Mesenchymal stem cell prevention of vascular remodeling in high flow-induced pulmonary hypertension through a paracrine mechanism

Luan, Yun; Zhang, Xue; Kong, Feng; Cheng, Guanghui; Qi, Tonggang; Zhang, Zhaohua

doi:10.1016/j.intimp.2012.08.001

Cited by 42 publications

(31 citation statements)

References 38 publications

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“…Several cytokines, including TNFα, IL-1β, IL-6 and IL-8 are implicated in the pathogenesis of PAH91011121316. Of these, only TNFα selectively reduced BMPR2 mRNA and BMPR-II protein in distal PASMCs (dPASMCs) and pulmonary arterial endothelial cells (PAECs) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Accordingly, PAH patients exhibit heightened circulating levels of inflammatory cytokines, including tumour necrosis factor-α (TNFα), that correlate with poor survival1112. Of note, transgenic mice overexpressing TNFα in the lung develop spontaneous PAH13 and lung TNFα expression is elevated in rats or dogs with pulmonary hypertension induced with monocrotaline (MCT-PAH) or a high flow left-to-right shunt141516. Etanercept, a soluble TNF-receptor II dimer, prevents and reverses MCT-PAH in rats17 and reverses PAH in endotoxemic pigs18.…”

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confidence: 99%

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TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling

et al. 2017

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Heterozygous germ-line mutations in the bone morphogenetic protein type-II receptor (BMPR-II) gene underlie heritable pulmonary arterial hypertension (HPAH). Although inflammation promotes PAH, the mechanisms by which inflammation and BMPR-II dysfunction conspire to cause disease remain unknown. Here we identify that tumour necrosis factor-α (TNFα) selectively reduces BMPR-II transcription and mediates post-translational BMPR-II cleavage via the sheddases, ADAM10 and ADAM17 in pulmonary artery smooth muscle cells (PASMCs). TNFα-mediated suppression of BMPR-II subverts BMP signalling, leading to BMP6-mediated PASMC proliferation via preferential activation of an ALK2/ACTR-IIA signalling axis. Furthermore, TNFα, via SRC family kinases, increases pro-proliferative NOTCH2 signalling in HPAH PASMCs with reduced BMPR-II expression. We confirm this signalling switch in rodent models of PAH and demonstrate that anti-TNFα immunotherapy reverses disease progression, restoring normal BMP/NOTCH signalling. Collectively, these findings identify mechanisms by which BMP and TNFα signalling contribute to disease, and suggest a tractable approach for therapeutic intervention in PAH.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling

et al. 2017

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“…During chronic hypoxia, MSCs may restore lung vascular homeostasis by inhibiting inflammation and vascular remodeling, thereby promoting vascular stability or they may potentially contribute to vessel wall remodeling (16). Significantly, MSCs have been shown to release growth factors when stressed by hypoxia in vitro (51,60), and as discussed by Foronjy and Majka, understanding the lung microenviroment is important because the endogenous MSC pool may react in opposing ways to different environmental cues (27).…”

Section: Role Of Mscs In Lung Diseasementioning

confidence: 99%

MSC Microvesicles for the Treatment of Lung Disease: A New Paradigm for Cell-Free Therapy

