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Etude de l'activité hématopoïétique du tissu adipeux chez la souris et l'homme

Abstract : The adipose tissue (AT) contains a lot of leukocytes that play a fundamental role in the regulation of AT metabolic activity. In a physiological situation, AT-leukocytes mostly display an anti-inflammatory profile (M2 macrophages, eosinophils, CD4 Th2 T cells and regulatory T cells). Obesity induces a shift in AT immune cells towards a pro-inflammatory phenotype (M1 macrophages, neutrophils, CD8 and CD4 Th1 T cells). This inflammatory state contributes to the development of the metabolic syndrome. In adults, circulating leukocytes are mostly produced in the bone marrow (BM) by hematopoietic stem cells (HSC). A few years ago, we have shown AT harbors a specific resident HSC population that can renew innate immune cells and especially macrophages in the AT, via in situ differentiation. This endogenous hematopoietic activity differs according to the localization of the fat pad, suggesting that like BM-HSC, AT HSC might be controlled by their environment. Considering the important role of leukocytes in the AT physiopathology and the role of resident HSC in this tissue, the objectives of this work were the followings: 1) To characterize the role of the AT hematopoiesis in the onset of metabolic diseases. 2) To characterize the AT HSC niche from a cellular and a molecular point of view, and the regulation of their activity by this environment. 3) To demonstrate the presence of an endogenous AT-hematopoiesis in humans. First, by using transplantation of sorted AT-HSC and gain and loss of function studies we showed that some of the inflammatory AT-macrophages inducing metabolic disease originate from resident AT-HSC. Transplantation of AT-HSC sorted from high fat diet-fed (HFD) mice is sufficient to induce AT-macrophage accumulation, and to transfer metabolic disease in control mice. Conversely, the transplantation of control AT-HSC improves both AT-inflammation and glucose homeostasis in HFD mice. Second, we showed that AT-HSC are preferentially localized in the core of sub-cutaneous AT that contains beige adipocytes, instead of the periphery that mostly harbors unilocular white adipocytes. Activation or inhibition of beige adipocytes induces a loss of this preferential localization, suggesting that modifications of the subcutaneous AT core region metabolism impact HSC behavior. This suggests that beige adipocytes might be a part of a hematopoietic niche in the AT. However, we were unable to characterize the cellular and/or molecular constituants of this niche. Finally, we showed for the first time that as in mice, human AT contains resident HSC. In methylcellulose semi-solid medium, human AT-HSC are able to produce myeloid clones. In vivo, after transplantation of human AT-HSC in immunodeficient mice, human immune cells are observed in the AT. These results show that human AT exhibit a functional endogenous hematopoietic activity. Altogether, we show in this study that the AT hematopoietic activity plays a crucial role in the control of energy balance. Although AT HSC are localized preferentially at the vicinity of beige adipocytes, molecular signals controlling this population remain to be characterized. Finally, we demonstrate for the first time an endogenous hematopoiesis in human AT, highlighting the physiopathological importance of our previous results obtained in mice.
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Submitted on : Thursday, July 5, 2018 - 3:40:07 PM
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Vincent Cuminetti. Etude de l'activité hématopoïétique du tissu adipeux chez la souris et l'homme. Biologie cellulaire. Université Paul Sabatier - Toulouse III, 2017. Français. ⟨NNT : 2017TOU30154⟩. ⟨tel-01831088⟩

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