Bone Marrow Adipocytes Prevent Hematopoietic Expansion in Homeostasis and in Bone Marrow Transplantation

In mammalian bone marrow (BM), osteoblasts and endothelium constitute functional niches that support hematopoietic stem cells (HSC). Adult BM also contains numerous adipocytes, whose numbers correlate inversely with the hematopoietic activity of the marrow. As described by Neumann’s law in 1882, distal skeletal regions are adipocytic and thus non-hematopoietic in the adult. Fatty infiltration of the hematopoietic red marrow also occurs following irradiation or chemotherapy and is a diagnostic feature in biopsies from patients with marrow aplasia. However, whether adipocytes participate in hematopoietic regulation or simply expand to fill marrow space is unclear. We have found that murine hematopoiesis is reduced in adipocyte-rich marrow during homeostasis, and that adipocytes antagonize marrow recovery post-irradiation. By flow cytometry, colony forming assay, and competitive repopulation, we found a reduced frequency of HSCs and short-term hematopoietic progenitors in the adipocyte-rich vertebrae of the tail compared to the adipocyte-free vertebrae of the thorax. In A-ZIP/F1 “fatless” mice, which are genetically incapable of forming adipocytes, post-irradiation marrow engraftment is accelerated relative to wild type mice. Likewise, pharmacologic inhibition of adipocyte formation with the PPARg inhibitor Bisphenol-A-DiGlycidyl-Ether (BADGE) enhances hematopoietic recovery after BM transplant. Moreover, we have found that mice deficient in the adipocyte-specific protein adiponectin, which has been described to inhibit hematopoietic progenitor expansion in vitro, have increased progenitors in fatty marrow both during homeostasis and after BM transplant. Our data implicate adipocytes as negative regulators of the bone marrow microenvironment, and demonstrate that antagonizing adipogenesis is advantageous for enhancing hematopoietic recovery in the setting of bone marrow transplantation.