Current Issue : April - June Volume : 2014 Issue Number : 2 Articles : 6 Articles
Introduction: Although autologous bone marrow cell (BMC) therapy has emerged as a promising treatment for\r\nacute myocardial infarction (AMI), trials reported mixed results. In the BONAMI trial, active smoking reduced cardiac\r\nfunction recovery after reperfused AMI. Therefore, we hypothesized that variability in the functionality of BMCs retrieved\r\nfrom patients with cardiovascular risk factors may partly explain these mixed results. We investigated the characteristics of\r\nprogenitor cells in active smokers and non-smokers with AMI and their potential impact on BMC therapy efficacy.\r\nMethods: Bone marrow and blood samples from 54 smoking and 47 non-smoking patients enrolled in the BONAMI\r\ncell therapy trial were analyzed.\r\nResults: The white BMC and CD45dimCD34+ cell numbers were higher in active smokers (P = 0.001, P = 0.03,\r\nrespectively). In marked contrast, either bone marrow or blood endothelial progenitor CD45dimCD34 + KDR + cells\r\n(EPCs) were decreased in active smokers (P = 0.005, P = 0.04, respectively). Importantly, a multivariate analysis including\r\ncardiovascular risk factors confirmed the association between active smoking and lower EPC number in bone marrow\r\n(P = 0.04) and blood (P = 0.04). Furthermore, baseline circulating EPC count predicted infarct size decrease at three\r\nmonths post-AMI in non-smokers (P = 0.01) but not in active smokers. Interestingly, baseline circulating EPCs were no\r\nlonger predictive of cardiac function improvement in the BMC therapy group.\r\nConclusions: These data suggest that circulating EPCs play an important role in cardiac repair post-AMI only in\r\nnon-smokers and that active smoking-associated EPC alterations may participate in the impairment of cardiac\r\nfunction recovery observed in smokers after AMI, an effect that was overridden by BMC therapy....
Introduction: Embryonic stem (ES) cells are considered a potentially advantageous source of hepatocytes for both\r\ntransplantation and the development of bioartificial livers. However, the efficient large-scale generation of functional\r\nhepatocytes from ES cells remains a major challenge, especially for those methods compatible with clinical\r\napplications.\r\nMethods: In this study, we investigated whether a large number of functional hepatocytes can be differentiated\r\nfrom mouse ES (mES) cells using a simulated microgravity bioreactor. mES cells were cultured in a rotating\r\nbioreactor in the presence of exogenous growth factors and hormones to form embryoid bodies (EBs), which then\r\ndifferentiated into hepatocytes.\r\nResults: During the rotating culture, most of the EB-derived cells gradually showed the histologic characteristics of\r\nnormal hepatocytes. More specifically, the expression of hepatic genes and proteins was detected at a higher level\r\nin the differentiated cells from the bioreactor culture than in cells from a static culture. On further growing, the\r\nEBs on tissue-culture plates, most of the EB-derived cells were found to display the morphologic features of\r\nhepatocytes, as well as albumin synthesis. In addition, the EB-derived cells grown in the rotating bioreactor\r\nexhibited higher levels of liver-specific functions, such as glycogen storage, cytochrome P450 activity, low-density\r\nlipoprotein, and indocyanine green uptake, than did differentiated cells grown in static culture. When the\r\nEB-derived cells from day-14 EBs and the cells� culture supernatant were injected into nude mice, the transplanted\r\ncells were engrafted into the recipient livers.\r\nConclusions: Large quantities of high-quality hepatocytes can be generated from mES cells in a rotating bioreactor\r\nvia EB formation. This system may be useful in the large-scale generation of hepatocytes for both cell transplantation\r\nand the development of bioartificial livers....
Introduction: The existence of breast cancer stem-like cells (BCSCs) has profound implications for cancer\r\nprevention. Genistein, a predominant isoflavone found in soy products, has multiple robust anti-tumor effects in\r\nvarious cancers, especially in the breast and prostate cancer. In this study, we aimed to evaluate genistein inhibition\r\nof BCSCs and its potential mechanism by culturing MCF-7 breast cancer cells and implanting these cells into\r\nnude mice.\r\nMethods: Cell counting, colony formation and cell apoptosis analysis were used to evaluate the effect of genistein\r\non breast cancer cells� growth, proliferation and apoptosis. We then used mammosphere formation assay and\r\nCD44CD24 staining to evaluate the effect of genistein on BCSCs in vitro. A nude mice xenograft model was\r\nemployed to determine whether genistein could target BCSCs in vivo, as assessed by real-time polymerase chain\r\nreaction (PCR) and immunohistochemical staining. The potential mechanism was investigated utilizing real-time\r\nPCR, western blotting analysis and immunohistochemical staining.\r\nResults: Genistein inhibited the MCF-7 breast cancer cells� growth and proliferation and promoted apoptosis. Both\r\nin vitro and in vivo genistein decreased breast cancer stem cells, and inhibited breast cancer stem-like cells through\r\ndown-regulation of the Hedgehog-Gli1 Signaling Pathway.\r\nConclusions: We demonstrated for the first time that genistein inhibits BCSCs by down-regulating Hedgehog-Gli1\r\nsignaling pathway. These findings provide support and rationale for investigating the clinical application of\r\ngenistein in treating breast cancer, and specifically by targeting breast cancer stem cells....
