The therapeutic effect of mesenchymal stem cells on pulmonary myeloid cells following neonatal hyperoxic lung injury in mice

Al-Rubaie, Ali; Wise, Andrea F; Sozo, Foula; Matteo, Robert De; Samuel, Chrishan S.; Harding, Richard; Ricardo, Sharon D.

doi:10.1186/s12931-018-0816-x

Cited by 28 publications

(18 citation statements)

References 48 publications

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“…Furthermore, the expression of their ligands, Csf1 and Ccl2, was upregulated in the hyperoxia-specific clusters Neutro.2 and Mac.4, respectively(Fig. 6h).These observations are consistent with the study by Kalymbetova et al, where Ccr2 -/and CSF1R-depleted mice developed milder structural changes in hyperoxia-exposed lungs50 .The cell count and transcriptional activity of Mac.3 cells (cluster 4), was stable in normal development, as well as after exposure to hyperoxia (Supplementary Figure 6a-c), and expressed high levels of inflammatory mediators, consistent with data by Gibbings et al51 (Supplementary Figure 6k).The concept of M1/M2 polarization of macrophages has been linked to normal development, as well as to several lung pathologies, including BPD2,52,53 . Consistent with previous studies, our results suggested that the expression of M2 genes was increased in alveolar macrophages during postnatal development 2(Supplementary Figure 6l).Furthermore, hyperoxia enhanced the M1 signature of Mac.2 macrophages and induced a new population of macrophages -Mac.4characterized by the activation of both M1 and M2 genes (Supplementary Figure 6m).…”

supporting

confidence: 84%

Multiplexed single-cell transcriptomic analysis of normal and impaired lung development in the mouse

Hurskainen

Mižíková

Cook

et al. 2019

Preprint

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During late lung development alveolar and microvascular development is finalized to enable sufficient gas exchange. Impaired late lung development manifests as bronchopulmonary dysplasia (BPD) in preterm infants. Single-cell RNA sequencing (scRNA-seq) allows for assessment of complex cellular dynamics during biological processes, such as development. Here, we use MULTI-seq to generate scRNA-seq profiles of over 66,000 cells from 36 mice during normal or impaired lung development secondary to hyperoxia. We observed dynamic populations of cells, including several rare cell types and putative progenitors. Hyperoxia exposure, which mimics the BPD phenotype, alters the composition of all cellular compartments, particularly alveolar epithelium, capillary endothelium and macrophage populations. We identified several BPD-associated signatures, including Pdgfra in fibroblasts, Activin A in capillary endothelial cells, and Csf1-Csf1r and Ccl2-Ccr2 signaling in macrophages and neutrophils. Our data provides a novel single-cell view of cellular changes associated with late lung development in health and in disease.

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supporting

confidence: 84%

Multiplexed single-cell transcriptomic analysis of normal and impaired lung development in the mouse

Hurskainen

Mižíková

Cook

et al. 2019

Preprint

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“…However, hyperoxia may promote inflammation, contribute to acute lung injury and impair antimicrobial immunity. Hyperoxia is thought to trigger a multicellular immune response, implicating monocytes, macrophages, neutrophils and NKT cells, as noted in separate studies [13][14][15][16][17][18] . However, a global view of the immune populations during hyperoxia has not been previously studied.…”

Section: Discussionmentioning

confidence: 90%

“…Pulmonary responses to hyperoxia likely involve multiple immune cell populations. Separate studies have reported that hyperoxia inhibits macrophage proliferation 13,14 , heightens the ratio of F4/80 low CD206 low (proinflammatory, "M1") to F4/80 high CD206 high (anti-inflammatory, "M2") alveolar macrophages 15 , and promotes influx of CD11b high CD11c low cells ("inflammatory monocytes") and CD11b high CD11c high macrophages ("exudative macrophages") into the bronchoalveolar space 16 . Increased infiltration of parenchyma by invariant NKT cells 17 and late recruitment of neutrophils 18 have also been described.…”

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confidence: 99%

Characterization of pulmonary immune responses to hyperoxia by high-dimensional mass cytometry analyses

Hanidziar

Nakahori

Cahill

et al. 2020

Sci Rep

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Prolonged exposure to hyperoxia has deleterious effects on the lung, provoking both inflammation and alveolar injury. The elements of hyperoxic injury, which result in high rates of lethality in experimental models, are thought to include multicellular immune responses. To characterize these alterations in immune cell populations, we performed time-of-flight mass cytometry (CyTOF) analysis of CD45expressing immune cells in whole lung parenchyma and the bronchoalveolar space of mice, exposed to 48 hours of hyperoxia together with normoxic controls. At the tested time point, hyperoxia exposure resulted in decreased abundance of immunoregulatory populations (regulatory B cells, myeloid regulatory cells) in lung parenchyma and markedly decreased proliferation rates of myeloid regulatory cells, monocytes and alveolar macrophages. Additionally, hyperoxia caused a shift in the phenotype of alveolar macrophages, increasing proportion of cells with elevated CD68, CD44, CD11c, PD-L1, and CD205 expression levels. These changes occurred in the absence of histologically evident alveolar damage and abundance of neutrophils in the parenchyma or alveolar space did not change at these time points. Collectively, these findings demonstrate that pulmonary response to hyperoxia involves marked changes in specific subsets of myeloid and lymphoid populations. These findings have important implications for therapeutic targeting in acute lung injury. open Scientific RepoRtS | (2020) 10:4677 | https://doi.

