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  • br Material and methods br Results br Discussion Pre

    2018-10-20


    Material and methods
    Results
    Discussion Pre-transplant myeloablation has been consistently seen to be associated with an increase in the number of adipocytes in the bone marrow (Snyder, 1965; Naveiras et al., 2009; Cao et al., 2011). These marrow adipocytes were considered as passive space fillers till Naveiras et al. demonstrated that irradiation-induced bone marrow adipocytes actively suppress hematopoiesis and that pharmacological inhibition of adipogenesis with a PPAR-γ antagonist resulted in an increase in donor cell engraftment (Naveiras et al., 2009). However, the molecular mechanisms behind irradiation-induced marrow adipogenesis have not been extensively investigated. Here we have identified a previously unknown mechanism behind irradiation-induced marrow adipogenesis. Our findings reveal that BMP4 is secreted by the bone marrow myeloperoxidase in response to irradiation, which then commits the BMSCs to the adipocyte lineage, contributing to an increase in adipocyte formation. While the role of BMP4 in inducing osteogenesis and bone formation in bone marrow stromal cells has been reported (Rahman et al., 2015); its potential to have an adipogenic effect on BMSCs was not known. We for the first time report here the adipogenic effect of BMP4 on BMSCs. Although irradiation-induced secretion of various interleukins and inflammatory cytokines has been reported (Bigildeev et al., 2013; Fukumoto et al., 2013), we focused our studies on BMP4 for two important reasons; (i) its secretion in the BM niche is crucial for hematopoietic recovery (Goldman et al., 2009); (ii) it is known to have an adipogenic effect on the embryonic fibroblasts (Tang et al., 2004; Bowers et al., 2006) and is also critically required for the onset of adipogeneic differentiation (Suenaga et al., 2013). Osteoblasts, endothelial cells and megakaryocytes present in the BM microenvironment have been shown to express BMP4 (Goldman et al., 2009). Consistent with this, we found that stromal cells express maximum amount of Bmp4-specific mRNA as compared to any other cell type under steady-state condition and its levels increase significantly in response to irradiation. However, under steady state conditions stromal cells are fewer in numbers in the marrow microenvironment (~3%), and therefore, their effective contribution to total BMP4 expression becomes less (19.35%). On the other hand, under irradiated conditions both, the relative % of stromal cells as well as the Bmp4 expressed by them increase, and therefore, post-irradiation their relative contribution to the total BMP4 secretion increases significantly (43.11%). T cells are known to be relatively radio-resistant, as compared to other marrow cells (Bosco et al., 2010). Consistent with this report, we found that the T cells form a significant percentage of the surviving population of marrow cells after 48h of irradiation, as compared to that under steady state conditions (44.08% vs. 8.16% respectively). T cells isolated from the marrow of irradiated mice showed a strikingly higher expression of Bmp4, as compared to non-irradiated counterparts. This irradiation-induced increase in Bmp4 expression, coupled with their radio-resistance, makes T-cells the major contributors of BMP4 secretion in the marrow microenvironment after irradiation. Under steady state conditions, B cells contribute maximally to total BMP4 expression in the marrow, but under irradiated conditions their contribution is negligible. Adipogenesis in the marrow is associated with bone marrow failure and occurs during bone marrow transplants 2–4weeks after irradiation. Here we have shown that BMP4 levels in the marrow rise steeply at day 5 post-irradiation and then return to normal. This could raise concerns about it causing marrow adipogenesis. However, we have also shown that BMP4 is important mainly during the commitment phase (Fig. 3A) and its presence is not required during adipogenic differentiation. These data suggest that similar “hit and run” phenomenon may also be occurring in the marrow compartment during myelosuppression.