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Hypoxia induces senescence of bone marrow mesenchymal stem cells via altered gut microbiota.

ABSTRACT: Systemic chronic hypoxia is a feature of many diseases and may influence the communication between bone marrow (BM) and gut microbiota. Here we analyse patients with cyanotic congenital heart disease (CCHD) who are experiencing chronic hypoxia and characterize the association between bone marrow mesenchymal stem cells (BMSCs) and gut microbiome under systemic hypoxia. We observe premature senescence of BMSCs and abnormal D-galactose accumulation in patients with CCHD. The hypoxia that these patients experience results in an altered diversity of gut microbial communities, with a remarkable decrease in the number of Lactobacilli and a noticeable reduction in the amount of enzyme-degraded D-galactose. Replenishing chronic hypoxic rats with Lactobacillus reduced the accumulation of D-galactose and restored the deficient BMSCs. Together, our findings show that chronic hypoxia predisposes BMSCs to premature senescence, which may be due to gut dysbiosis and thus induced D-galactose accumulation.

SUBMITTER: Xing J

PROVIDER: S-EPMC5964076 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Hypoxia induces senescence of bone marrow mesenchymal stem cells via altered gut microbiota.

Xing Junyue J Ying Yongquan Y Mao Chenxi C Liu Yiwei Y Wang Tingting T Zhao Qian Q Zhang Xiaoling X Yan Fuxia F Zhang Hao H

Nature communications 20180522 1

Systemic chronic hypoxia is a feature of many diseases and may influence the communication between bone marrow (BM) and gut microbiota. Here we analyse patients with cyanotic congenital heart disease (CCHD) who are experiencing chronic hypoxia and characterize the association between bone marrow mesenchymal stem cells (BMSCs) and gut microbiome under systemic hypoxia. We observe premature senescence of BMSCs and abnormal D-galactose accumulation in patients with CCHD. The hypoxia that these pati ...[more]

PMID: 29789585

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Project description:BACKGROUND:Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease for which age is the most important risk factor. Different mechanisms associated with aging, including stem cell dysfunction, have been described to participate in the pathophysiology of IPF. We observed an extrapulmonary effect associated with IPF: increase in cell senescence of bone marrow-derived mesenchymal stem cells (B-MSCs). METHODS:B-MSCs were obtained from vertebral bodies procured from IPF patients and age-matched normal controls. Cell senescence was determined by cell proliferation and expression of markers of cell senescence p16INK4A, p21, and ?-galactosidase activity. Mitochondrial function and DNA damage were measured. Paracrine induction of senescence and profibrotic responses were analyzed in vitro using human lung fibroblasts. The reparative capacity of B-MSCs was examined in vivo using the bleomycin-induced lung fibrosis model. RESULTS:In our study, we demonstrate for the first time that B-MSCs from IPF patients are senescent with significant differences in mitochondrial function, with accumulation of DNA damage resulting in defects in critical cell functions when compared with age-matched controls. Senescent IPF B-MSCs have the capability of paracrine senescence by inducing senescence in normal-aged fibroblasts, suggesting a possible link between senescent B-MSCs and the late onset of the disease. IPF B-MSCs also showed a diminished capacity to migrate and were less effective in preventing fibrotic changes observed in mice after bleomycin-induced injury, increasing illness severity and proinflammatory responses. CONCLUSIONS:We describe extrapulmonary alterations in B-MSCs from IPF patients. The consequences of having senescent B-MSCs are not completely understood, but the decrease in their ability to respond to normal activation and the risk of having a negative impact on the local niche by inducing inflammation and senescence in the neighboring cells suggests a new link between B-MSC and the onset of the disease.

Dataset Information

Hypoxia induces senescence of bone marrow mesenchymal stem cells via altered gut microbiota.

Publications

Hypoxia induces senescence of bone marrow mesenchymal stem cells via altered gut microbiota.

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