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Senescent cells secrete several molecules, collectively named senescence-associated secretory phenotype (SASP). In the SASP of cells that became senescent following several in vitro chemical and physical stress, we identified the IGFBP-4 protein that can be considered a general stress mediator. This factor appeared to play a key role in senescence-paracrine signaling. We provided evidences showing that genotoxic injury, such as low dose irradiation, may promote an IGFBP-4 release in bloodstream both in mice irradiated with 100 mGy X-ray and in human subjects that received Computer Tomography. Increased level of circulating IGFBP-4 may be responsible of pro-aging effect. We found a significant increase of senescent cells in the lungs, heart, and kidneys of mice that were intraperitoneally injected with IGFBP-4 twice a week for two months. We then analyzed how genotoxic stressors may promote the release of IGFBP-4 and the molecular pathways associated with the induction of senescence by this protein.

Background Mitochondrial dysfunction, characterized by abnormalities of mitochondrial biogenesis, dynamics, trafficking, and alterations in the synthesis of high-energy molecules, seems to play a fundamental role in the pathogenesis of neurodegeneration in Huntington’s disease (HD). Meldonium is a small molecule that inhibits endogenous carnitine synthesis and carnitine cell uptake. The decrease of carnitine availability inside the cell induces a significant reprogramming of cell metabolic pathways that apparently counters the mitochondrial dysfunction, at least in the case of heart or brain ischemia. Aims To evaluate neuroprotective actions of meldonium in both in vitro and in vivo HD models. Methods We used STHdhQ111/Q111 cells expressing a mutated form of the huntingtin protein (mHtt), and a transgenic Drosophila model of HD in which the expression of Htt, with a 128Q expansion (Q128HD-FL) in the nervous system, led to progressive motor performance deficits. Results We found that meldonium could prevent cytotoxicity induced by serum deprivation in STHdhQ111/Q111 cells. Meldonium could also reduce the accumulation of mHtt aggregates inside the cell. In addition, meldonium was able to upregulate the expression of PGC-1α, which is a master co-regulator of mitochondrial biogenesis, energy homeostasis, and antioxidant defense, as well as a potential HD target. As expected, the increase of PGC-1α was accompanied by the increment of mitochondrial mass and by the rebalancing of mitochondrial dynamics with a promotion of the mitochondrial fusion. Interestingly, when given per os, meldonium significantly alleviated motor dysfunction and prolonged the survival of transgenic Drosophila model of HD. Conclusions Our study strongly suggests, after considering these factors together, that meldonium (itself or as a lead structure for the synthesis of novel drugs) is a potential treatment for the management of HD.

Mesenchymal stem cells, a subpopulation of mesenchymal stromal cells (MSCs), are present in the stroma of several tissues. MSC in vitro cultivation for clinical treatments may greatly affect MSC properties. A primary handicap is replicative senescence that impairs MSC functions. Hyaluronan (HA) is present in the extracellular matrix that composes the stem cell niche environment and is under investigation as a key factor for in vitro stem cell growth. We evaluated the effect on MSC cultivation of HA hybrid cooperative complexes (HCC) that are obtained from high (H) and low (L) weight molecules (NAHYCO(TM)). We compared this HCC with H-HA and L-HA. We investigated the effects of these HAs on proliferation, cell cycle, apoptosis, senescence, and differentiation following the addition of the polymer solutions in the culture media at concentrations that did not drastically modify the medium viscosity. Interestingly, 0,16% HCC significantly delayed the senescence compared with the controls. This occurred without alteration of the cell cycle, cytotoxicity, or apoptosis. HCCs also promoted adipogenic and chondrogenic differentiation. Our finding could suggest a potential functional role of HCC above the updated scientific reports of its effects and pave the way to optimization of MSC cultivation for therapeutic application.

