Stem cell depletion and compromised bone marrow resulting from radiation exposure fosters long-term deterioration of numerous physiologic systems, with the degradation of the skeletal system ultimately increasing the risk of fractures. To study the interrelationship of damaged bone marrow cell populations with trabecular microarchitecture, 8-and 16-week-old C57BL/6 male mice were sublethally irradiated with 5 Gy of 137 Cs g-rays, and adult stem cells residing in the bone marrow, as well as bone quantity and quality, were evaluated in the proximal tibia after 2 days, 10 days, and 8 weeks compared with age-matched controls. Total extracted bone marrow cells in the irradiated 8-week, young adult mice, including the hematopoietic cell niches, collapsed by 65% AE 11% after 2 days, remaining at those levels through 10 days, only recovering to age-matched control levels by 8 weeks. As early as 10 days, double-labeled surface was undetectable in the irradiated group, paralleled by a 41% AE 12% and 33% AE 4% decline in bone volume fraction (BV/TV) and trabecular number (Tb.N), respectively, and a 50% AE 10% increase in trabecular separation (Tb.Sp) compared with the age-matched controls, a compromised structure that persisted to 8 weeks postirradiation. Although the overall collapse of the bone marrow population and devastation of bone quality was similar between the ''young adult'' and ''mature'' mice, the impact of irradiation-and the speed of recovery-on specific hematopoietic subpopulations was dependent on age, with the older animals slower to restore key progenitor populations. These data indicate that, independent of animal age, complications arising from irradiation extend beyond the collapse of the stem cell population and extend toward damage to key organ systems. It is reasonable to presume that accelerating the recovery of these stem cell pools will enable the prompt repair of the skeletal system and ultimately reduce the susceptibility to fractures. ß
Obesity markedly increases susceptibility to a range of diseases and simultaneously undermines the viability and fate selection of haematopoietic stem cells (HSCs), and thus the kinetics of leukocyte production that is critical to innate and adaptive immunity. Considering that blood cell production and the differentiation of HSCs and their progeny is orchestrated, in part, by complex interacting signals emanating from the bone marrow microenvironment, it is not surprising that conditions that disturb bone marrow structure inevitably disrupt both the numbers and lineage-fates of these key blood cell progenitors. In addition to the increased adipose burden in visceral and subcutaneous compartments, obesity causes a marked increase in the size and number of adipocytes encroaching into the bone marrow space, almost certainly disturbing HSC interactions with neighbouring cells, which include osteoblasts, osteoclasts, mesenchymal cells and endothelial cells. As the global obesity pandemic grows, the short-term and long-term consequences of increased bone marrow adiposity on HSC lineage selection and immune function remain uncertain. This Review discusses the differentiation and function of haematopoietic cell populations, the principal physicochemical components of the bone marrow niche, and how this environment influences HSCs and haematopoiesis in general. The effect of adipocytes and adiposity on HSC and progenitor cell populations is also discussed, with the goal of understanding how obesity might compromise the core haematopoietic system.
The bone marrow (BM) niche is the primary site of hematopoiesis, and cues from this microenvironment are critical to maintain hematopoiesis. Obesity increases lifetime susceptibility to a host of chronic diseases, and has been linked to defective leukogenesis. The pressures obesity exerts on hematopoietic tissues led us to study the effects of a high fat diet (HFD: 60% Kcal from fat) on B cell development in BM. Seven week old male C57Bl/6J mice were fed either a high fat (HFD) or regular chow (RD) diet for periods of 2 days, 1 week and 6 weeks. B-cell populations (B220+) were not altered after 2 d of HFD, within 1 w B-cell proportions were reduced by −10%, and by 6 w by −25% as compared to RD (p<0.05). BM RNA was extracted to track the expression of B-cell development markers Il-7, Ebf-1 and Pax-5. At 2 d, the expression of Il-7 and Ebf-1 were reduced by −20% (p = 0.08) and −11% (p = 0.06) whereas Pax-5 was not significantly impacted. At one week, however, the expressions of Il-7, Ebf-1, and Pax-5 in HFD mice fell by -19%, −20% and −16%, and by six weeks were further reduced to −23%, −29% and −34% as compared to RD (p<0.05 for all), a suppression paralleled by a +363% increase in adipose encroachment within the marrow space (p<0.01). Il-7 is a critical factor in the early B-cell lineage which is secreted by supportive cells in the BM niche, and is necessary for B-cell commitment. These data indicate that BM Il-7 expression, and by extension B-cell differentiation, are rapidly impaired by HFD. The trend towards suppressed expression of Il-7 following only 2 d of HFD demonstrates how susceptible the BM niche, and the cells which rely on it, are to diet, which ultimately could contribute to disease susceptibility in metabolic disorders such as obesity.
Non-invasive three-dimensional imaging of live rodents is a powerful research tool that has become critical for advances in many biomedical fields. For investigations into adipose development, obesity, or diabetes, accurate and precise techniques that quantify adiposity in vivo are critical. Because total body fat mass does not accurately predict health risks associated with the metabolic syndrome, imaging modalities should be able to stratify total adiposity into subcutaneous and visceral adiposity. Micro-computed tomography (micro-CT) acquires high-resolution images based on the physical density of the material and can readily discriminate between subcutaneous and visceral fat. Here, a micro-CT based method to image the adiposity of live rodents is described. An automated and validated algorithm to quantify the volume of discrete fat deposits from the computed tomography is available. Data indicate that scanning the abdomen provides sufficient information to estimate total body fat. Very high correlations between micro-CT determined adipose volumes and the weight of explanted fat pads demonstrate that micro-CT can accurately monitor site-specific changes in adiposity. Taken together, in vivo micro-CT is a non-invasive, highly quantitative imaging modality with greater resolution and selectivity, but potentially lower through-put, than many other methods to precisely determine total and regional adipose volumes and fat infiltration in live rodents.
Deterioration of the immune and skeletal systems, each of which parallel obesity, reflects a fragile interrelationship between adiposity and osteoimmunology. Using a murine model of diet-induced obesity, this study investigated the ability of mechanical signals to protect the skeletal-immune systems at the tissue, cellular, and molecular level. A long-term (7 mo) high-fat diet increased total adiposity (+62%), accelerated age-related loss of trabecular bone (-61%), and markedly reduced B-cell number in the marrow (-52%) and blood (-36%) compared to mice fed a regular diet. In the final 4 mo of the protocol, the application of low-magnitude mechanical signals (0.2 g at 90 Hz, 15 min/d, 5 d/wk) restored both bone structure and B cells to those levels measured in control mice fed a regular diet. These phenotypic outcomes were achieved, in part, by reductions in osteoclastic activity and a biasing of hematopoietic stem cell differentiation toward the lymphoid B-cell lineage and away from a myeloid fate. These results emphasize that obesity undermines both the skeletal and immune systems, yet brief exposure to mechanical signals, perhaps as a surrogate to the salutary influence of exercise, diminishes the consequences of diabetes and obesity, restoring bone structure and normalizing B-cell populations by biasing of the fate of stem cells through mechanosensitive pathways.
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