Aging impairs tissue repair. This is pronounced in skeletal muscle, whose regeneration by muscle stem cells (MuSCs) is robust in young adult animals but inefficient in older organisms. Despite this functional decline, old MuSCs are amenable to rejuvenation through strategies that improve the systemic milieu, such as heterochronic parabiosis. One such strategy, exercise, has long been appreciated for its benefits on healthspan, but its effects on aged stem cell function in the context of tissue regeneration are incompletely understood. Here we show that exercise in the form of voluntary wheel running accelerates muscle repair in old animals and improves old MuSC Reprints and permissions information is available at http://www.nature.com/reprints.
Long non-coding RNAs (lncRNAs) are a class of regulatory genes that participate in a wide range of biological processes, including proliferation, differentiation and development, as well as in a broad spectrum of diseases. Although the role of lncRNAs in TGF-β-induced epithelial-to-mesenchymal transition (EMT) has been well established, little is known about the role of lncRNAs as immediate-early regulators of EMT. Here lnc-Spry1 is identified as an immediate-early regulator of EMT that is downregulated by TGF-β. It is also found that knockdown of lnc-Spry1 promotes a mesenchymal-like phenotype and results in increased cell migration and invasion. In addition, it is shown that lnc-Spry1 depletion preferentially affects the expression of TGF-β-regulated gene targets. Moreover, lnc-Spry1 associates with U2AF65 splicing factor, suggesting a role in alternative splicing. Depletion of lnc-Spry1 induces, as TGF-β, isoform switching of fibroblast growth factor receptors, resulting in FGF-2-sensitive cells. Taken together, these results show that lnc-Spry1 could act as an early mediator of TGF-β signaling and reveal different roles for a lncRNA in modulating transcriptional and posttranscriptional gene expression. Cell Death and Differentiation (2017) 24, 785-797; doi:10.1038/cdd.2017.9; published online 10 February 2017EMT is a basic cellular process in which epithelial cells lose their epithelial characteristics and take on properties of mesenchymal cells. During EMT, epithelial cells lose their cell-cell junctions and the epithelial apical-basal polarity. The actin cytoskeleton is reorganized and cells acquire migratory and invasive properties.1-3 This process is essential in the generation of tissues and organs during embryogenesis, during wound healing and is associated with pathologies, such as fibrosis and cancer. In carcinomas, cancer cells can undergo EMT to escape the primary tumor, invade surrounding tissues and colonize remote sites via blood or lymphatic routes generating metastases. 4-6The EMT program can be activated efficiently and rapidly in epithelial cells in response to soluble factors or cytokines, including epidermal growth factor, fibroblast growth factors (FGFs) and transforming growth factors (TGF-βs). TGF-β may induce EMT through distinct signaling mechanisms causing substantial changes in gene expression. These changes involve three families of transcription factors: the zinc finger Snail, Zeb, and basic helix-loop-helix families. 7Beyond the well-established transcriptional reprogramming during EMT, posttranscriptional mechanisms, such as regulation by alternative pre-mRNA splicing and regulation by noncoding RNA, have an important role and provide an additional layer of complexity on the gene regulation during EMT. 8-12The mammalian genome encodes many thousands of lncRNAs, a class of transcripts 4200 nucleotides with limited protein-coding potential.13 They can act as molecular signals, tethers, decoys, guides or scaffolds at every level of gene regulation in a wide range of biological proc...
Adult skeletal muscle stem cells (MuSCs) are important for muscle regeneration and constitute a potential source of cell therapy. However, upon isolation, MuSCs rapidly exit quiescence and lose transplantation potency. Maintenance of the quiescent state in vitro preserves MuSC transplantation efficiency and provides an opportunity to study the biology of quiescence. Here we show that Tubastatin A (TubA), an Hdac6 inhibitor, prevents primary cilium resorption, maintains quiescence, and enhances MuSC survival ex vivo. Phenotypic characterization and transcriptomic analysis of TubA-treated cells revealed that TubA maintains most of the biological features and molecular signatures of quiescence. Furthermore, TubA-treated MuSCs showed improved engraftment ability upon transplantation. TubA also induced a return to quiescence and improved engraftment of cycling MuSCs, revealing a potentially expanded application for MuSC therapeutics. Altogether, these studies demonstrate the ability of TubA to maintain MuSC quiescence ex vivo and to enhance the therapeutic potential of MuSCs and their progeny.
MicroRNAs (miRNAs) have been widely studied in order to elucidate their biological functions. MicroRNA microarrays or miRNA overexpression libraries generated by synthesis and cloning of individual miRNAs have been used to study their different roles. In this work, we have developed a novel methodology to express mature miRNAs and other small RNAs from a double convergent RNA polymerase III promoter. We show that the generated miRNAs function similarly to those processed from primary transcripts or pri-miRNAs. This system allowed us to produce a lentiviral library expressing the whole population of small RNAs present in a metastatic cell line. A functional screening using this library led to the identification of hsa-miR-30b and hsa-miR-30c as negative regulators of cell death induced by loss of attachment (anoikis). Importantly, we demonstrated that the acquisition of anoikis resistance via these miRNAs is achieved through down-regulation of caspase 3 expression. Moreover, overexpression of these miRNAs resulted in a decrease of other types of caspase 3-dependent cell death and enhanced the survival of MCF10A acinar cells in morphogenesis assays, suggesting a putative role as oncomirs. In summary, this novel methodology provides a powerful and effective way for identifying novel small RNAs involved in a particular biological process.
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