1. Division of Pediatric Hematology/Oncology, Children's Hospital Boston and Dana Farber Cancer Institute; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School; Division of Hematology, Brigham and Women's Hospital; Harvard Stem Cell Institute; Manton Center for Orphan Diseases; Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA
2. Departments of Orthopaedic Surgery and Oral and Developmental Biology, Harvard Medical School and School of Dental Medicine, Boston, Massachusetts, 02115, USA
3. Department of Radiology, Division of Nuclear Medicine/PET, Children's Hospital Boston, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA
4. These authors contributed equally to this work.

Correspondence to: George Q. Daley¹ Correspondence and requests for materials should be addressed to G.Q.D. (Email: george.daley@childrens.harvard.edu).

Abstract

Osteoblasts and endothelium constitute functional niches that support haematopoietic stem cells in mammalian bone marrow^{1, 2, 3}. Adult bone marrow also contains adipocytes, the number of which correlates inversely with the haematopoietic activity of the marrow. Fatty infiltration of haematopoietic red marrow follows irradiation or chemotherapy and is a diagnostic feature in biopsies from patients with marrow aplasia⁴. To explore whether adipocytes influence haematopoiesis or simply fill marrow space, we compared the haematopoietic activity of distinct regions of the mouse skeleton that differ in adiposity. Here we show, by flow cytometry, colony-forming activity and competitive repopulation assay, that haematopoietic stem cells and short-term progenitors are reduced in frequency in the adipocyte-rich vertebrae of the mouse tail relative to the adipocyte-free vertebrae of the thorax. In lipoatrophic A-ZIP/F1 'fatless' mice, which are genetically incapable of forming adipocytes⁵, and in mice treated with the peroxisome proliferator-activated receptor- inhibitor bisphenol A diglycidyl ether, which inhibits adipogenesis⁶, marrow engraftment after irradiation is accelerated relative to wild-type or untreated mice. These data implicate adipocytes as predominantly negative regulators of the bone-marrow microenvironment, and indicate that antagonizing marrow adipogenesis may enhance haematopoietic recovery in clinical bone-marrow transplantation.

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