Naveiras, O. et al. Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature 460, 259-263

Division of Pediatric Hematology/Oncology, Children's Hospital Boston and Dana Farber Cancer Institute, Massachusetts 02115, USA.
Nature (Impact Factor: 42.35). 07/2009; 460(7252):259-63. DOI: 10.1038/nature08099
Source: PubMed

ABSTRACT Osteoblasts and endothelium constitute functional niches that support haematopoietic stem cells in mammalian bone marrow. Adult bone marrow also contains adipocytes, the number of which correlates inversely with the haematopoietic activity of the marrow. Fatty infiltration of haematopoietic red marrow follows irradiation or chemotherapy and is a diagnostic feature in biopsies from patients with marrow aplasia. To explore whether adipocytes influence haematopoiesis or simply fill marrow space, we compared the haematopoietic activity of distinct regions of the mouse skeleton that differ in adiposity. Here we show, by flow cytometry, colony-forming activity and competitive repopulation assay, that haematopoietic stem cells and short-term progenitors are reduced in frequency in the adipocyte-rich vertebrae of the mouse tail relative to the adipocyte-free vertebrae of the thorax. In lipoatrophic A-ZIP/F1 'fatless' mice, which are genetically incapable of forming adipocytes, and in mice treated with the peroxisome proliferator-activated receptor-gamma inhibitor bisphenol A diglycidyl ether, which inhibits adipogenesis, marrow engraftment after irradiation is accelerated relative to wild-type or untreated mice. These data implicate adipocytes as predominantly negative regulators of the bone-marrow microenvironment, and indicate that antagonizing marrow adipogenesis may enhance haematopoietic recovery in clinical bone-marrow transplantation.

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    • "MMPs and stem cell mobilization 5 osteoblast function and the circadian oscillation of HSC retention factors [16] [17]. While the aforementioned cell types mainly support the maintenance of the HSCs, adipocytes within the bone marrow have been identified as negative regulators of hematopoiesis [18]. "
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    ABSTRACT: Hematopoietic stem cells (HSCs) have the capability to migrate back and forth between their preferred microenvironment in bone marrow niches and the peripheral blood, but under steady-state conditions only a marginal number of stem cells can be found in the circulation. Different mobilizing agents, however, which create a highly proteolytic milieu in the bone marrow, can drastically increase the number of circulating HSCs. Among other proteases secreted and membrane-bound matrix metalloproteinases (MMPs) are known to be involved in the induced mobilization process and can digest niche-specific extracellular matrix components and cytokines responsible for stem cell retention to the niches. Iatrogenic stem cell mobilization and stem cell homing to their niches are clinically employed on a routine basis, although the exact mechanisms of both processes are still not fully understood. In this review we provide an overview on the various roles of MMPs in the induced release of HSCs from the bone marrow. Copyright © 2015. Published by Elsevier B.V.
    Matrix biology: journal of the International Society for Matrix Biology 01/2015; 4. DOI:10.1016/j.matbio.2015.01.011 · 3.65 Impact Factor
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    • "content in vivo [26]. On the contrary, BM adipocytes have negative effect on HSC pool size and function [29]. Most recently, it was demonstrated that nestin-expression MSCs (NES + MSCs) are tightly related to the maintenance of HSCs and can breed osteoblasts in the BM HSC niche [30]. "
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    ABSTRACT: Though discovered later than osteoblastic niche, vascular niche has been regarded as an alternative indispensable niche operating regulation on hematopoietic stem cells (HSCs). As significant progresses gained on this type niche, it is gradually clear that the main work of vascular niche is undertaking to support hematopoiesis. However, compared to what have been defined in the mechanisms through which the osteoblastic niche regulates hematopoiesis, we know less in vascular niche. In this review, based on research data hitherto we will focus on component foundation and various functions of vascular niche that guarantee the normal hematopoiesis process within bone marrow microenvironments. And the possible pathways raised by various research results through which this environment undergoes its function will be discussed as well.
    04/2014; 2014(1-2):128436. DOI:10.1155/2014/128436
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    • "An additional advantage of the μCT imaging is the high resolution (commonly ~10 μm isotropic resolution ) as compared with MR based imaging (commonly ~75–100 μm isotropic resolution) [57] [58]. In our study we were able to visualize increases in MAT in the metaphysis extending into the diaphysis during high fat feeding, correlating with histology and other data in the literature , indicating that marrow adipose normally shares space within the trabecular bone [9] [31]. Further, in contrast to MR spectroscopy, μCT imaging is pre-calibrated [59] and does not necessitate sophisticated "
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    ABSTRACT: Marrow adipose tissue (MAT), associated with skeletal fragility and hematologic insufficiency, remains poorly understood and difficult to quantify. We tested the response of MAT to high fat diet (HFD) and exercise using a novel volumetric analysis, and compared it to measures of bone quantity. We hypothesized that HFD would increase MAT and diminish bone quantity, while exercise would slow MAT acquisition and promote bone formation. Eight week-old female C57BL/6 mice were fed a regular (RD) or HFD, and exercise groups were provided voluntary access to running wheels (RD-E, HFD-E). Femoral MAT was assessed by μCT (lipid binder osmium) using a semi-automated approach employing rigid co-alignment, regional bone masks and was normalized for total femoral volume (TV) of the bone compartment. MAT was 2.6-fold higher in HFD relative to RD mice. Exercise suppressed MAT in RD-E mice by more than half compared with RD. Running similarly inhibited MAT acquisition in HFD mice. Exercise significantly increased bone quantity in both diet groups. Thus, HFD caused significant accumulation of MAT; importantly running exercise limited MAT acquisition while promoting bone formation during both diets. That MAT is exquisitely responsive to diet and exercise, and its regulation by exercise appears to be inversely proportional to effects on exercise induced bone formation, is relevant for an aging and sedentary population.
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