Hematopoietic stem cells found in lineage-positive subsets in the bone marrow of 5-fluorouracil-treated mice.
It is known that treatment of mice with 5-fluorouracil (5-FU, 150 mg/kg) confers radioprotection. To investigate this effect, we performed bone marrow transplantation (BMT) using C57BL/6-Ly5 congenic mice treated with 5-FU five days prior to experiments. The mononuclear cells (MNC) in 5-FU-treated bone marrow (BM) were 10 times more radioprotective than those in untreated BM. Moreover, the number of BM MNC expressing c-kit on their surface from 5-FU-treated mice was markedly decreased relative to those from untreated controls. These results showed that the surface characteristics of cells that contributed to this radio-protective effect differ from those of stem cells as reported recently. BM MNC of mice treated with 5-FU were separated on the basis of expression of the lineage-specific antigens (Lin), c-kit, and Ly6A/E. When injected into lethally irradiated mice, 1,000 Lin+ and Lin-c-kit+Ly6A/E+ cells showed radioprotective effects such that 100% and 60% survived, respectively. Flow cytometric analysis 165 days after BMT showed that 88.8% and 65.1% of peripheral blood (PB) in mice transplanted with Lin+ and Lin-c-kit+Ly6A/E+ was derived from donor mice, respectively. After six months, donor-derived Lin-c-kit+Ly6A/E+ cells which showed radioprotective effects on a secondary irradiated host were detected from mice transplanted with Lin+ cells from 5-FU-treated mice. Taken together, these findings demonstrated that stem cells expressing Lin+ present in the BM of mice treated with 5-FU other than Lin-c-kit+Ly6A/E+ cells and these Lin+ cells play an important role in the recovery of myeloablative mice.
Pharmaceutical Research Laboratory, Kirin Brewery Co., Ltd., Gunma, Japan.
N
N
Nishi
M
M
Osawa
R
R
Ishikawa
M
M
Nishikawa
H
H
Tsumura
H
H
Inoue
T
T
Sudo
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects* / Q000528:radiation effects; D001854:Bone Marrow Cells; D016026:Bone Marrow Transplantation; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis / Q000096:biosynthesis; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D014965:X-Rays
D011837:Radiation-Protective Agents; D019009:Proto-Oncogene Proteins c-kit; D005472:Fluorouracil