RNA-Sequencing approach for exploring the therapeutic effect of umbilical cord mesenchymal stem/stromal cells on lipopolysaccharide-induced acute lung injury

Abstract

Acute lung injury (ALI) is significantly associated with morbidity and mortality in patients with critical diseases. In recent years, studies have identified that mesenchymal stem/stromal cells (MSCs) ameliorate ALI and pulmonary fibrosis. However, the mechanism underlying this outcome in ALI has not yet been investigated. In this study, RNA sequencing technology was used to analyze the gene expression profile of lung tissue in lipopolysaccharide (LPS)-induced ALI rats following treatment with human umbilical cord MSC (HUCMSC). Differential expression analyses, gene ontology annotation, Kyoto Encyclopedia of Genes and Genomes enrichment, protein–protein interaction network identification, and hub gene analysis were also performed. HUCMSC treatment decreased inflammatory factor production and alveolar exudates, and attenuated lung damage in LPS-induced ALI rats. The RNA-Seq data indicated that HUCMSC treatment activated the IL-17, JAK-STAT, NF-κB, and TNF-α signaling pathways, increased oxygen transport, and decreased extracellular matrix organization. HUCMSC exert beneficial effects on ALI via these signaling pathways by reducing inflammation, inhibiting pulmonary fibrosis, and improving lung ventilation. Moreover, our study further revealed the hub genes (Tbx2, Nkx2-1, and Atf5) and signaling pathways involved in HUCMSC treatment, thus providing novel perspectives for future research into the molecular mechanisms underlying cell treatment of ALI. HUCMSC can regulate multiple genes and signaling pathways, which can prevent LPS-induced lung damage in an ALI rat model.

Umbilical cord MSC‐derived exosomes improve alveolar macrophage function and reduce LPS‐induced acute lung injury

“…Having clarified the improved effects of MSC spheroids‐EXO on LPS‐induced ALI mice, we were curious about the differences at the molecular level. RNA‐seq analyses of the lung tissues harvested from 4 groups of mice were performed according to a standard process, as we previously reported 12 . As shown in Figure 3A, the principal component analysis of messenger RNA (mRNA) expression data shows the alternated properties of different groups: A: Control group (age‐sex matched healthy mice with no intervention), B: ALI + PBS treatment group, C: ALI + MSC‐EXO treatment group, D: ALI + MSC spheroids‐EXO treatment group.…”

“…RNA-seq analyses of the lung tissues harvested from 4 groups of mice were performed according to a standard process, as we previously reported. 12 As shown in Figure 3A, the principal component analysis of messenger RNA (mRNA) expression data shows the alternated properties of different groups: A: Control group (age-sex matched healthy mice with no intervention), B: ALI + PBS treatment group, C: ALI + MSC-EXO treatment group, D: ALI + MSC spheroids-EXO treatment group. Heatmap analysis indicated relatively tidy correlation coefficients among the samples in the same group (Figure 3B).…”

“…[9][10][11] Several studies have demonstrated the possible use of MSCs in animal models of ALI. [12][13][14][15] Intravenous administration of MSCs has been shown to accumulate in the pulmonary area and promote endogenous repair by protecting the alveolar epithelial cells and preventing the immune system from releasing a storm of cytokines. 16,17 This ultimately helps restore the lung microenvironment and to avoid lung fibrosis.…”

“…The MSC secretome, which includes cytokines, chemokines, growth factors, and proteins, has also been investigated for its potential therapeutic effects 9–11 . Several studies have demonstrated the possible use of MSCs in animal models of ALI 12–15 . Intravenous administration of MSCs has been shown to accumulate in the pulmonary area and promote endogenous repair by protecting the alveolar epithelial cells and preventing the immune system from releasing a storm of cytokines 16,17 .…”

Effect and safety of mesenchymal stem cells for patients with COVID‐19: Systematic review and meta‐analysis with trial sequential analysis

“…16 MSCs are not brandnew therapy in the treatments of pulmonary diseases. Previous studies have demonstrated that patients with chronic obstructive pulmonary disease, 16 ARDS 17 or pulmonary fibrosis 18,19 could benefit from MSCbased therapy which reduces the inflammation and pulmonary tissue damage, improves the respiratory function, pulmonary microenvironment and reduces the mortality. At the same time, the anti-infammatory and immunomodulatory characteristics of MSC-based therapy make them as ideal candidates for the treatment of patients with acute and chronic inflammatory lung diseases.…”