Excessive activation of NMDA receptor inhibits the protective effect of endogenous bone marrow mesenchymal stem cells on promoting alveolarization in bronchopulmonary dysplasia

Yue, Yinyan; Luo, Ziqiang; Liao, Zhengbu; Zhang, Liming; Liu, Shuai; Wang, Mingjie; Zhao, Feiyan; Cao, Chuanding; Ding, Ying; Yue, Shaojie

doi:10.1152/ajpcell.00392.2018

Cited by 11 publications

(5 citation statements)

References 47 publications

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“…In the intrauterine hypoxia group, BM-MSCs proliferation and cell viability decreased markedly. These results suggest that intrauterine hypoxia caused by high concentrations of glutamate may result in excessive activation of important agonist NMDARs and damage the function of BM-MSCs (21). Also, increased glutamate concentration in lung tissue activates NMDARs and mediates the process of acute lung injury and lung fibrosis.…”

Section: Introductionmentioning

confidence: 87%

N-methyl-D-aspartate receptor blockers attenuate bleomycin-induced pulmonary fibrosis by inhibiting endogenous mesenchymal stem cells senescence

Huang¹,

Zhou²,

Li³

et al. 2022

Ann Transl Med

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Background: A large number of our previous studies showed that endogenous glutamate and N-methyl-D-aspartate receptor (NMDAR) activation may be involved in various types of acute lung injury, airway inflammation, asthma, and pulmonary fibrosis. In animal models, the transplantation of exogenous bone marrow mesenchymal stem cells (BM-MSCs) is the most promising treatment for idiopathic pulmonary fibrosis. However, there are limited reports on the status of endogenous BM-MSCs in the process of bleomycin-induced pulmonary fibrosis in animals. Methods:We constructed a mouse model of bleomycin-induced pulmonary fibrosis. In vitro, the senescence model of BM-MSCs was constructed with hydrogen peroxide and high concentration of N-methyl-D-aspartate (NDMA). The changes in aging-related indexes were detected by senescence associated beta-galactosidase (SA-β-gal) staining, western blot, flow cytometry and real time-PCR. The epithelial-mesenchymal transformation (EMT) changes of mouse lung epithelial cells (MLE-12) co-cultured with senescent BM-MSCs were detected by immunofluorescence and western blotting. Results:We observed that endogenous BM-MSCs senescence occurs during bleomycin-induced pulmonary fibrosis in mice, and the model group had a higher expression level of the NMDAR subunit than the control group. We observed a significant increase in NMDAR subunit expression in a hydrogen peroxide-induced senescent cell model in vitro. BM-MSCs showed senescence-related phenotype and cell cycle arrest after high concentration of NMDA treatment. At the same time, the expression levels of the classic Wingless and int-1 (Wnt) pathway protein β-cantenin and downstream cyclin D1 also changed. In the co-culture of aged BM-MSCs and MLE-12 cells, EMT can be promoted in MLE-12 cells, and MK-801 can partially antagonize the occurrence of EMT. The NMDAR antagonist can partially prevent the above phenomenon.Conclusions: High concentrations of NMDA can promote senescence of BM-MSCs. NMDAR blockers may inhibit endogenous BM-MSCs aging through the WNT signaling pathway, thereby reducing the effect of bleomycin-induced pulmonary fibrosis.

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Section: Introductionmentioning

confidence: 87%

N-methyl-D-aspartate receptor blockers attenuate bleomycin-induced pulmonary fibrosis by inhibiting endogenous mesenchymal stem cells senescence

Huang¹,

Zhou²,

Li³

et al. 2022

Ann Transl Med

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“…In preclinical studies, newborn mice or rats exposed to a hyperoxia (75%) microenvironment are widely used to mimic the pathogensis of human BPD [27]. Over the years, systematic administration, or local injection (intranasal [28] or intratracheal [29]) of MSCs have defined the beneficial impact on attenuating experimental BPD through inhibition of Nmethyl-D-aspartic acid (NMDA) receptors [30], reninangiotensin system (RAS) [31], TLR4 expression [32], decorin [29] and CTGF secretion [33], accompanied by upregulating the production of aminoacyl-peptide hydrolase [34], PTX3 [35], VEGF [33], stromal cell-derived factor 1 [36], macrophage stimulating factor 1 [37], and osteopontin [37], leading to increased survival rate, downregulated inf lammation-and hyperoxia-induced defect ive alveolarization, and reduced lung fibrosis in experimental BPD mice. Moreover, MSC stably transfected with a truncated version of CC chemokine ligand 2 (CCL2) promotes macrophage activation, and is seen to be more effective than MSCs alone [38].…”

