MicroRNAs (miRNAs) are small non-coding RNAs that regulate diverse genetic expression networks through their control of mRNA stability or translation. Their role in aging mechanisms has been proposed in various model systems. In this report, the expression profiling of 462 human miRNAs in the reversible growth arrest state of quiescence, and irreversible states of replicative senescence and hydrogen peroxide-induced premature senescence, are compared to young replicating lung fibroblasts. Greater numbers of up-regulated than down-regulated miRNAs are observed when cells stop proliferating, particularly in premature senescence, somewhat less in replicative senescence, and less still in quiescence. Several altered miRNA expressions are shared by the three growth arrest states, including the up-regulation of miR-34a, -624, -638 and miR-377, and the down-regulation of miR-365 and miR-512-5p. miRNAs up-regulated in both permanent growth arrest states but not in quiescence include let-7g, miR-26a, -136, -144, -195 and miR-200b. In each of the growth arrest states, miR-34a and let-7f have the most robust up-regulation in H(2)O(2)-induced premature senescence, followed by miR-638 and miR-663 in replicative senescence, and finally, miR-331-3p and miR-595 in quiescence. Our comprehensive evaluation of miRNA target correlations with known biomarkers for replicative senescence suggests that miRNAs may repress pathways controlling not only cell cycle traverse and proliferation, but also insulin-like signaling, DNA repair and apoptosis, all of which are cellular functions deficient in senescent human fibroblasts.
It is well known that bone marrow-derived mesenchymal stem cells (MSCs) are involved in wound healing and regeneration responses. In this study, we globally profiled the proteome of MSCs to investigate critical factor(s) that may promote wound healing. Cysteine-rich protein 61 (Cyr61) was found to be abundantly present in MSCs. The presence of Cyr61 was confirmed by immunofluorescence staining and immunoblot analysis. Moreover, we showed that Cyr61 is present in the culture medium (secretome) of MSCs. The secretome of MSCs stimulates angiogenic response in vitro, and neovascularization in vivo. Depletion of Cyr61 completely abrogates the angiogenic-inducing capability of the MSC secretome. Importantly, addition of recombinant Cyr61 polypeptides restores the angiogenic activity of Cyr61-depleted secretome.Collectively, these data demonstrate that Cyr61 polypeptide in MSC secretome contributes to the angiogenesis-promoting activity, a key event needed for regeneration and repair of injured tissues.Wound healing in adults depends on the presence of functional stem cells capable of replicating and differentiating into other type of cells. Bone marrow-derived mesenchymal stem cells (MSCs) are known for their ability to differentiate into other cell types, such as bone, cartilage, muscle, adipocytes, stromal cells, as well as fibroblasts (Prockop, 1997;Weissman, 2000;Phinney and Prockop, 2007). It has been also demonstrated that MSCs can differentiate into endothelial cells, suggesting the potential of MSCs in neovascularization (Tomanek and Schatteman, 2000). In addition, the possible involvement of human bonemarrow-derived stem cells in neovacularization was proposed, based on the fact that these cells are able to contribute to tumor angiogenesis in vivo (Reyes et al., 2002). Furthermore, accumulating evidence suggests that bone marrow-derived MSCs may promote tissue repair by secreting factors which are able to recruit various types of cells critical for regeneration of injured tissue (Chamberlain et al., 2007;Phinney and Prockop, 2007). Therefore, investigating the proteins secreted by MSCs is essential to understand the molecular mechanisms by which MSCs regulate wound healing and regeneration processes. In that study, they found a number of MSC secreted products that may have functional implications in modulating injury repairing processes. In addition, the transcriptome analysis of human and murine MSCs has also identified a variety of regulatory proteins that function in angiogenesis, hematopoiesis, neural activities, immunity and defense (Phinney, 2007).In the present study, we investigate possible factor(s) synthesized by MSCs that may be functionally important in tissue regeneration. We used high-resolution, two-dimensional liquid chromatography tandem mass spectrometry (LC-MS/MS) to globally profile the proteome of murine MSCs (mMSCs). We found Cyr61 (also known as CCN1), a member of the CCN family of polypeptides, to be expressed in mMSCs. The presence of this protein in MSCs was confirmed by immu...
The decline in cognitive robustness with aging can be attributed to complex genetic pathways involving many cellular dysfunctions, cumulative over time, precipitating in frailty and loss of wellness in the elderly brain. The size and health of the neuronal cell population determines cognitive robustness in mammals. A transgenic mouse model over-expressing Bcl-2 has been shown to rescue neurons from naturally occurring cell death (NOCD). Here we show that in the brain of calorie-restricted (CR) mice, there is an age-dependent decreased expression of microRNAs mmu-miR-181a-1*, mmu-miR-30e and mmu-miR-34a, with a corresponding gain in Bcl-2 expression, and decreases in pro-apoptosis genes such as Bax and cleavage of Caspases. Functional characterization shows that these miRNAs repress Bcl-2 expression by the 3'UTR reporter assays, accompanied by loss of this gene's endogenous expression, and a gain in pro-apoptosome-specific proteins. Over-expression of these miRNAs increases the rate of apoptosis, accompanied by a decline in Bcl-2 expression in miRNA-transfected mouse and human cell lines. We report here that down-regulation of miR-34a, -30e, and -181a permits their shared target gene expression (Bcl-2) to remain at a high level without post-transcriptional repression, accompanied by concomitant low levels of Bax expression and Caspase cleaving; this chain event may be a part of the underlying mechanism contributing to the gain in neuronal survival in long-lived CR-fed mice.
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