Mesenchymal stromal cell-derived nanovesicles ameliorate bacterial outer membrane vesicle-induced sepsis via IL-10
Park, Kyong-Su ; Svennerholm, Kristina ; Shelke, Ganesh V ; Bandeira, Elga ; Lässer, Cecilia ; Jang, Su Chul ; Chandode, Rakesh ; Gribonika, Inta LU
and Lötvall, Jan
(2019)
In Stem Cell Research & Therapy
10(1).
- Abstract
BACKGROUND: Sepsis remains a source of high mortality in hospitalized patients despite proper antibiotic approaches. Encouragingly, mesenchymal stromal cells (MSCs) and their produced extracellular vesicles (EVs) have been shown to elicit anti-inflammatory effects in multiple inflammatory conditions including sepsis. However, EVs are generally released from mammalian cells in relatively low amounts, and high-yield isolation of EVs is still challenging due to a complicated procedure. To get over these limitations, vesicles very similar to EVs can be produced by serial extrusions of cells, after which they are called nanovesicles (NVs). We hypothesized that MSC-derived NVs can attenuate the cytokine storm induced by bacterial outer... (More)
BACKGROUND: Sepsis remains a source of high mortality in hospitalized patients despite proper antibiotic approaches. Encouragingly, mesenchymal stromal cells (MSCs) and their produced extracellular vesicles (EVs) have been shown to elicit anti-inflammatory effects in multiple inflammatory conditions including sepsis. However, EVs are generally released from mammalian cells in relatively low amounts, and high-yield isolation of EVs is still challenging due to a complicated procedure. To get over these limitations, vesicles very similar to EVs can be produced by serial extrusions of cells, after which they are called nanovesicles (NVs). We hypothesized that MSC-derived NVs can attenuate the cytokine storm induced by bacterial outer membrane vesicles (OMVs) in mice, and we aimed to elucidate the mechanism involved.
METHODS: NVs were produced from MSCs by the breakdown of cells through serial extrusions and were subsequently floated in a density gradient. Morphology and the number of NVs were analyzed by transmission electron microscopy and nanoparticle tracking analysis. Mice were intraperitoneally injected with Escherichia coli-derived OMVs to establish sepsis, and then injected with 2 × 109 NVs. Innate inflammation was assessed in peritoneal fluid and blood through investigation of infiltration of cells and cytokine production. The biodistribution of NVs labeled with Cy7 dye was analyzed using near-infrared imaging.
RESULTS: Electron microscopy showed that NVs have a nanometer-size spherical shape and harbor classical EV marker proteins. In mice, NVs inhibited eye exudates and hypothermia, signs of a systemic cytokine storm, induced by intraperitoneal injection of OMVs. Moreover, NVs significantly suppressed cytokine release into the systemic circulation, as well as neutrophil and monocyte infiltration in the peritoneum. The protective effect of NVs was significantly reduced by prior treatment with anti-interleukin (IL)-10 monoclonal antibody. In biodistribution study, NVs spread to the whole mouse body and localized in the lung, liver, and kidney at 6 h.
CONCLUSIONS: Taken together, these data indicate that MSC-derived NVs have beneficial effects in a mouse model of sepsis by upregulating the IL-10 production, suggesting that artificial NVs may be novel EV-mimetics clinically applicable to septic patients.
(Less)
- author
- Park, Kyong-Su
; Svennerholm, Kristina
; Shelke, Ganesh V
; Bandeira, Elga
; Lässer, Cecilia
; Jang, Su Chul
; Chandode, Rakesh
; Gribonika, Inta
LU
and Lötvall, Jan
- publishing date
- 2019-08-01
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Animals, Antibodies, Monoclonal/immunology, Bacterial Outer Membrane/metabolism, Disease Models, Animal, Endocytosis, Escherichia coli/metabolism, Exosomes/metabolism, Extracellular Vesicles/chemistry, Interleukin-10/immunology, Mesenchymal Stem Cells/cytology, Mice, Mice, Inbred C57BL, Monocytes/cytology, Nanostructures/chemistry, Neutrophil Infiltration, Peritoneum/metabolism, Proteome/analysis, RAW 264.7 Cells, Sepsis/pathology, Tissue Distribution
- in
- Stem Cell Research & Therapy
- volume
- 10
- issue
- 1
- article number
- 231
- publisher
- BioMed Central (BMC)
- external identifiers
-
- scopus:85070250419
- pmid:31370884
- ISSN
- 1757-6512
- DOI
- 10.1186/s13287-019-1352-4
- language
- English
- LU publication?
