title: Bone marrow is a source of regenerated cardiomyocytes in doxorubicin-induced cardiomyopathy and granulocyte colony-stimulating factor enhances migration of bone marrow cells and attenuates cardiotoxicity of doxorubicin under electron microscopy.
abstract: BACKGROUND
  It has been reported previously that granulocyte colony-stimulating factor (GCSF) injection improves infarcted heart function, but the mechanism remains unclear. In this study we sought to determine whether GCSF-mobilized bone marrow cells could regenerate neo-myocardium and repair doxorubicin-induced cardiomyopathy.
  
  
  METHODS
  C57BL/6 mice were irradiated and bone marrow cells (BMC; 1 x 10(6)) from green fluorescent protein (GFP) mice (GFP-BMC) were transplanted intravenously, followed by splenectomy. Doxorubicin (2.5 mg/kg, 6 times for 2 weeks) was administered intraperitoneally 2 weeks later. GCSF (50 microg/kg/day for 8 days) was administered sub-cutaneously after doxorubicin injection (Group I, n = 11) and 3 weeks later (Group II, n = 8), and saline was injected in Group III animals (n = 8). Eight weeks after doxorubicin injection, the excised hearts were studied immunologically and electron microscopically.
  
  
  RESULTS
  Survival rates were 81.8% in Group I, 50.0% in Group II and 62.5% in Group III. The number of GFP-BMC in Group I (15.4 +/- 7.4 per high-power field) was highest (p < 0.05). In all groups, cardiac troponin I-positive cells derived from GFP-BMC were observed in the hearts. GFP-BMC in hearts stained positively against cardiac troponin I (4.3 +/- 2.5%), myosin heavy chain (5.0 +/- 4.3%), atrial natriuretic peptide (ANP; 3.9 +/- 2.4%) and connexin 43 (11.9 +/- 7.3%) in Group I. Myofibrils, mitochondria and fundamental architecture were almost all preserved in Group I, whereas hearts were severely damaged in Groups II and III.
  
  
  CONCLUSIONS
  Bone marrow was shown to be one of the sources of regenerated cardiomyocytes in the doxorubicin-induced cardiomyopathic heart. Early administration of GCSF enhanced the migration of bone marrow cells into the heart, and attenuated the cardiotoxicity of doxorubicin.
authors.affiliation: Department of Organ Transplantation, National Cardiovascular Center, Osaka, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Tomita
authors.forename: Michiko
authors.initials: M
authors.lastname: Ishida
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nakatani
authors.forename: Shinya
authors.initials: S
authors.lastname: Fukuhara
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Hisashi
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Ohtsu
authors.forename: Michiharu
authors.initials: M
authors.lastname: Suga
authors.forename: Chikao
authors.initials: C
authors.lastname: Yutani
authors.forename: Toshikatsu
authors.initials: T
authors.lastname: Yagihara
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamada
authors.forename: Soichiro
authors.initials: S
authors.lastname: Kitamura
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000032:analysis; D001854:Bone Marrow Cells / Q000166:cytology* / Q000502:physiology*; D016026:Bone Marrow Transplantation; D009202:Cardiomyopathies; D002465:Cell Movement / Q000187:drug effects*; D004317:Doxorubicin / Q000494:pharmacology*; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000648:ultrastructure; D009210:Myofibrils / Q000648:ultrastructure; D018995:Myosin Heavy Chains / Q000032:analysis; D012038:Regeneration / Q000187:drug effects / Q000502:physiology*; D019210:Troponin I / Q000032:analysis
chemical_list: D019210:Troponin I; D016179:Granulocyte Colony-Stimulating Factor; D004317:Doxorubicin; D009320:Atrial Natriuretic Factor; D018995:Myosin Heavy Chains