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“…At P14, the freshly excised lungs were placed into cold uorescence activated cell sorting (FACS) buffer (PBS containing 0.2% BSA, 0.02% NaN 3 and 5mM EDTA) for a maximum of 30 minutes. The main airways were removed and the lungs were cut into small pieces which were then digested mechanically and enzymatically as previously reported [18].…”

Section: Lung Preparation For Macrophage Isolationmentioning

confidence: 99%

“…In a recent study [18], we reported the therapeutic effects of human mesenchymal stem cells (hMSCs) on the polarisation of lung macrophages, the development of lung in ammation, and collagen deposition following hyperoxic lung injury in neonatal mice. To date, the therapeutic effectiveness of hMSCs on the gene expression of lung macrophages in response to hyperoxia, and the changes in total and small RNA associated with differing macrophage phenotypes, are yet to be determined.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional Analysis Reveals Alteration of Lung Macrophages Following Mesenchymal Stem Cell Therapy in Neonatal Mice With Hyperoxia-Induced Injury

Al-Rubaie

DeMatteo

Sozo

et al. 2020

Preprint

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Background Lung immaturity is one of the most serious consequences of growth restriction and premature birth. Preterm babies often require mechanical ventilation to survive, but exposure to high levels of oxygen can permanently damage the lungs and interrupts normal development. As lung macrophages play an important role in hyperoxic lung injury and repair, our objective was to use next generation sequencing (NGS) to identify changes in the macrophage transcriptome following neonatal hyperoxia, with and without treatment with human mesenchymal stem cells (hMSCs). We provide the first report of RNA-sequencing of lung macrophages following neonatal hyperoxia and hMSCs therapy. Methods Neonatal mice exposed to normoxia (21%O2) or hyperoxia (90% O2) from birth to postnatal day 4 were randomized to receive either hMSCs or vehicle via intratracheal delivery on postnatal day 4. Mouse lungs from normoxia and hyperoxia groups with and without hMSCs therapy were examined at day 14. RNA-sequencing was performed on flow-cytometric CD45+CD11b+CD11c+ sorted lung macrophages. Purified total RNA was used to construct barcoded multiplex-compatible sequencing libraries using: 1) Illumina Stranded mRNA Sample Preparation chemistry (for transcriptomics) and 2) Bio Scientific NEXTFlex Small RNA chemistry (for small RNA). Results Sorted CD45+CD11b+CD11c+ lung macrophages from hyperoxia-exposed neonatal mice showed differentially expressed macrophage genes and miRNA compared to mice exposed to normoxia or hyperoxia+hMSCs. The administration of hMSCs was found to differentially upregulate 421 genes and downregulate 651 genes in CD45+CD11b+CD11c+ lung macrophages from neonatal mice exposed to hyperoxia, compared to normoxia. Integrity pathway analysis (IPA) analysis of macrophage-specific gene pathways revealed the effectiveness of hMSCs in altering macrophage function towards an anti-inflammatory ‘M2’ phenotype. Small-RNA sequencing provided further evidence on the effects of hMSCs, where 1,098 small RNAs transcriptomes were expressed as either significantly up- or down-regulated in response to hMSCs therapy following hyperoxia-induced lung damage. Conclusions Pathway analysis of the predicted mRNA targets of differentially expressed genes provides insight into miRNAs that preferentially target several important pathways. These miRNAs will be functionally relevant for lung macrophages, and will provide a greater understanding of the interaction between macrophage genotype and the associated phenotypes in the setting of inflammation or tissue repair.

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The therapeutic effect of mesenchymal stem cells on pulmonary myeloid cells following neonatal hyperoxic lung injury in mice

Cited by 28 publications

References 48 publications

Multiplexed single-cell transcriptomic analysis of normal and impaired lung development in the mouse

Multiplexed single-cell transcriptomic analysis of normal and impaired lung development in the mouse

Characterization of pulmonary immune responses to hyperoxia by high-dimensional mass cytometry analyses

Transcriptional Analysis Reveals Alteration of Lung Macrophages Following Mesenchymal Stem Cell Therapy in Neonatal Mice With Hyperoxia-Induced Injury

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