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Mesenchymal stromal cells-derived extracellular vesicles repsogramme macrophages in ARDS models through the miR-181a-5p-PTEN-psTAT5-SOCS1 axis

Su, Yue ; Dutra Silva, Johnatas ; Doherty, Declan ; A Simpson, David ; J Weiss, Daniel ; Rolandsson Enes, Sara LU orcid ; F McAuley, Daniel ; M O´Kane, Cecilia ; P Brazil, Derek and D Krasnodembskaya, Anna (2023) In Thorax 78(6). p.617-630
Abstract
Rationale A better understanding of the mechanism of action of mesenchymal stromal cells (MSCs) and their extracellular vesicles (EVs) is needed to support their use as novel therapies for acute respiratory distress syndrome (ARDS). Macrophages are important mediators of ARDS inflammatory response. Suppressor of cytokine signalling (SOCS) proteins are key regulators of the macrophage phenotype switch. We therefore investigated whether SOCS proteins are involved in mediation of the MSC effect on human macrophage reprogramming.

Methods Human monocyte-derived macrophages (MDMs) were stimulated with lipopolysaccharide (LPS) or plasma samples from patients with ARDS (these samples were previously classified into hypo-inflammatory and... (More)
Rationale A better understanding of the mechanism of action of mesenchymal stromal cells (MSCs) and their extracellular vesicles (EVs) is needed to support their use as novel therapies for acute respiratory distress syndrome (ARDS). Macrophages are important mediators of ARDS inflammatory response. Suppressor of cytokine signalling (SOCS) proteins are key regulators of the macrophage phenotype switch. We therefore investigated whether SOCS proteins are involved in mediation of the MSC effect on human macrophage reprogramming.

Methods Human monocyte-derived macrophages (MDMs) were stimulated with lipopolysaccharide (LPS) or plasma samples from patients with ARDS (these samples were previously classified into hypo-inflammatory and hyper-inflammatory phenotype) and treated with MSC conditioned medium (CM) or EVs. Protein expression was measured by Western blot. EV micro RNA (miRNA) content was determined by miRNA sequencing. In vivo: LPS-injured C57BL/6 mice were given EVs isolated from MSCs in which miR-181a had been silenced by miRNA inhibitor or overexpressed using miRNA mimic.

Results EVs were the key component of MSC CM responsible for anti-inflammatory modulation of human macrophages. EVs significantly reduced secretion of tumour necrosis factor-α and interleukin-8 by LPS-stimulated or ARDS plasma-stimulated MDMs and this was dependent on SOCS1. Transfer of miR-181a in EVs downregulated phosphatase and tensin homolog (PTEN) and subsequently activated phosphorylated signal transducer and activator of transcription 5 (pSTAT5) leading to upregulation of SOCS1 in macrophages. In vivo, EVs alleviated lung injury and upregulated pSTAT5 and SOCS1 expression in alveolar macrophages in a miR181-dependent manner. Overexpression of miR-181a in MSCs significantly enhanced therapeutic efficacy of EVs in this model.

Conclusion miR-181a-PTEN-pSTAT5-SOCS1 axis is a novel pathway responsible for immunomodulatory effect of MSC EVs in ARDS. (Less)
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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Thorax
volume
78
issue
6
pages
617 - 630
publisher
BMJ Publishing Group
external identifiers
  • scopus:85136478066
  • pmid:35948417
ISSN
1468-3296
DOI
10.1136/thoraxjnl-2021-218194
language
English
LU publication?
yes
id
60b1cf3c-7b02-4f4c-9f83-4f688e5ca246
date added to LUP
2022-12-16 09:47:07
date last changed
2023-12-16 03:03:44
@article{60b1cf3c-7b02-4f4c-9f83-4f688e5ca246,
  abstract     = {{Rationale A better understanding of the mechanism of action of mesenchymal stromal cells (MSCs) and their extracellular vesicles (EVs) is needed to support their use as novel therapies for acute respiratory distress syndrome (ARDS). Macrophages are important mediators of ARDS inflammatory response. Suppressor of cytokine signalling (SOCS) proteins are key regulators of the macrophage phenotype switch. We therefore investigated whether SOCS proteins are involved in mediation of the MSC effect on human macrophage reprogramming.<br/><br/>Methods Human monocyte-derived macrophages (MDMs) were stimulated with lipopolysaccharide (LPS) or plasma samples from patients with ARDS (these samples were previously classified into hypo-inflammatory and hyper-inflammatory phenotype) and treated with MSC conditioned medium (CM) or EVs. Protein expression was measured by Western blot. EV micro RNA (miRNA) content was determined by miRNA sequencing. In vivo: LPS-injured C57BL/6 mice were given EVs isolated from MSCs in which miR-181a had been silenced by miRNA inhibitor or overexpressed using miRNA mimic.<br/><br/>Results EVs were the key component of MSC CM responsible for anti-inflammatory modulation of human macrophages. EVs significantly reduced secretion of tumour necrosis factor-α and interleukin-8 by LPS-stimulated or ARDS plasma-stimulated MDMs and this was dependent on SOCS1. Transfer of miR-181a in EVs downregulated phosphatase and tensin homolog (PTEN) and subsequently activated phosphorylated signal transducer and activator of transcription 5 (pSTAT5) leading to upregulation of SOCS1 in macrophages. In vivo, EVs alleviated lung injury and upregulated pSTAT5 and SOCS1 expression in alveolar macrophages in a miR181-dependent manner. Overexpression of miR-181a in MSCs significantly enhanced therapeutic efficacy of EVs in this model.<br/><br/>Conclusion miR-181a-PTEN-pSTAT5-SOCS1 axis is a novel pathway responsible for immunomodulatory effect of MSC EVs in ARDS.}},
  author       = {{Su, Yue and Dutra Silva, Johnatas and Doherty, Declan and A Simpson, David and J Weiss, Daniel and Rolandsson Enes, Sara and F McAuley, Daniel and M O´Kane, Cecilia and P Brazil, Derek and D Krasnodembskaya, Anna}},
  issn         = {{1468-3296}},
  language     = {{eng}},
  number       = {{6}},
  pages        = {{617--630}},
  publisher    = {{BMJ Publishing Group}},
  series       = {{Thorax}},
  title        = {{Mesenchymal stromal cells-derived extracellular vesicles repsogramme macrophages in ARDS models through the miR-181a-5p-PTEN-psTAT5-SOCS1 axis}},
  url          = {{http://dx.doi.org/10.1136/thoraxjnl-2021-218194}},
  doi          = {{10.1136/thoraxjnl-2021-218194}},
  volume       = {{78}},
  year         = {{2023}},
}