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.

Effects of regulating gut microbiota on the serotonin metabolism in the chronic unpredictable mild stress rat model

“…Sequences with ≥97% similarity were assigned to the same operational taxonomic units (OTUs). Additionally, based on the normalized OTUs, alpha diversity using Shannon index was applied to analyze the complexity of species diversity for the samples . A high α diversity indicates a high richness of genera within the sample.…”

Impact of Mesenchymal Stem Cell Senescence on Inflammaging

“…Oncometabolite 2-HG-induced mutation of IDH1 and 2 impairs osteoblast differentiation, presumably suggesting a mechanism underlying hypoxia-mediated reduced osteogenic differentiation of MSCs (90). Moreover, systemic chronic hypoxia facilitates premature senescence of MSCs in BM by altering the diversity of gut microbial communities, particularly a decrease in Lactobacilli colonies and subsequent accumulation of D-galactose, a well-known agent for senescence induction (92).…”

Cross talk between 26S proteasome and mitochondria in human mesenchymal stem cells’ ability to survive under hypoxia stress

“…Additionally, several studies have illustrated the effects of hypoxia on proliferation and differentiation potential of MSCs [19,26,28,29,36,51]; they stated that preconditioning MSCs by exposing them to moderate degree of hypoxia (2-7% of oxygen) inhibits apoptosis and senescence pathways and increases proliferation and differentiation potential of MSCs [13,14,28]. However, several preclinical and clinical trials reported that after transplanting MSCs into sites where severe hypoxia (1% or less than 1%) exists, they could not survive for long time, and ultimately they died and washed off [8,26,48]. Since the diseases such as myocardial infarction, where severe hypoxia dominates, were considered the target where MSCs transplantation is absolutely needed, it is of the top priorities to understand the mechanisms that affect the fickle tolerance abilities of MSCs under different hypoxia levels.…”

“…Moreover, many animal models have showed that MSCs could migrate efficiently from the bone marrow to remote organs and tissues under moderate hypoxic condition. On the other side, more severe hypoxia that dominates in many diseases such as myocardial infarction, renal diseases, reduces the proliferation of MSCs and induces their death [8,48]. However, the exact mechanism of why MSCs can tolerate moderate hypoxia not severe hypoxia needs to be investigated.…”