title: Rosiglitazone Promotes Bone Marrow Adipogenesis to Impair Myelopoiesis under Stress.
abstract: OBJECTIVE
  The therapeutic use of thiazolidinediones (TZDs) causes unwanted hematological side effects, although the underlying mechanisms of these effects are poorly understood. This study tests the hypothesis that rosiglitazone impairs the maintenance and differentiation of hematopoietic stem/progenitor cells, which ultimately leads to hematological abnormalities.
  
  
  METHODS
  Mice were fed a rosiglitazone-supplemented diet or a normal diet for 6 weeks. To induce hematopoietic stress, all mice were injected once with 250 mg/kg 5-fluorouracil (5-Fu) intraperitoneally. Next, hematopoietic recovery, hematopoietic stem/progenitor cells (HSPCs) subsets, and myeloid differentiation after 5-Fu treatment were evaluated. The adipogenesis induced by rosiglitazone was assessed by histopathology and oil red O staining. The effect of adipocytes on HSPCs was studied with an in vitro co-culture system.
  
  
  RESULTS
  Rosiglitazone significantly enhanced bone marrow adipogenesis and delayed hematopoietic recovery after 5-Fu treatment. Moreover, rosiglitazone inhibited proliferation of a granulocyte/monocyte progenitor (GMP) cell population and granulocyte/macrophage colony-stimulating factor (GM-CSF) colonies, although the proliferation and mobilization of Lin-c-kit+Sca-1+ cells (LSK) was maintained following hematopoietic stress. These effects could be partially reversed by the selective PPARγ antagonist BADGE. Finally, we demonstrated in a co-culture system that differentiated adipocytes actively suppressed the myeloid differentiation of HSPCs.
  
  
  CONCLUSIONS
  Taken together, our results demonstrate that rosiglitazone inhibits myeloid differentiation of HSPCs after stress partially by inducing bone marrow adipogenesis. Targeting the bone marrow microenvironment might be one mechanism by which rosiglitazone impairs stress-induced hematopoiesis.
authors.affiliation: Department of Hematology, Peking University People's Hospital, Beijing, China.|Institute of Hematology, Peking University, Beijing, China.|Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China.|Collaborative Innovation Center of Hematology, Peking University, Beijing, China.
authors.forename: Wenyi
authors.initials: W
authors.lastname: Lu
authors.affiliation: Department of Hematology, Peking University People's Hospital, Beijing, China.|Institute of Hematology, Peking University, Beijing, China.|Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China.
authors.forename: Weimin
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Hematology, Peking University People's Hospital, Beijing, China.|Institute of Hematology, Peking University, Beijing, China.|Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China.
authors.forename: Shujuan
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Hematology, Peking University People's Hospital, Beijing, China.|Institute of Hematology, Peking University, Beijing, China.|Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China.
authors.forename: Yonghuai
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of Hematology, Peking University People's Hospital, Beijing, China.|Institute of Hematology, Peking University, Beijing, China.|Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China.|Collaborative Innovation Center of Hematology, Peking University, Beijing, China.
authors.forename: Kaiyan
authors.initials: K
authors.lastname: Liu
mesh_terms: D017667:Adipocytes / Q000187:drug effects; D050156:Adipogenesis / Q000187:drug effects*; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects*; D002460:Cell Line; D005260:Female; D005472:Fluorouracil; D006410:Hematopoiesis / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000009:adverse effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D023461:Myeloid Progenitor Cells / Q000187:drug effects; D038042:Myelopoiesis / Q000187:drug effects; D047495:PPAR gamma / Q000378:metabolism; D000077154:Rosiglitazone; D013312:Stress, Physiological; D045162:Thiazolidinediones / Q000009:adverse effects*
chemical_list: D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D005472:Fluorouracil