Background Myeloid-derived suppressor cells (MDSCs) are potent suppressors of immune function and may play a key role in the development and progression of metastatic cancers. Aerobic exercise has been shown to have anticancer effects, yet the mechanisms behind this protection are largely unknown. Therefore, we examined the effects of physical activity on MDSC accumulation and function. Methods Female BALB/c mice were assigned to one of two primary groups: sedentary tumor (SED+ TUM) or wheel run tumor (WR+TUM). After 6 weeks of voluntary wheel running, all animals were randomly subdivided into 4 different timepoint groups; 16, 20, 24, and 28 days posttumor injection. All mice were inoculated with 4T1 mammary carcinoma cells in the mammary fat pad and WR groups continued to run for the specified time post-injection. Spleen, blood, and tumor samples were analyzed using flow cytometry to assess proportions of MDSCs. Results Cells expressing MDSC biomarkers were detected in the spleen, blood, and tumor beginning at d16. However, since there was no evidence of immunosuppressive function until d28, we refer to them as immature myeloid cells (IMCs). Compared to SED+TUM, levels of IMCs in the spleen were significantly lower (p < 0.05) in WR+TUM at day 16 (33.0 ± 5.2%; 23.1 ± 10.2% of total cells, respectively) and day 20 (33.9 ± 8.1%; 24.3 ± 5.1% of total cells, respectively). Additionally, there were fewer circulating IMCs in WR+TUM at day 16 and MDSC levels were significantly lower (p < 0.05) in the tumor at day 28 in WR+TUM. Additionally, a non-significant 62% and 26% reduction in metastatic lung nodules was observed at days 24 and 28, respectively. At day 28, MDSCs harvested from SED+TUM significantly
Emerging evidence suggests a significant functional role of adipose tissue in maintaining whole-body metabolic health. It is well established that obesity leads to compositional and morphological changes in adipose tissue that can contribute to the development of cardiometabolic disorders. Thus, the function and size of adipocytes as well as perfusion and inflammation can significantly impact health outcomes independent of body mass index. Lifestyle interventions such as exercise can improve metabolic homeostasis and reduce the risk for developing cardiometabolic disorders. Adipose tissue displays remarkable plasticity in response to external stimuli such as dietary intervention and exercise. Here we review systemic and local effects of exercise that modulate white and brown adipose tissue cellularity, metabolic function and remodeling in humans and animals.
Myeloid‐derived suppressor cells (MDSCs) are a population of immature myeloid immune cells that promote tumor progression and metastasis by suppressing both innate and adaptive immune responses. Exercise modulates immune function and is generally thought to protect against tumor growth and metastasis, yet the mechanisms behind this protection are largely unknown.PURPOSETo examine how exercise impacts circulating and tissue resident lymphocyte and MDSC populations.METHODSFemale mice were randomly assigned to treatment groups: exercise tumor (EX+TUM), sedentary tumor (SED+TUM), exercise (EX) or sedentary control (SED). EX groups underwent wheel running preconditioning for 6 weeks before tumor challenge. Following the 6‐week training period, animals in TUM groups were inoculated in the mammary fat pad with 1×104 4T1 mammary carcinoma cells and ran an additional 4‐weeks. Proportions of CD4+, CD8+, and CD335+ lymphocytes, as well as total MDSCs (CD11b+Ly6C+ Monocytic MDSCs (M‐MDSC) plus CD11b+Ly6G+ polymorphonuclear MDSCs (PMN‐MDSC)) were analyzed by flow cytometry in spleen, blood, and tumor.RESULTSNo effect of exercise was observed in CD4+ or CD8+ lymphocyte populations. The 4T1 mammary tumors significantly expanded MDSC populations in both spleen and blood regardless of exercise treatment. This tumor‐induced MDSC expansion was associated with enlarged spleens in sedentary animals (SED+TUM: 0.62g ± 0.11g) whereas the spleens in exercised animals with tumors were smaller (EX+TUM: 0.44g ± 0.11g) and did not differ from controls (EX: 0.08g ± 0.01g and SED: 0.11g ± 0.01g). Although there was no change in tumor volumes or tumor weights, exercise significantly reduced proportions of tumor‐infiltrating MDSCs (EX+TUM: 4.1% ± 1.6% vs. SED+TUM: 15.9% ± 2.3%). Further, tumor‐bearing exercised animals maintained a higher proportion of CD335+ natural killer cells in their spleens (EX+TUM: 0.6% ± 0.3%) relative to sedentary animals (SED+TUM: 0.4% ± 0.1%), which showed significant splenic CD335+ depletion relative to EX (1.3% ± 0.6%) controls.CONCLUSIONSThe observed reduction in tumor‐resident MDSCs suggests that exercise may improve antitumor immunity by decreasing MDSC‐related immune suppression in the tumor microenvironment and by preserving CD335+ lymphocyte populations. Exercise may reduce the severity of the aberrant myelopoiesis in tumor bearing animals as is evident by reduced splenomegaly in exercised animals.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Autocrine and paracrine signaling regulating adipogenesis in white adipose tissue remains largely unclear. Here we used single-cell RNA-sequencing (RNA-seq) and single nuclei RNA-sequencing (snRNA-seq) to identify markers of adipose progenitor cells (APCs) and adipogenic modulators in visceral adipose tissue (VAT) of humans and mice. Our study confirmed the presence of major cellular clusters in humans and mice and established important sex and diet-specific dissimilarities in cell proportions. Here we show that bone morphogenetic protein (BMP)-binding endothelial regulator (BMPER) is a conserved marker for APCs and adipocytes in VAT in humans and mice. Further, BMPER is highly enriched in lineage negative stromal vascular cells and its expression is significantly higher in visceral compared to subcutaneous APCs in mice. BMPER expression and release peaked by day four post-differentiation in 3T3-L1 preadipocytes. We reveal that BMPER is required for adipogenesis both in 3T3-L1 preadipocytes and in mouse APCs. Together, this study identified BMPER as a positive modulator of adipogenesis.
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