Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment.
Osteoblasts and endothelium constitute functional niches that support haematopoietic stem cells in mammalian bone marrow. 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 aplasia. 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 adipocytes, and in mice treated with the peroxisome proliferator-activated receptor-gamma inhibitor bisphenol A diglycidyl ether, which inhibits adipogenesis, 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.
Naveiras
Olaia
O
Division of Pediatric Hematology/Oncology, Children's Hospital Boston and Dana Farber Cancer Institute, Massachusetts 02115, USA.
Nardi
Valentina
V
Wenzel
Pamela L
PL
Hauschka
Peter V
PV
Fahey
Frederic
F
Daley
George Q
GQ
D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D050156:Adipogenesis / Q000187:drug effects; D050154:Adiposity / Q000502:physiology; D000818:Animals; D001559:Benzhydryl Compounds; D001854:Bone Marrow Cells / Q000166:cytology* / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D002460:Cell Line; D004852:Epoxy Compounds / Q000494:pharmacology; D005269:Femur; D006410:Hematopoiesis / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006706:Homeostasis; D051379:Mice; D008810:Mice, Inbred C57BL; D010012:Osteogenesis; D013131:Spine / Q000166:cytology / Q000378:metabolism; D017154:Stromal Cells; D013623:Tail; D013909:Thorax; D013977:Tibia; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D004852:Epoxy Compounds; C019273:bisphenol A diglycidyl ether; D000098826:Bisphenol A Compounds