mTORC1 controls the adaptive transition of quiescent stem cells from G0 to G(Alert).
2014; 510 (7505): 393-396
The mortal strand hypothesis: Non-random chromosome inheritance and the biased segregation of damaged DNA
SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY
2013; 24 (8-9): 653-660
A unique property of many adult stem cells is their ability to exist in a non-cycling, quiescent state. Although quiescence serves an essential role in preserving stem cell function until the stem cell is needed in tissue homeostasis or repair, defects in quiescence can lead to an impairment in tissue function. The extent to which stem cells can regulate quiescence is unknown. Here we show that the stem cell quiescent state is composed of two distinct functional phases, G0 and an 'alert' phase we term GAlert. Stem cells actively and reversibly transition between these phases in response to injury-induced systemic signals. Using genetic mouse models specific to muscle stem cells (or satellite cells), we show that mTORC1 activity is necessary and sufficient for the transition of satellite cells from G0 into GAlert and that signalling through the HGF receptor cMet is also necessary. We also identify G0-to-GAlert transitions in several populations of quiescent stem cells. Quiescent stem cells that transition into GAlert possess enhanced tissue regenerative function. We propose that the transition of quiescent stem cells into GAlert functions as an 'alerting' mechanism, an adaptive response that positions stem cells to respond rapidly under conditions of injury and stress, priming them for cell cycle entry.
View details for DOI 10.1038/nature13255
View details for PubMedID 24870234
Maintenance of muscle stem-cell quiescence by microRNA-489
2012; 482 (7386): 524-U247
If a eukaryotic cell is to reproduce, it must duplicate its genetic information in the form of DNA, and faithfully segregate that information during a complex process of cell division. During this division process, the resulting cells inherit one, and only one, copy of each chromosome. Over thirty years ago, it was predicted that the segregation of sister chromosomes could occur non-randomly, such that a daughter cell would preferentially inherit one of the two sister chromosomes according to some characteristic of that chromosome's template DNA strand. Although this prediction has been confirmed in studies of various cell-types, we know little of both the mechanism by which the asymmetric inheritance occurs and the significance it has to cells. In this essay, we propose a new model of non-random chromosome segregation-the mortal strand hypothesis-and discuss tests of the model that will provide insight into the molecular choreography of this intriguing phenomenon.
View details for DOI 10.1016/j.semcdb.2013.05.006
View details for Web of Science ID 000327252900006
Stem cell ageing and non-random chromosome segregation
PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES
2011; 366 (1561): 85-93
Among the key properties that distinguish adult mammalian stem cells from their more differentiated progeny is the ability of stem cells to remain in a quiescent state for prolonged periods of time. However, the molecular pathways for the maintenance of stem-cell quiescence remain elusive. Here we use adult mouse muscle stem cells (satellite cells) as a model system and show that the microRNA (miRNA) pathway is essential for the maintenance of the quiescent state. Satellite cells that lack a functional miRNA pathway spontaneously exit quiescence and enter the cell cycle. We identified quiescence-specific miRNAs in the satellite-cell lineage by microarray analysis. Among these, miRNA-489 (miR-489) is highly expressed in quiescent satellite cells and is quickly downregulated during satellite-cell activation. Further analysis revealed that miR-489 functions as a regulator of satellite-cell quiescence, as it post-transcriptionally suppresses the oncogene Dek, the protein product of which localizes to the more differentiated daughter cell during asymmetric division of satellite cells and promotes the transient proliferative expansion of myogenic progenitors. Our results provide evidence of the miRNA pathway in general, and of a specific miRNA, miR-489, in actively maintaining the quiescent state of an adult stem-cell population.
View details for DOI 10.1038/nature10834
View details for Web of Science ID 000300770500050
View details for PubMedID 22358842
Chromatin Modifications as Determinants of Muscle Stem Cell Quiescence and Chronological Aging
2013; 4 (1): 189-204
Adult stem cells maintain the mature tissues of metazoans. They do so by reproducing in such a way that their progeny either differentiate, and thus contribute functionally to a tissue, or remain uncommitted and replenish the stem cell pool. Because ageing manifests as a general decline in tissue function, diminished stem cell-mediated tissue maintenance may contribute to age-related pathologies. Accordingly, the mechanisms by which stem cell regenerative potential is sustained, and the extent to which these mechanisms fail with age, are fundamental determinants of tissue ageing. Here, we explore the mechanisms of asymmetric division that account for the sustained fitness of adult stem cells and the tissues that comprise them. In particular, we summarize the theory and experimental evidence underlying non-random chromosome segregation-a mitotic asymmetry arising from the unequal partitioning of chromosomes according to the age of their template DNA strands. Additionally, we consider the possible consequences of non-random chromosome segregation, especially as they relate to both replicative and chronological ageing in stem cells. While biased segregation of chromosomes may sustain stem cell replicative potential by compartmentalizing the errors derived from DNA synthesis, it might also contribute to the accrual of replication-independent DNA damage in stem cells and thus hasten chronological ageing.