The use of high-linear energy transfer charged particles is gaining attention as a medical tool because of the emission of radiations with an efficient cell-killing ability. Considerable interest has developed in the use of targeted alpha-particle therapy for the treatment of micrometastases. Moreover, the use of helium beams is gaining momentum, especially for treating pediatric tumors. We analyzed the effects of alpha particles on bone marrow mesenchymal stromal cells (MSCs), which have a subpopulation of stem cells capable of generating adipocytes, chondrocytes, and osteocytes. Further, these cells contribute toward maintenance of homeostasis in the body. MSCs were irradiated with low and high doses of alpha particles or X-rays and a comparative biological analysis was performed. At a low dose (40 mGy), alpha particles exhibited a limited negative effect on the biology of MSCs compared with X-rays. No significant perturbation of cell cycle was observed, and a minimal increase in apoptosis or senescence was detected. Self-renewal was preserved as revealed by the CFU assay. On the contrary, with 2000 mGy alpha particles, we observed adverse effects on the vitality, functionality, and stemness of MSCs. These results are the consequence of different proportion of cells targeted by alpha particles or X-rays and the quality of induced DNA damage. The present study suggests that radiotherapy with alpha particles may spare healthy stem cells more efficaciously than X-ray treatments, an observation that should be taken into consideration by physicians while planning irradiation of tumor areas close to stem cell niches, such as bone marrow. J. Cell. Biochem. 118: 2993-3002, 2017. © 2017 Wiley Periodicals, Inc.

Several investigators have cultivated marrow stromal cells and have identified a population of mesenchymal stem cells (MSCs). These cells expand extensively in vitro and exhibit multilineage differentiation potential. The lack of MSC-specific markers impedes identification of MSC functions. Further in vivo studies of these cells may elucidate the nature of MSCs. Although the nature of MSCs remains unclear, nonclonal stromal cultures are used as a source of putative MSCs for therapeutic purposes. Preclinical studies and clinical trials assumed that transplanted MSCs exert their effects through their differentiation properties or through the release of molecules that restore tissue functions and modulate immune cells. These studies reported contradictory results and failed to meet expectations. Thus, it is important to note that current protocols for MSC therapy are primarily based on the use of in vitro expanded nonclonal MSCs. Clearly defining the physiological features of in situ MSCs and the in vitro and in vivo properties of nonclonal cultures of stromal cells, which are often misidentified as pure stem cell cultures, may explain the reported failures of MSC therapy. This review will address these issues. (C) 2014 Wiley Periodicals, Inc.

Knowledge of the characteristics of the normal human aorta has been constrained by lack of data on fresh aortic tissue, especially from healthy individuals. In this study, the gene expression and morphological characteristics of the thoracic ascending aorta (AA) of healthy organ donors have been evaluated, with the aim of providing reference data for the analysis of pathological AAs. We analysed by RT-PCR the differential expression of mRNAs coding for myocardin, smoothelin, alpha-smooth muscle actin (alpha-SMA) and the ED-A isoform of fibronectin (ED-A FN) in AA specimens from donors, integrating the results with immunohistochemical analysis of the same targets. Morphological and morphometric characteristics of the AAs were also evaluated. In order to account for possible regional variations in wall structure, the convexity of the aortic profile was compared to the concavity. No differences in gene expression occurred for any of the target genes between the concavity and the convexity of AAs. Immunohistochemistry revealed a different distribution of total FN and of its ED-A isoform in the media and in the intima. Smoothelin is expressed by the majority of cells in the media, with some positive cells also in the intima. Alpha-SMA is expressed in all the tunicae. Immunohistochemistry also revealed in the convexity of 50% of AAs the presence of discrete areas in the subadventital media with altered structure and cell morphology and with altered gene expression, resulting positive for ED-A FN and alpha-SMA, but not for smoothelin, indicating the occurrence of early lesions also in macroscopically healthy AAs

Recent evidence has shown that vascular function depends not only on cells within the vessels, but is also significantly modulated by circulating cells derived from the bone marrow. A number of studies indicate that an early reendothelialization by circulating endothelial precursors after vascular injury prevents excessive cell proliferation and restenosis. Conversely, other studies concluded that the homing of other cell fractions, consisting mainly of smooth muscle precursors, cause pathological remodelling. Different cell types have been identified and characterized so far as circulating precursors able to participate in vascular repair by homing and differentiating towards endothelial cells or smooth muscle cells. Among these, endothelial precursor cells, smooth muscle progenitor cells, mesenchymal stem cells and others have been described. The origins, the hierarchy, the role and the markers of these different cell populations are still controversial. Nevertheless, different strategies have been developed so far in animal models to induce the mobilization and the recruitment of stem cells to the injury site, based on physical training, hormone injection and application of stem cell-capturing coated stents. It should also be mentioned that the limited data currently available derived from clinical trials provide contrasting results about the effective role of vascular cell precursors in restenosis prevention, thus indicating that conclusions derived from studies in animal models cannot always be directly applied to humans and that caution should be used in the manipulation of circulating progenitor cells for therapeutic strategies.