]. Silva et al [31] on the other hand did not find any effects of dendritic-cell derived EVs on osteogenic differentiation, despite the accumulation of these EV inside the MSCs. Also the interactions between OCs, osteoblasts and mesenchymal precursors partially take place through tranfer of EVs.…”

“…Silva et al . on the other hand did not find any effects of dendritic‐cell derived EVs on osteogenic differentiation, despite the accumulation of these EV inside the MSCs. Also the interactions between OCs, osteoblasts and mesenchymal precursors partially take place through tranfer of EVs.…”

“…These results suggest that many, if not all, mononuclear phagocytes interact with MSCs through their EVs. The EVs were found in clusters close to the nuclei, suggesting active endocytosis of the EVs leading to processing of their molecular cargo [31]. Other mechanisms of interaction with the AT-MSCs cannot be ruled out, such as EV-mediated activation of membrane-bound receptors that trigger signalling pathways, or fusion with the cell membrane leading to release of the EV cargo into the cell cytoplasm [24].…”

Sensory neurons sprouting is dependent on osteoclast-derived extracellular vesicles involving the activation of epidermal growth factor receptors

“…To assess the contribution of the β1 integrin subunit on the phosphorylation of EGFR and osteoclast-induced axonal sprouting, stimulation of DRG with osteoclast secretome was conducted in the absence or presence of β1 integrin function-blocking antibodies, as previously described in (J. Silva et al, 2017).…”