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Background: Adipose tissue is a primary in vivo site of inflammation in obesity. Excess visceral adipose tissue (VAT), when compared to subcutaneous adipose tissue (SAT), imparts an increased risk of obesity-related comorbidities and mortality, and exhibits differences in inflammation. Defining depot-specific differences in inflammatory function may reveal underlying mechanisms of adipose-tissue-based inflammation. Methods: Stromovascular cell fractions (SVFs) from VAT and SAT from obese humans undergoing bariatric surgery were studied in an in vitro culture system with transcriptional profiling, flow cytometric phenotyping, enzyme-linked immunosorbent assay and intracellular cytokine staining. Results: Transcriptional profiling of SVF revealed differences in inflammatory transcript levels in VAT relative to SAT, including elevated interferon- (IFN-) transcript levels. VAT demonstrated a broad leukocytosis relative to SAT that included macrophages, T cells and natural killer (NK) cells. IFN- induced a proinflammatory cytokine expression pattern in SVF and adipose tissue macrophages (ATM). NK cells, which constitutively expressed IFN-, were present at higher frequency in VAT relative to SAT. Both T and NK cells from SVF expressed IFN- on activation, which was associated with tumor necrosis factor- expression in macrophages. Conclusion: These data suggest involvement of NK cells and IFN- in regulating ATM phenotype and function in human obesity and a potential mechanism for the adverse physiologic effects of VAT.

We recently demonstrated that acute myeloid leukemia (AML) cell lines and patient-derived blasts release exosomes that carry RNA and protein; following an in vitro transfer, AML exosomes produce proangiogenic changes in bystander cells. We reasoned that paracrine exosome trafficking may have a broader role in shaping the leukemic niche. In a series of in vitro studies and murine xenografts, we demonstrate that AML exosomes downregulate critical retention factors ( Scf , Cxcl12 ) in stromal cells, leading to hematopoietic stem and progenitor cell (HSPC) mobilization from the bone marrow. Exosome trafficking also regulates HSPC directly, and we demonstrate declining clonogenicity, loss of CXCR4 and c-Kit expression, and the consistent repression of several hematopoietic transcription factors, including c-Myb , Cebp-β and Hoxa-9 . Additional experiments using a model of extramedullary AML or direct intrafemoral injection of purified exosomes reveal that the erosion of HSPC function can occur independent of direct cell–cell contact with leukemia cells. Finally, using a novel multiplex proteomics technique, we identified candidate pathways involved in the direct exosome-mediated modulation of HSPC function. In aggregate, this work suggests that AML exosomes participate in the suppression of residual hematopoietic function that precedes widespread leukemic invasion of the bone marrow directly and indirectly via stromal components.