Project description:This SuperSeries is composed of the following subset Series: GSE35955: Effects of aging on Human Mesenchymal Stem Cells GSE35956: Effects of Primary Osteoporosis and Advanced Age on Human Mesenchymal Stem Cells GSE35957: Effects of Cellular Senescence on Human Mesenchymal Stem Cells GSE35958: Effects of Primary Osteoporosis on Human Mesenchymal Stem Cells Refer to individual Series
Project description:Pathological processes like osteoporosis or steroid-induced osteonecrosis of the hip are accompanied by increased bone marrow adipogenesis. Such disorder of adipogenic/osteogenic differentiation, which affects also bone marrow derived mesenchymal stem cells (BMSCs) contributes to bone loss during aging. Therefore, we investigated the effects of extracellular vesicles (EVs) isolated from human (h)BMSCs during different stages of osteogenic differentiation on osteogenic and adipogenic differentiation capacity of naïve hBMSCs.
Project description:Although the mTOR-4E-BP1 signaling pathway is implicated in aging and aging-related disorders, the role of 4E-BP1 in regulating human stem cell homeostasis remains largely unknown. Here, we report that the expression of 4E-BP1 decreases along with the senescence of human mesenchymal stem cells (hMSCs). Genetic inactivation of 4E-BP1 in hMSCs accelerates cellular senescence, compromises mitochondrial respiration and increases mitochondrial ROS production. Mechanistically, the absence of 4E-BP1 destabilizes proteins in mitochondrial respiration complexes, especially several key subunits of the complex III including UQCRC2. Ectopic expression of 4E-BP1 attenuates mitochondrial abnormalities and alleviates cellular senescence in 4E-BP1-deficient hMSCs as well as in physiologically aged hMSCs. These findings together demonstrate that 4E-BP1 functions as a geroprotector to alleviate human stem cell senescence and maintain mitochondrial homeostasis, particularly for the mitochondrial respiration complex III and provide a new potential target to counteract human stem cell senescence.
Project description:Protein homeostasis is linked with aging and aging associated diseases. Oxidative protein folding occurs in the endoplasmic reticulum (ER) and produces H2O2 as a byproduct. The role of oxidative protein folding in human stem cells aging remains unknown. Here, we succeed to knockout protein disulfide isomerase (PDI), a key oxidoreductase for catalyzing oxidative protein folding, in human embryonic stem cells (hESCs) and human mesenchymal stem cells (hMSCs). Deletion of PDI does not affect the self-renewal of hESCs but significantly delays hMSCs senescence. Mechanistically, knockout of PDI slows down the rate of oxidative protein folding and decreases the leakage of ER-derived H2O2 into the nucleus, therefore alleviating oxidative stress and the secretory-associated senescence phenotype (SASP). Among the SASP-related genes, SERPINE1 is identified as a key driver for cell senescence. These findings establish a novel link between oxidative protein folding and aging. The previously unrecognized function of PDI in regulating cell senescence provides a potential target for aging and aging-related disease intervention.
Project description:Global gene expressions of human bone-derived 11Lin-CD45-CD271+SSEA-4+ mesenchymal stem/stromal cells from young and elderly patients were analyzed. Results provide an insight into the molecular mechanisms of aging and cellular senescence.
