Dataset Information

Mesenchymal stromal/stem cells modulate response to experimental sepsis-induced lung injury via regulation of miR-27a-5p in recipient mice.

ABSTRACT: INTRODUCTION:Mesenchymal stromal cell (MSC) therapy mitigates lung injury and improves survival in murine models of sepsis. Precise mechanisms of therapeutic benefit remain poorly understood. OBJECTIVES:To identify host-derived regulatory elements that may contribute to the therapeutic effects of MSCs, we profiled the microRNAome (miRNAome) and transcriptome of lungs from mice randomised to experimental polymicrobial sepsis-induced lung injury treated with either placebo or MSCs. METHODS AND RESULTS:A total of 11 997 genes and 357 microRNAs (miRNAs) expressed in lungs were used to generate a statistical estimate of association between miRNAs and their putative mRNA targets; 1395 miRNA:mRNA significant association pairs were found to be differentially expressed (false discovery rate ?0.05). MSC administration resulted in the downregulation of miR-27a-5p and upregulation of its putative target gene VAV3 (adjusted p=1.272E-161) in septic lungs. In human pulmonary microvascular endothelial cells, miR-27a-5p expression levels were increased while VAV3 was decreased following lipopolysaccharide (LPS) or tumour necrosis factor (TNF) stimulation. Transfection of miR-27a-5p mimic or inhibitor resulted in increased or decreased VAV3 message, respectively. Luciferase reporter assay demonstrated specific binding of miR-27a-5p to the 3'UTR of VAV3. miR27a-5p inhibition mitigated TNF-induced (1) delayed wound closure, increased (2) adhesion and (3) transendothelial migration but did not alter permeability. In vivo, cell infiltration was attenuated by intratracheal coinstillation of the miR-27a-5p inhibitor, but this did not protect against endotoxin-induced oedema formation. CONCLUSIONS:Our data support involvement of miR-27a-5p and VAV3 in cellular adhesion and infiltration during acute lung injury and a potential role for miR-27a-based therapeutics for acute respiratory distress syndrome.

SUBMITTER: Younes N

PROVIDER: S-EPMC7361025 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Mesenchymal stromal/stem cells modulate response to experimental sepsis-induced lung injury via regulation of miR-27a-5p in recipient mice.

Younes Nadim N Zhou Louis L Amatullah Hajera H Mei Shirley H J SHJ Herrero Raquel R Lorente Jose Angel JA Stewart Duncan J DJ Marsden Philip P Liles W Conrad WC Hu Pingzhao P Dos Santos Claudia C CC

Thorax 20200616 7

<h4>Introduction</h4>Mesenchymal stromal cell (MSC) therapy mitigates lung injury and improves survival in murine models of sepsis. Precise mechanisms of therapeutic benefit remain poorly understood.<h4>Objectives</h4>To identify host-derived regulatory elements that may contribute to the therapeutic effects of MSCs, we profiled the microRNAome (miRNAome) and transcriptome of lungs from mice randomised to experimental polymicrobial sepsis-induced lung injury treated with either placebo or MSCs.< ...[more]

PMID: 32546573

Similar Datasets

Project description:BackgroundEven though mesenchymal stromal cells (MSCs) mitigate lung and distal organ damage in experimental polymicrobial sepsis, mortality remains high. We investigated whether preconditioning with eicosapentaenoic acid (EPA) would potentiate MSC actions in experimental sepsis by further decreasing lung and distal organ injury, thereby improving survival.MethodsIn C57BL/6 mice, sepsis was induced by cecal hligation and puncture (CLP); sham-operated animals were used as control. Twenty-four hours after surgery, CLP mice were further randomized to receive saline, adipose tissue-derived (AD)-MSCs (105, nonpreconditioned), or AD-MSCs preconditioned with EPA for 6 h (105, EPA-preconditioned MSCs) intravenously. After 24 h, survival rate, sepsis severity score, lung mechanics and histology, protein level of selected biomarkers in lung tissue, cellularity in blood, distal organ damage, and MSC distribution (by technetium-99m tagging) were analyzed. Additionally, the effects of EPA on the secretion of resolvin-D1 (RvD1), prostaglandin E2 (PGE2), interleukin (IL)-10, and transforming growth factor (TGF)-β1 by MSCs were evaluated in vitro.ResultsNonpreconditioned and EPA-preconditioned AD-MSCs exhibited similar viability and differentiation capacity, accumulated mainly in the lungs and kidneys following systemic administration. Compared to nonpreconditioned AD-MSCs, EPA-preconditioned AD-MSCs further reduced static lung elastance, alveolar collapse, interstitial edema, alveolar septal inflammation, collagen fiber content, neutrophil cell count as well as protein levels of interleukin-1β and keratinocyte chemoattractant in lung tissue, and morphological abnormalities in the heart (cardiac myocyte architecture), liver (hepatocyte disarrangement and Kupffer cell hyperplasia), kidney (acute tubular necrosis), spleen (increased number of megakaryocytes and lymphocytes), and small bowel (villi architecture disorganization). EPA preconditioning of MSCs resulted in increased secretion of pro-resolution and anti-inflammatory mediators (RvD1, PGE2, IL-10, and TGF-β).ConclusionsCompared to nonpreconditioned cells, EPA-preconditioned AD-MSCs yielded further reductions in the lung and distal organ injury, resulting in greater improvement in sepsis severity score and higher survival rate in CLP-induced experimental sepsis. This may be a promising therapeutic approach to improve outcome in septic patients.

Dataset Information

Mesenchymal stromal/stem cells modulate response to experimental sepsis-induced lung injury via regulation of miR-27a-5p in recipient mice.

Publications

Mesenchymal stromal/stem cells modulate response to experimental sepsis-induced lung injury via regulation of miR-27a-5p in recipient mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets