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Lack of Adipocytes Alters Hematopoiesis in Lipodystrophic Mice.

ABSTRACT: Adult hematopoiesis takes place in the perivascular zone of the bone cavity, where endothelial cells, mesenchymal stromal/stem cells and their derivatives such as osteoblasts are key components of bone marrow (BM) niches. Defining the contribution of BM adipocytes to the hematopoietic stem cell niche remains controversial. While an excess of medullar adiposity is generally considered deleterious for hematopoiesis, an active role for adipocytes in shaping the niche has also been proposed. We thus investigated the consequences of total adipocyte deletion, including in the BM niche, on adult hematopoiesis using mice carrying a constitutive deletion of the gene coding for the nuclear receptor peroxisome proliferator-activated receptor-? (PPAR?). We show that Pparg ^?/? lipodystrophic mice exhibit severe extramedullary hematopoiesis (EMH), which we found to be non-cell autonomous, as it is reproduced when wild-type donor BM cells are transferred into Pparg ^?/? recipients. This phenotype is not due to a specific alteration linked to Pparg deletion, such as chronic inflammation, since it is also found in AZIP^tg/+ mice, another lipodystrophic mouse model with normal PPAR? expression, that display only very moderate levels of inflammation. In both models, the lack of adipocytes alters subpopulations of both myeloid and lymphoid cells. The CXCL12/CXCR4 axis in the BM is also dysregulated in an adipocyte deprived environment supporting the hypothesis that adipocytes are required for normal hematopoietic stem cell mobilization or retention. Altogether, these data suggest an important role for adipocytes, and possibly for the molecular interactions they provide within the BM, in maintaining the appropriate microenvironment for hematopoietic homeostasis.

SUBMITTER: Wilson A

PROVIDER: S-EPMC6244608 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Lack of Adipocytes Alters Hematopoiesis in Lipodystrophic Mice.

Wilson Anne A Fu He H Schiffrin Mariano M Winkler Carine C Koufany Meriem M Jouzeau Jean-Yves JY Bonnet Nicolas N Gilardi Federica F Renevey François F Luther Sanjiv A SA Moulin David D Desvergne Béatrice B

Frontiers in immunology 20181113

Adult hematopoiesis takes place in the perivascular zone of the bone cavity, where endothelial cells, mesenchymal stromal/stem cells and their derivatives such as osteoblasts are key components of bone marrow (BM) niches. Defining the contribution of BM adipocytes to the hematopoietic stem cell niche remains controversial. While an excess of medullar adiposity is generally considered deleterious for hematopoiesis, an active role for adipocytes in shaping the niche has also been proposed. We thus ...[more]

PMID: 30483254

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Project description:Osteoblasts are emerging regulators of myeloid malignancies since genetic alterations in them, such as constitutive activation of ?-catenin, instigate their appearance. The LDL receptor-related protein 5 (LRP5), initially proposed to be a co-receptor for Wnt proteins, in fact favors bone formation by suppressing gut-serotonin synthesis. This function of Lrp5 occurring in the gut is independent of ?-catenin activation in osteoblasts. However, it is unknown whether Lrp5 can act directly in osteoblast to influence other functions that require ?-catenin signaling, particularly, the deregulation of hematopoiesis and leukemogenic properties of ?-catenin activation in osteoblasts, that lead to development of acute myeloid leukemia (AML). Using mice with gain-of-function (GOF) Lrp5 alleles (Lrp5(A214V)) that recapitulate the human high bone mass (HBM) phenotype, as well as patients with the T253I HBM Lrp5 mutation, we show here that Lrp5 GOF mutations in both humans and mice do not activate ?-catenin signaling in osteoblasts. Consistent with a lack of ?-catenin activation in their osteoblasts, Lrp5(A214V) mice have normal trilinear hematopoiesis. In contrast to leukemic mice with constitutive activation of ?-catenin in osteoblasts (Ctnnb1(CAosb)), accumulation of early myeloid progenitors, a characteristic of AML, myeloid-blasts in blood, and segmented neutrophils or dysplastic megakaryocytes in the bone marrow, are not observed in Lrp5(A214V) mice. Likewise, peripheral blood count analysis in HBM patients showed normal hematopoiesis, normal percentage of myeloid cells, and lack of anemia. We conclude that Lrp5 GOF mutations do not activate ?-catenin signaling in osteoblasts. As a result, myeloid lineage differentiation is normal in HBM patients and mice. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis, Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza.

Dataset Information

Lack of Adipocytes Alters Hematopoiesis in Lipodystrophic Mice.

Publications

Lack of Adipocytes Alters Hematopoiesis in Lipodystrophic Mice.

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