Low-fat marrow: Good for the blood

Lipidomics Gateway (24 June 2009) [doi:10.1038/lipidmaps.2009.13]

Bone-marrow adipocytes reduce hematopoiesis and may represent a novel target for enhancing post-transplant recovery.

Previously viewed as a passive fat store, adipocytes have gradually been recognized as an important endocrine tissue. Despite this belated recognition, adipocytes found in bone marrow have been largely viewed as space filler. Writing in Nature, Daley and colleagues report that bone marrow adipocytes negatively regulate hematopoiesis and participate in regulation of osteogenesis. Inhibition of adipogenesis enhances hematopoietic recovery after bone marrow transplantation in mice and may be a viable therapeutic target for human patients.

Bone marrow from the tail vertebrae of 12-week-old mice (bottom) contains more adipocytes than marrow from thoracic vertebrae (top).

Most blood cell types are generated from hematopoietic stem cells (HSCs) located in red bone marrow. Besides HSCs and the short-term repopulating late progenitor cells derived from them, this tissue also contains bone and endothelial precursor cells and dominates the bone-marrow space of infants. With age, red marrow is gradually replaced by yellow marrow, consisting mainly of adipocytes. To determine whether bone-marrow adipocytes influence hematopoiesis, Daley and colleagues began by examining the mouse skeleton to find areas that were naturally higher or lower in adipocytes. A gradient down the murine spine was apparent, from low adiposity in thoracic vertebrae to high in the tail. Flow cytometry and fluorescence-activated cell sorting revealed that total HSCs and all associated progenitor classes were reduced up to three-fold in the adipocyte-rich bone marrow compared with that from the thoracic vertebrae. Late progenitor cells derived from the fattier marrow were less likely to be in a replication phase of the cell cycle.

To determine whether the association of adipocyte-rich marrow with reduced hematopoiesis is causative or just correlative, the authors examined a 'fatless' mouse that is genetically unable to produce adipocytes. Consistently, it did not have the reduced hematopoiesis seen in tail bone marrow of the wild type. Fatless and wild-type mice were exposed to lethal irradiation to kill endogenous progenitors and then transplanted with untreated wild-type marrow. Hematopoietic recovery was increased in the fatless mice by enhanced engraftment of short-term progenitors. Bone metabolism and deposition of new bone was also increased in the irradiated fatless mice, suggesting a three-way co-regulation of hematopoiesis, osteogenesis and adipogenesis.

Irradiated mice treated with an inhibitor of the peroxisome proliferator-activated receptor-γ had reduced bone-marrow adipogenesis and increased hematopoiesis, linking these two processes mechanistically. Inhibitor treatment did not increase in vitro hematopoiesis of bone-marrow cells separated from adipocytes, suggesting that adipocytes have a negative effect on hematopoiesis that can be overcome pharmacologically.

These results emphasize the complex role of adipocytes and suggest that inhibiting adipogenesis might benefit human marrow or cord blood transplant recipients. Further studies are needed to identify which adipocyte-derived signals are involved in the hematopoietic suppression observed in fatty marrow.

Emma Leah