Changes in autophagy, proteasome activity and metabolism to determine a specific signature for acute and chronic senescent mesenchymal stromal cells.
Changes in autophagy, proteasome activity and metabolism to determine a specific signature for acute and chronic senescent mesenchymal stromal cells.
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DOI：
10.18632/oncotarget.6277
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发表时间：
2015-11-24
期刊：
影响因子：
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通讯作者：
Galderisi U
中科院分区：
文献类型：
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作者：
Capasso S;Alessio N;Squillaro T;Di Bernardo G;Melone MA;Cipollaro M;Peluso G;Galderisi U
由于我们对诱导细胞衰老的机制没有深入的了解，因此仍然缺乏对衰老细胞的明确定义。此外，衰老细胞是异质的，因为并非所有细胞都表达相同的基因并呈现相同的表型。为了进一步阐明衰老细胞的分类，可以通过对细胞代谢、自噬和蛋白酶体活性的研究来获得线索。在这种情况下，我们决定研究间充质基质细胞（MSC）衰老中的这些生物学特征。这些细胞含有能够分化成中胚层衍生物（脂肪细胞、软骨细胞、骨细胞）的干细胞亚群。此外，它们还有助于许多器官的稳态维持，因此，它们的衰老可能对人体功能非常有害。我们通过氧化应激、阿霉素处理、X射线照射和复制衰竭诱导MSC衰老。前三种被认为是急性衰老的诱导剂，而广泛的增殖触发复制性衰老，也称为慢性衰老。在所有条件下，但复制和高IR剂量衰老，我们检测到减少的自噬通量，而蛋白酶体活性受损的过氧化物处理和照射的细胞。在代谢状态中也观察到差异。一般来说，所有衰老细胞都表现出代谢不灵活性，并且更喜欢使用葡萄糖作为能量燃料。低剂量X射线辐照细胞和复制衰老细胞分别显示出利用脂肪酸和谷氨酰胺作为替代燃料的剩余能力。我们的研究可能有助于区分不同的衰老表型。
A sharp definition of what a senescent cell is still lacking since we do not have in depth understanding of mechanisms that induce cellular senescence. In addition, senescent cells are heterogeneous, in that not all of them express the same genes and present the same phenotype. To further clarify the classification of senescent cells, hints may be derived by the study of cellular metabolism, autophagy and proteasome activity. In this scenario, we decided to study these biological features in senescence of Mesenchymal Stromal Cells (MSC). These cells contain a subpopulation of stem cells that are able to differentiate in mesodermal derivatives (adipocytes, chondrocytes, osteocytes). In addition, they can also contribute to the homeostatic maintenance of many organs, hence, their senescence could be very deleterious for human body functions. We induced MSC senescence by oxidative stress, doxorubicin treatment, X-ray irradiation and replicative exhaustion. The first three are considered inducers of acute senescence while extensive proliferation triggers replicative senescence also named as chronic senescence. In all conditions, but replicative and high IR dose senescence, we detected a reduction of the autophagic flux, while proteasome activity was impaired in peroxide-treated and irradiated cells. Differences were observed also in metabolic status. In general, all senescent cells evidenced metabolic inflexibility and prefer to use glucose as energy fuel. Irradiated cells with low dose of X-ray and replicative senescent cells show a residual capacity to use fatty acids and glutamine as alternative fuels, respectively. Our study may be useful to discriminate among different senescent phenotypes.