Lymphatic exosomes promote dendritic cell migration along guidance cues

Brown, Markus; Johnson, Louise A.; Leone, Dario A.; Marynen, Peter; Vaahtomeri, Kari; Senfter, Daniel; Bukosza, Nora; Schachner, Helga; Asfour, Gabriele; Langer, Brigitte; Hauschild, Robert; Parapatics, Katja; Hong, Young‐Kwon; Bennett, Keiryn L.; Kain, Renate; Detmar, Michael; Sixt, Michael; Jackson, David G.; Kerjaschki, Dontscho

doi:10.1083/jcb.201612051

Cited by 66 publications

(61 citation statements)

References 70 publications

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“…A recent study has revealed that exosomes have cell motility control potential (Brown et al, ). To investigate the effect of exosomes on the migration of hBMSCs, a Transwell assay was performed, and the exosomes collected at different stages of osteogenesis were added into the lower chamber.…”

Section: Resultsmentioning

confidence: 99%

Immunoregulatory role of exosomes derived from differentiating mesenchymal stromal cells on inflammation and osteogenesis

Wei

Crawford

et al. 2019

J Tissue Eng Regen Med

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Bone marrow-derived mesenchymal stem/stromal cells (BMSCs) can differentiate into bone-forming osteoblasts, playing a crucial role in bone regeneration. Exosomes are naturally cell-secreted nanovesicles and are lately regraded as an emerging mediator of cellular communication in physiological and pathological conditions. The present study aimed at investigating the complex cellular communications, especially those among the differentiating BMSCs, immune cells (e.g., macrophages), and newly recruited BMSCs via exosome-mediated pathways. Exosomes were first isolated from osteogenically differentiating BMSCs at various stages (Day 0, Day 3, Day 7, and Day 14, respectively). The cellular uptake of isolated exosomes was examined in macrophages and human BMSCs (hBMSCs). The exosomes collected at various osteogenic differentiation stages (0d-exo, 3d-exo, 7d-exo, and 14d-exo) had no effect on the viability of hBMSCs. The uptake of exosomes (0d-exo, 3d-exo, and 7d-exo) significantly decreased proinflammatory-gene expression and the level of an M1 phenotypic marker. Our results then revealed that 3d-exo, 7d-exo, and 14d-exo led to a remarkable increase in mesenchymal stem/stromal cell migration. In addition, 0d-exo significantly promoted the expression of early osteogenic markers, such as alkaline phosphatase and bone morphogenetic protein 2, indicating a pro-osteogenic role of hBMSC-derived exosomes. Collectively, these results suggest that exosomes derived from differentiating mesenchymal stem/stromal cells play a unique osteoimmunomodulatory role in the regulation of bone dynamics.

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Section: Resultsmentioning

confidence: 99%

Immunoregulatory role of exosomes derived from differentiating mesenchymal stromal cells on inflammation and osteogenesis

Wei

Crawford

et al. 2019

J Tissue Eng Regen Med

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“…The IEα 52–68 traffics to the early endosome and then to the MIIC where it is loaded onto MHCII and efficiently presented by DC both in vivo and in vitro to restricted CD4‐T‐cells independently from the MCHII present onto the exosomes . Similarly, rejection of murine heart transplants is dependent on release of exosomes from donor DC which are taken up by host DC in local lymph nodes while activated human lymphatic endothelial cells secrete exosomes that express C‐X‐C chemokine receptor type 1 (CXCR1) ligand increasing migration of DC . Finally, iDC internalize exosomes released from mast cells pulsed with BSA or OVA via CD91 dependent pathway and this promotes their maturation and enables them to induce efficient CD4 T‐cell proliferation; by contrast, exosomes from macrophages and B‐cells were ineffective.…”

Section: Exosomesmentioning

confidence: 99%

Dendritic cells and routing cargo into exosomes

2018

Self Cite

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Extracellular vesicles, released from cells, are important for intercellular communication. They are heterogeneous but fall into two broad categories based on origin and function: microvesicles formed by outward budding from the plasma membrane; and exosomes that originate as intraluminal vesicles in multivesicular endosomes that fuse with the plasma membrane to release them. Extracellular vesicles generally and exosomes in particular have powerful effects on specific immune responses, and recent advances highlight their potential therapeutic uses. Dendritic cells (DC) that have internalized antigen release exosomes that express MHC class II molecules loaded with antigenic peptides, co-stimulatory molecules and intact antigen. Depending on the setting, these stimulate CD4 T-cell proliferation either directly or only in the context of accessory antigen naïve DC. Here, we discuss the reasons for this; and review current knowledge about the loading of antigen, class II and other cargo into exosomes released by DC and other professional antigen-presenting cells in the context of advances in exosome biology more generally.

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“…EVs are thought to mediate cell-cell communication [1] and may carry a variety of proteins, lipids and RNA with potential to impact target cell physiology. It has been proposed that EVs modulate tumor environments to allow for tumor seeding and growth and promote angiogenesis [2][3][4][5][6][7][8]. EVs have also been implicated in the prion-like spread of neuropathogenic protein aggregates in several neurodegenerative diseases [9][10][11][12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

A cell-based assay for CD63-containing extracellular vesicles

Cashikar

Hanson

2019

PLoS ONE

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Extracellular vesicles (EVs) are thought to be important in cell-cell communication and have elicited extraordinary interest as potential biomarkers of disease. However, quantitative methods to enable elucidation of mechanisms underlying release are few. Here, we describe a cell-based assay for monitoring EV release using the EV-enriched tetraspanin CD63 fused to the small, ATP-independent reporter enzyme, Nanoluciferase. Release of CD63-containing EVs from stably expressing cell lines was monitored by comparing luciferase activity in culture media to that remaining in cells. HEK293, U2OS, U87 and SKMel28 cells released 0.3%-0.6% of total cellular CD63 in the form of EVs over 5 hrs, varying by cell line. To identify cellular machinery important for secretion of CD63-containing EVs, we performed a screen of biologically active chemicals in HEK293 cells. While a majority of compounds did not significantly affect EV release, treating cells with the plecomacrolides bafilomycin or concanamycin, known to inhibit the V-ATPase, dramatically increased EV release. Interestingly, alkalization of the endosomal lumen using weak bases had no effect, suggesting a pH-independent enhancement of EV release by V-ATPase inhibitors. The ability to quantify EVs in small samples will enable future detailed studies of release kinetics as well as further chemical and genetic screening to define pathways involved in EV secretion.

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Lymphatic exosomes promote dendritic cell migration along guidance cues

Cited by 66 publications

References 70 publications

Immunoregulatory role of exosomes derived from differentiating mesenchymal stromal cells on inflammation and osteogenesis

Immunoregulatory role of exosomes derived from differentiating mesenchymal stromal cells on inflammation and osteogenesis

Dendritic cells and routing cargo into exosomes

A cell-based assay for CD63-containing extracellular vesicles

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