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Mesenchymal stromal cells (MSCs) are not a homogenous population but comprehend several cell types, such as stem cells, progenitor cells, fibroblasts, and other types of cells. Among these is a population of pluripotent stem cells, which represent around 1-3% of MSCs. These cells, named multilineage-differentiating stress enduring (Muse) cells, are stress-tolerant cells. Stem cells may undergo several rounds of intrinsic and extrinsic stresses due to their long life and must have a robust and effective DNA damage checkpoint and DNA repair mechanism, which, following a genotoxic episode, promote the complete recovery of cells rather than triggering senescence and/or apoptosis. We evaluated how Muse cells can cope with DNA damaging stress in comparison with MSCs. We found that Muse cells were resistant to chemical and physical genotoxic stresses better than non-Muse cells. Indeed, the level of senescence and apoptosis was lower in Muse cells. Our results proved that the DNA damage repair system (DDR) was properly activated following injury in Muse cells. While in non-Muse cells some anomalies may have occurred because, in some cases, the activation of the DDR persisted by 48 hr post damage, in others no activation took place. In Muse cells, the non-homologous end joining (NHEJ) enzymatic activity increases compared to other cells, while single-strand repair activity (NER, BER) does not. In conclusion, the high ability of Muse cells to cope with genotoxic stress is related to their quick and efficient sensing of DNA damage and activation of DNA repair systems., Competing Interests: CONFLICTS OF INTEREST None.

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.

Low doses of radiation may have profound effects on cellular function. Individuals may be exposed to low doses of radiation either intentionally for medical purposes or accidentally, such as those exposed to radiological terrorism or those who live near illegal radioactive waste dumpsites.We studied the effects of low dose radiation on human bone marrow mesenchymal stromal cells (MSC), which contain a subpopulation of stem cells able to differentiate in bone, cartilage, and fat; support hematopoiesis; and contribute to body's homeostasis.The main outcome of low radiation exposure, besides reduction of cell cycling, is the triggering of senescence, while the contribution to apoptosis is minimal. We also showed that low radiation affected the autophagic flux. We hypothesize that the autophagy prevented radiation deteriorative processes, and its decline contributed to senescence.An increase in ATM staining one and six hours post-irradiation and return to basal level at 48 hours, along with persistent gamma-H2AX staining, indicated that MSC properly activated the DNA repair signaling, though some damages remained unrepaired, mainly in non-cycling cells. This suggested that the impaired DNA repair capacity of irradiated MSC seemed mainly related to the reduced activity of a non-homologous end-joining (NHEJ) system rather than HR (homologous recombination).