Introduction: Despite having a proven immunosuppressive potential in vitro, human mesenchymal stromal cells\r\n(MSCs) are reported to display variable efficacy in vivo and, in fact, their proven benefit in the clinical practice is still\r\nlimited and controversial.\r\nMethods: The interplay between clinical grade MSCs and pre-activated donor lymphocytes or selected lymphocyte\r\nsubsets was studied in vitro. The kinetics of MSC growth and viability was evaluated by adhesion-dependent\r\nchanges of culture plate impedance and biochemically by a colorimetric assay. Activation of natural killer (NK) cells\r\nwas assessed as well, using a flow cytometry assay.\r\nResults: A strong inhibition of MSC growth was rapidly induced by the addition of pre-activated lymphocytes\r\nbut not of resting lymphocytes. Inhibition seems not to be attributable to a single cell population, as similar\r\nresults can be obtained by depleting NK cells or by using either selected CD4+ or CD8+ lymphocytes. In addition,\r\nconditioned medium (CM) from activated lymphocytes was able to inhibit MSC growth in a dose-dependent\r\nmanner. Furthermore, licensing with IFN-? partially protected MSCs from pre-activated lymphocytes but not from\r\ntheir CM. These results suggest an inhibitory role of lymphocyte-activation-derived substances. However, the\r\nidentification of a single molecule responsible for MSC inhibition remained elusive, even if preliminary experiments\r\nshowed that ATP and, to a lesser extent, TNF-a might play a role.\r\nConclusions: These results suggest that survival of MSCs can be affected by soluble mediators released by\r\nactivated lymphocytes. Thus it can be hypothesized that MSC immunosuppressive action in vivo could be impaired\r\nby ongoing immune activation through the release of inflammatory mediators...
Introduction: Human amniotic fluid stem (hAFS) cells have been shown to differentiate into multiple lineages,\r\nincluding myoblasts. However, molecular mechanisms underlying the myogenic differentiation of hAFS cells and\r\ntheir regenerative potential for muscle injury remain to be elucidated.\r\nMethods: In order to induce myogenic differentiation of hAFS cells, lentiviruses for MYOD were constructed and\r\ntransduced into hAFS cells. Formation of myotube-like cells was analyzed by immunocytochemistry, and expression\r\nof molecular markers for myoblasts was analyzed by reverse transcription polymerase chain reaction and Western\r\nblotting. For in vivo muscle regeneration, MYOD transduced hAFS cells were injected into left tibialis anterior\r\n(TA) muscles injured with cardiotoxin, and muscle regeneration was analyzed using hematoxylin and eosin,\r\nimmunocytochemistry and formation of neuro-muscular junction.\r\nResults: MYOD expression in hAFS cells successfully induced differentiation into multinucleated myotube-like cells.\r\nConsistently, significant expression of myogenic marker genes, such as MYOG, DES, DMD and MYH, was induced by MYOD.\r\nAnalysis of pre-myogenic factors showed that expression of PAX3, MEOX1 and EYA2 was significantly increased\r\nby MYOD. MYOD was phosphorylated and localized in the nucleus. These results suggest that in hAFS cells,\r\nMYOD is phosphorylated and localized in the nucleus, thus inducing expression of myogenic factors, resulting in\r\nmyogenic differentiation of hAFS cells. To test regenerative potential of MYOD-transduced hAFS cells, we transplanted them\r\ninto injured muscles of immunodeficient BALB/cSlc-nu mice. The results showed a substantial increase in the volume of TA\r\nmuscle injected with MYOD-hAFS cells. In addition, TA muscle tissue injected with MYOD-hAFS cells has more numbers of\r\nneuro-muscular junctions compared to controls, indicating functional restoration of muscle injury by MYOD-hAFS cells.\r\nConclusions: Collectively, our data suggest that transduction of hAFS cells with MYOD lentiviruses induces skeletal\r\nmyogenic differentiation in vitro and morphological and functional regeneration of injured muscle in vivo....
Introduction: Overweight status should not be considered merely an aesthetic concern; rather, it can incur health\r\nrisks since it may trigger a cascade of events that produce further fat tissue through altered levels of circulating\r\nsignaling molecules.\r\nThere have been few studies addressing the effect of overweight status on the physiological functions of stem\r\ncells, including mesenchymal stem cells (MSCs), which are the progenitors of adipocytes and osteocytes and are a\r\nsubset of the bone marrow stromal cell population.\r\nMethods: We decided to investigate the influence of overweight individuals� sera on in vitro MSC proliferation and\r\ndifferentiation.\r\nResults: We observed that in vitro incubation of bone marrow stromal cells with the sera of overweight individuals\r\npromotes the adipogenic differentiation of MSCs while partially impairing proper osteogenesis.\r\nConclusions: These results, which represent a pilot study, might suggest that becoming overweight triggers further\r\nweight gains by promoting a bias in the differentiation potential of MSCs toward adipogenesis. The circulating factors\r\ninvolved in this phenomenon remain to be determined, since the great majority of the well known pro-inflammatory\r\ncytokines and adipocyte-secreted factors we investigated did not show relevant modifications in overweight serum\r\nsamples compared with controls....
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