- no
- id
- 33d1d37b-5712-401f-ba52-0bc9d0ebe1ef
- date added to LUP
- 2025-12-20 13:34:14
- date last changed
- 2025-12-22 14:52:06
@article{33d1d37b-5712-401f-ba52-0bc9d0ebe1ef,
abstract = {{<p>BACKGROUND: Sepsis remains a source of high mortality in hospitalized patients despite proper antibiotic approaches. Encouragingly, mesenchymal stromal cells (MSCs) and their produced extracellular vesicles (EVs) have been shown to elicit anti-inflammatory effects in multiple inflammatory conditions including sepsis. However, EVs are generally released from mammalian cells in relatively low amounts, and high-yield isolation of EVs is still challenging due to a complicated procedure. To get over these limitations, vesicles very similar to EVs can be produced by serial extrusions of cells, after which they are called nanovesicles (NVs). We hypothesized that MSC-derived NVs can attenuate the cytokine storm induced by bacterial outer membrane vesicles (OMVs) in mice, and we aimed to elucidate the mechanism involved.</p><p>METHODS: NVs were produced from MSCs by the breakdown of cells through serial extrusions and were subsequently floated in a density gradient. Morphology and the number of NVs were analyzed by transmission electron microscopy and nanoparticle tracking analysis. Mice were intraperitoneally injected with Escherichia coli-derived OMVs to establish sepsis, and then injected with 2 × 109 NVs. Innate inflammation was assessed in peritoneal fluid and blood through investigation of infiltration of cells and cytokine production. The biodistribution of NVs labeled with Cy7 dye was analyzed using near-infrared imaging.</p><p>RESULTS: Electron microscopy showed that NVs have a nanometer-size spherical shape and harbor classical EV marker proteins. In mice, NVs inhibited eye exudates and hypothermia, signs of a systemic cytokine storm, induced by intraperitoneal injection of OMVs. Moreover, NVs significantly suppressed cytokine release into the systemic circulation, as well as neutrophil and monocyte infiltration in the peritoneum. The protective effect of NVs was significantly reduced by prior treatment with anti-interleukin (IL)-10 monoclonal antibody. In biodistribution study, NVs spread to the whole mouse body and localized in the lung, liver, and kidney at 6 h.</p><p>CONCLUSIONS: Taken together, these data indicate that MSC-derived NVs have beneficial effects in a mouse model of sepsis by upregulating the IL-10 production, suggesting that artificial NVs may be novel EV-mimetics clinically applicable to septic patients.</p>}},
author = {{Park, Kyong-Su and Svennerholm, Kristina and Shelke, Ganesh V and Bandeira, Elga and Lässer, Cecilia and Jang, Su Chul and Chandode, Rakesh and Gribonika, Inta and Lötvall, Jan}},
issn = {{1757-6512}},
keywords = {{Animals; Antibodies, Monoclonal/immunology; Bacterial Outer Membrane/metabolism; Disease Models, Animal; Endocytosis; Escherichia coli/metabolism; Exosomes/metabolism; Extracellular Vesicles/chemistry; Interleukin-10/immunology; Mesenchymal Stem Cells/cytology; Mice; Mice, Inbred C57BL; Monocytes/cytology; Nanostructures/chemistry; Neutrophil Infiltration; Peritoneum/metabolism; Proteome/analysis; RAW 264.7 Cells; Sepsis/pathology; Tissue Distribution}},
language = {{eng}},
month = {{08}},
number = {{1}},
publisher = {{BioMed Central (BMC)}},
series = {{Stem Cell Research & Therapy}},
title = {{Mesenchymal stromal cell-derived nanovesicles ameliorate bacterial outer membrane vesicle-induced sepsis via IL-10}},
url = {{http://dx.doi.org/10.1186/s13287-019-1352-4}},
doi = {{10.1186/s13287-019-1352-4}},
volume = {{10}},
year = {{2019}},
}