View details for DOI 10.1098/rstb.2010.0279
View details for Web of Science ID 000284718700013
View details for PubMedID 21115534
A sexy spin on nonrandom chromosome segregation.
Cell stem cell
2013; 12 (6): 641-643
The ability to maintain quiescence is critical for the long-term maintenance of a functional stem cell pool. To date, the epigenetic and transcriptional characteristics of quiescent stem cells and how they change with age remain largely unknown. In this study, we explore the chromatin features of adult skeletal muscle stem cells, or satellite cells (SCs), which reside predominantly in a quiescent state in fully developed limb muscles of both young and aged mice. Using a ChIP-seq approach to obtain global epigenetic profiles of quiescent SCs (QSCs), we show that QSCs possess a permissive chromatin state in which few genes are epigenetically repressed by Polycomb group (PcG)-mediated histone 3 lysine 27 trimethylation (H3K27me3), and a large number of genes encoding regulators that specify nonmyogenic lineages are demarcated by bivalent domains at their transcription start sites (TSSs). By comparing epigenetic profiles of QSCs from young and old mice, we also provide direct evidence that, with age, epigenetic changes accumulate and may lead to a functional decline in quiescent stem cells. These findings highlight the importance of chromatin mapping in understanding unique features of stem cell identity and stem cell aging.
View details for DOI 10.1016/j.celrep.2013.05.043
View details for Web of Science ID 000321901900018
View details for PubMedID 23810552
Reduced bacterial adhesion to fibrinogen-coated substrates via nitric oxide release
2008; 29 (30): 4039-4044
Nonrandom chromosome segregation is an intriguing phenomenon linked to certain asymmetric stem cell divisions. In a recent report in Nature, Yadlapalli and Yamashita (2013) observe nonrandom segregation of X and Y chromosomes in Drosophila germline stem cells and shed light on the complex mechanisms of this fascinating process.
View details for DOI 10.1016/j.stem.2013.05.013
View details for PubMedID 23746972
Nitric oxide-releasing xerogel-based fiber-optic pH sensors
2006; 78 (21): 7461-7466
The ability of nitric oxide (NO)-releasing xerogels to reduce fibrinogen-mediated adhesion of Staphylococcus aureus, Staphylococcus epidermidis, and Escherichia coli is described. A negative correlation was observed between NO surface flux and bacterial adhesion for each species tested. For S. aureus and E. coli, reduced adhesion correlated directly with NO flux from 0 to 30 pmol cm(-2)s(-1). A similar dependence for S. epidermidis was evident from 18 to 30 pmol cm(-2)s(-1). At a NO flux of 30 pmol cm(-2)s(-1), surface coverage of S. aureus, S. epidermidis, and E. coli was reduced by 96, 48, and 88%, respectively, compared to non-NO-releasing controls. Polymeric NO release was thus demonstrated to be an effective approach for significantly reducing fibrinogen-mediated adhesion of both gram-positive and gram-negative bacteria in vitro, thereby illustrating the advantage of active NO release as a strategy for inhibiting bacterial adhesion in the presence of pre-adsorbed protein.
View details for DOI 10.1016/j.biomaterials.2008.07.005
View details for Web of Science ID 000260025100002
View details for PubMedID 18657857
A xerogel-based optical pH sensor capable of releasing low levels of nitric oxide (NO) and measuring changes in solution pH is reported. Through simple dip-coating procedures, aminoalkoxysilane-based xerogel films modified with N-diazeniumdiolate NO donor precursors and the fluorescent pH indicator seminaphthorhodamine-1 carboxylate (SNARF-1) were sequentially deposited onto optical fibers. The resulting sensors were characterized by fast and linear response to pH throughout the physiological range (pH 7.0-7.8). Real-time chemiluminescence measurements confirmed that the presence of the overlying SNARF-1-containing TMOS layer did not have an inhibitory effect on N-diazeniumdiolate formation or NO release, and the NO-releasing coatings were capable of maintaining NO fluxes >0.4 pmol/cm(2) s up to 16 h. In vitro blood compatibility studies using porcine platelets confirmed the expected thromboresistivity of the NO-releasing xerogel coatings.
View details for DOI 10.1021/ac060995p
View details for Web of Science ID 000241670000028
View details for PubMedID 17073413