Capasso Stefania, Alessio Nicola, Squillaro Tiziana, Di Bernardo Giovanni, Melone Mariarosa A, Cipollaro Marilena, Peluso Gianfranco, Galderisi Umberto
Department of Experimental Medicine, Biotechnology and Molecular Biology Section, Second University of Naples, Naples, Italy.
Institute of Bioscience and Bioresources, CNR, Naples, Italy.
Oncotarget. 2015 Nov 24;6(37):39457-68. doi: 10.18632/oncotarget.6277.
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.
由于我们对诱导细胞衰老的机制缺乏深入了解，目前仍缺乏对衰老细胞的明确定义。此外，衰老细胞具有异质性，因为并非所有衰老细胞都表达相同的基因和呈现相同的表型。为了进一步明确衰老细胞的分类，我们可以从细胞代谢、自噬和蛋白酶体活性的研究中获得线索。在这种情况下，我们决定研究间充质基质细胞（MSC）衰老过程中的这些生物学特征。这些细胞包含能够分化为中胚层衍生物（脂肪细胞、软骨细胞、骨细胞）的干细胞亚群。此外，它们还能对许多器官的稳态维持做出贡献，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射线照射和复制性耗竭诱导MSC衰老。前三种被认为是急性衰老的诱导因素，而广泛增殖则触发复制性衰老，也称为慢性衰老。在所有情况下，但不包括复制性衰老和高剂量辐射衰老，我们检测到自噬通量降低，而过氧化氢处理和照射的细胞中蛋白酶体活性受损。在代谢状态方面也观察到了差异。一般来说，所有衰老细胞都表现出代谢灵活性降低，并且更倾向于使用葡萄糖作为能量燃料。低剂量X射线照射的细胞和复制性衰老细胞分别表现出使用脂肪酸和谷氨酰胺作为替代燃料的残余能力。我们的研究可能有助于区分不同的衰老表型。