Section: Bronchopulmonary Dysplasiamentioning

confidence: 99%

Effects of Mesenchymal Stromal Cell-Derived Extracellular Vesicles in Lung Diseases: Current Status and Future Perspectives

Guo

Deng

2020

Stem Cell Rev and Rep

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Mesenchymal stromal cells (MSCs) as a kind of pluripotent adult stem cell have shown great therapeutic potential in relation to many diseases in anti-inflammation and regeneration. The results of preclinical experiments and clinical trials have demonstrated that MSC-derived secretome possesses immunoregulatory and reparative abilities and that this secretome is capable of modulating innate and adaptive immunity and reprograming the metabolism of recipient cells via paracrine mechanisms. It has been recognized that MSC-derived secretome, including soluble proteins (cytokines, chemokines, growth factors, proteases), extracellular vesicles (EVs) and organelles, plays a key role in tissue repair and regeneration in bronchopulmonary dysplasia, acute respiratory distress syndrome (ARDS), bronchial asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), pulmonary arterial hypertension, and silicosis. This review summarizes the known functions of MSC-EV modulation in lung diseases, coupled with the future challenges of MSC-EVs as a new pharmaceutical agent. The identification of underlying mechanisms for MSC-EV might provide a new direction for MSC-centered treatment in lung diseases.Graphical abstract

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“…These histological changes were accompanied by evidence of BPD-characteristic lung inflammation as increased counts for total leukocytes, lymphocytes, macrophages and neutrophils were found in BALF, and increased gene expression of the BPD-associated cytokines IL-18, TNF-α, CXCL1, CTGF and TGF-β1 was found in lung tissue samples. IL-18 and TNF-α are pro-inflammatory cytokines previously reported to be associated with BPD or pulmonary hypertension in preterm infants or experimental models of BPD 27 – 30 . Interestingly, IL18 is activated by the inflammasome, and its secretion is dependent on GSDMD-p30 pore formation 17 – 19 .…”

Section: Discussionmentioning

confidence: 99%

Hyperoxia-activated circulating extracellular vesicles induce lung and brain injury in neonatal rats

Ali

Zambrano

Duncan

et al. 2021

Sci Rep

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Hyperoxia-induced lung injury plays a key role in the development of bronchopulmonary dysplasia (BPD), characterized by inflammatory injury and impaired lung development in preterm infants. Although BPD is a predictor of poor neurodevelopmental outcomes, currently it is uncertain how lung injury contributes to brain injury in preterm infants. Extracellular vesicles (EVs) are a heterogeneous group of cell-derived membranous structures that regulate intercellular and inter-organ communications. Gasdermin D (GSDMD) has emerged as a key executor of inflammasome-mediated cell death and inflammation. In this study, we utilized a neonatal rat model of BPD to assess if hyperoxia stimulates lung release of circulating EVs and if these EVs induce lung and brain injury. We found that hyperoxia-exposed rats had elevated numbers of plasma-derived EVs compared to rats maintained in room air. These EVs also had increased cargos of surfactant protein C, a marker of type II alveolar epithelial cells (AEC), and the active (p30) form of GSDMD. When these EVs were adoptively transferred into normal newborn rats via intravenous injection, they were taken up both by lung and brain tissues. Moreover, EVs from hyperoxic animals induced not only the pathological hallmarks of BPD, but also brain inflammatory injury in recipient rats, as well as inducing cell death in cultured pulmonary vascular endothelial cells and neural stem cells (NSC). Similarly, hyperoxia-exposed cultured AEC-like cells released EVs that also contained increased GSDMD-p30 and these EVs induced pyroptotic cell death in NSC. Overall, these data indicate that hyperoxia-activated circulating EVs mediate a lung to brain crosstalk resulting in brain injury and suggest a mechanism that links lung injury and neurodevelopmental impairment in BPD infants.

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Excessive activation of NMDA receptor inhibits the protective effect of endogenous bone marrow mesenchymal stem cells on promoting alveolarization in bronchopulmonary dysplasia

Cited by 11 publications

References 47 publications

N-methyl-D-aspartate receptor blockers attenuate bleomycin-induced pulmonary fibrosis by inhibiting endogenous mesenchymal stem cells senescence

N-methyl-D-aspartate receptor blockers attenuate bleomycin-induced pulmonary fibrosis by inhibiting endogenous mesenchymal stem cells senescence

Effects of Mesenchymal Stromal Cell-Derived Extracellular Vesicles in Lung Diseases: Current Status and Future Perspectives

Hyperoxia-activated circulating extracellular vesicles induce lung and brain injury in neonatal rats

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