Sdrimas

Kourembanas

2014

Antioxidants & Redox Signaling

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Significance: Bronchopulmonary dysplasia (BPD), also known as chronic lung disease of infancy, is a major complication of preterm birth that, despite improvements in neonatal respiratory support and perinatal care, remains an important cause of morbidity and mortality, often with severe adverse neurodevelopmental sequelae. Even with major advances in our understanding of the pathogenesis of this disease, BPD remains essentially without adequate treatment. Recent Advances: Cell-based therapies arose as a promising treatment for acute and chronic lung injury in many experimental models of disease. Currently, more than 3000 human clinical trials employing cell therapy for the treatment of diverse diseases, including cardiac, neurologic, immune, and respiratory conditions, are ongoing or completed. Among the treatments, mesenchymal stem cells (MSCs) are the most studied and have been extensively tested in experimental models of BPD, pulmonary hypertension, pulmonary fibrosis, and acute lung injury. Critical Issues: Despite the promising potential, MSC therapy for human lung disease still remains at an experimental stage and optimal transplantation conditions need to be determined. Although the mechanism of MSC action can be manifold, accumulating evidence suggests a predominant paracrine, immunomodulatory, and cytoprotective effect. Future Directions: The current review summarizes the effect of MSC treatment in models of lung injury, including BPD, and focuses on the MSC secretome and, specifically, MSC-derived microvesicles as potential key mediators of therapeutic action that can be the focus of future therapies. Antioxid. Redox Signal. 21, 1905Signal. 21, -1915

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“…A number of studies have indicated that the exogenous administration of BMSCs may protect against a variety of pulmonary diseases, including acute lung injury (16,17) and chronic lung disease (18). BMSCs exhibit a marked capacity for self-renewal, multidirectional differentiation (19), perception of the position of damage signals, repair and regeneration (20), immune function and the ability to prevent the immune rejection of allografts (21).…”

Section: Discussionmentioning

confidence: 99%

Effects of bone marrow-derived mesenchymal stem cells on the autophagic activity of alveolar macrophages in a rat model of silicosis

Zhu

Gao

Zhao

et al. 2016

Experimental and Therapeutic Medicine

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The aim of the present study was to evaluate the effects of bone marrow-derived mesenchymal stem cells (BMSCs) on the expression of the autophagy-associated proteins, microtubule-associated protein light chain 3 (LC-3) and autophagy-related gene Beclin-1 (Beclin-1), in alveolar macrophages (AMs) in a rat model of silicosis. Furthermore, the study investigated the molecular mechanisms underlying the effects of BMSC treatment. A population of 60 adult female Sprague-Dawley (SD) rats were allocated at random into three groups, namely the control, model and BMSC treatment groups (n=20 per group). BMSCs were isolated from five male SD rats (age, 6-8 weeks) and cultured in vitro. The silicosis model was established using a single 1.0-ml infusion of silicon dioxide suspension administered via non-exposed tracheal intubation. Rats in the BMSC treatment group received a 1.0-ml transplantation of BMSCs (1×106/ml). The rats were sacrificed on days 1, 7, 14 and 28 after modeling, and AMs were extracted from the rats using bronchoalveolar lavage. Third-generation BMSCs were identified using flow cytometry with fluorescein isothiocyanate staining, and the morphological characteristics of the AMs were observed using hematoxylin and eosin staining. The expression levels of LC-3 and Beclin-1 were determined using immunocytochemistry sand western blot analysis. The expression levels of LC-3 and Beclin-1 were found to be increased at all the time points in the model group. LC-3 and Beclin-1 levels began to increase at day 1, peaked at day 14 and decreased after day 28; however, the levels remained elevated compared with the basal expression levels. The AMs of the BMSC treatment group exhibited significantly alleviated pathological symptoms compared with the model group AMs, as indicated by significantly decreased expression levels of LC-3 and Beclin-1 at each time point. Therefore, the results indicated that autophagy was promoted in the AMs of the silicosis model rats. Furthermore, treatment with BMSCs was demonstrated to reduce the expression levels of LC-3 and Beclin-1, subsequently inhibiting autophagic activity and mitigating the damage associated with silicosis.

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Mesenchymal stem cell prevention of vascular remodeling in high flow-induced pulmonary hypertension through a paracrine mechanism

Cited by 42 publications

References 38 publications

TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling

TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling

MSC Microvesicles for the Treatment of Lung Disease: A New Paradigm for Cell-Free Therapy

Effects of bone marrow-derived mesenchymal stem cells on the autophagic activity of alveolar macrophages in a rat model of silicosis

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