Erratum: Systemic signals regulate ageing and rejuvenation of blood stem cell niches (Nature (2010) 463 (495-500))

Department of Stem Cell and Regenerative Biology, Harvard University, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Joslin Diabetes Center, One Joslin Place, Boston, Massachusetts 02115, USA.
Nature (Impact Factor: 41.46). 10/2010; 467(7317):872. DOI: 10.1038/nature09474
Source: PubMed


Ageing in multicellular organisms typically involves a progressive decline in cell replacement and repair processes, resulting in several physiological deficiencies, including inefficient muscle repair, reduced bone mass, and dysregulation of blood formation (haematopoiesis). Although defects in tissue-resident stem cells clearly contribute to these phenotypes, it is unclear to what extent they reflect stem cell intrinsic alterations or age-related changes in the stem cell supportive microenvironment, or niche. Here, using complementary in vivo and in vitro heterochronic models, we show that age-associated changes in stem cell supportive niche cells deregulate normal haematopoiesis by causing haematopoietic stem cell dysfunction. Furthermore, we find that age-dependent defects in niche cells are systemically regulated and can be reversed by exposure to a young circulation or by neutralization of the conserved longevity regulator, insulin-like growth factor-1, in the marrow microenvironment. Together, these results show a new and critical role for local and systemic factors in signalling age-related haematopoietic decline, and highlight a new model in which blood-borne factors in aged animals act through local niche cells to induce age-dependent disruption of stem cell function.

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    • "Recent studies have also shown that these two signaling pathways act directly on stem cell niches to regulate stem cells. For example, both IGF and Notch signaling maintain the hematopoietic stem cell niche to regulate hematopoiesis in mice (Mayack et al., 2010; Weber and Calvi, 2010). Therefore, an understanding of the mechanism by which systemic insulin signals are integrated with niche-local Notch signaling is central to stem cell biology. "
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    ABSTRACT: The stem cell niche houses and regulates stem cells by providing both physical contact and local factors that regulate stem cell identity. The stem cell niche also plays a role in integrating niche-local and systemic signals, thereby ensuring that the balance of stem cells meets the needs of the organism. However, it is not clear how these signals are merged within the niche. Nutrient-sensing insulin/FOXO signaling has been previously shown to directly control Notch activation in the Drosophila female germline stem cell (GSC) niche, which maintains the niche and GSC identity. Here, we demonstrate that FOXO directly activates transcription of fringe, a gene encoding a glycosyltransferase that modulates Notch glycosylation. Fringe facilitates Notch inactivation in the GSC niche when insulin signaling is low. We also show that the Notch ligand predominantly involved is GSC niche-derived Delta. These results reveal that FOXO-mediated regulation of fringe links the insulin and Notch signaling pathways in the GSC niche in response to nutrition, and emphasize that stem cells are regulated by complex interactions between niche-local and systemic signals.
    Developmental Biology 07/2013; 382(1). DOI:10.1016/j.ydbio.2013.07.018 · 3.55 Impact Factor
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    • "This improvement diminished when cells from either young or old mice were cultured on an environment reconstituted from MSCs from old animals [16]. In addition, the aged phenotype of adult stem cells such as hematopoietic stem cells was reversed by exposing them to a young stem cell environment [29]. The precise mechanism of the interaction of stem cells with their local environment is largely unknown. "
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    ABSTRACT: Mesenchymal stem cells (MSCs) hold great therapeutic potential. However, MSCs undergo replication senescence during the in vitro expansion process. Wharton's jelly from the human umbilical cord harbors a large number of MSCs. In this study, we hypothesized that Wharton's jelly would be beneficial for in vitro expansion of MSCs. Wharton's jelly extract (WJEs), which is mainly composed of extracellular matrix and cytokines, was prepared as coating substrate. Human MSCs were isolated and cultured on WJE-coated plates. Although the proliferation capacity of cells was not augmented by WJE in early phase culture, adynamic growth in late-phase culture was clearly reduced, suggesting that the replicative senescence of MSCs was efficiently slowed by WJE. This was confirmed by β-galactosidase staining and telomere length measurements of MSCs in late-phase culture. In addition, the decreased differentiation ability of MSCs after long-term culture was largely ameliorated by WJE. Reactive oxygen species (ROS), p53, and p16INK4a/pRb expression increased with passaging. Analysis at the molecular level revealed that WJE-based culture efficiently suppressed the enhancement of intracellular ROS, p53, and p16INK4a/pRb in MSCs. These data demonstrated that WJE provided an ideal microenvironment for MSCs culture expansion in vitro preserved MSC properties by delaying MSCs senescence, and allowed large numbers of MSCs to be obtained for basic research and clinical therapies.
    PLoS ONE 03/2013; 8(3):e58314. DOI:10.1371/journal.pone.0058314 · 3.23 Impact Factor
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    • "Thus, the efficacy and side effect of marketed oral antidiabetic drugs still need to be optimized. The recent introduction in the market of incretin analogs opened a new field to evaluate drugs with putative properties that may cause both proliferation and maturation of human pancreatic β-cells [16, 17, 83, 84]. Currently, a standard model of experimental diabetes to study effects of drugs, which could help in preventing the progressive loss of pancreatic islet function, remains to be established [76, 86, 89]. "
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    Evidence-based Complementary and Alternative Medicine 07/2012; 2012(8):142087. DOI:10.1155/2012/142087 · 1.88 Impact Factor
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