title: Role of hematopoietic microenvironment in prolonged impairment of B cell regeneration in age-related stromal-cell-impaired SAMP1 mouse: effects of a single dose of 5-fluorouracil.
abstract: In this study, we examined the age-associated defect of stromal cells, which support B cell development, treated with 5-fluorouracil (5-FU) to induce severe perturbation of hematopoiesis, including B lymphocyte development, using SAMP1 mice exhibiting senescence-mimicking stromal-cell impairment after 30 weeks of age. Significant findings of this study are as follows: first, a marked and prolonged decrease in number of CFU-preB cells in non-SCI mice (58% of the steady-state level) associated with more markedly depressed number of CFU-preB cells in SCI mice (20% of the steady-state level), despite the absence of difference in the number of CFU-GMs during the period; second, in the non-SCI mice, a significant and prolonged up-regulation of GM-CSF and IL-6, positive regulators of myelopoiesis and suppressive factors of B lymphopoiesis, was observed. In SCI mice, greater and prolonged suppression of B lymphopoiesis was clearly demonstrated by the significant up-regulation of the negative regulator TNF-alpha associated with the concomitant marked down-regulation of the positive regulator SDF-1, although the increases of GM-CSF and IL-6 were limited. That is, 'negative complementation' makes preB recovery after 5-FU treatment impaired and prolonged. Principal component analysis clearly showed differences in the cytokine expression patterns in both early and later phases and the time course of the expression pattern of each cytokine between SCI and non-SCI mice without supervising information. An impaired regulation of the expressions of not only positive but also negative regulators after 5-FU treatment was, in part, the cause of the impaired regeneration of CFU-preB cells in SCI mice.
authors.affiliation: Department of Functional Morphology, Nihon University School of Medicine, 30-1 Ohyaguchikami-machi, Itabashiku, Tokyo, Japan. tsuboi@med.nihon-u.ac.jp
authors.forename: Isao
authors.initials: I
authors.lastname: Tsuboi
authors.forename: Yoko
authors.initials: Y
authors.lastname: Hirabayashi
authors.forename: Tomonori
authors.initials: T
authors.lastname: Harada
authors.forename: Morimichi
authors.initials: M
authors.lastname: Koshinaga
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Kawamata
authors.forename: Jun
authors.initials: J
authors.lastname: Kanno
authors.forename: Tohru
authors.initials: T
authors.lastname: Inoue
authors.forename: Shin
authors.initials: S
authors.lastname: Aizawa
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D000963:Antimetabolites / Q000633:toxicity*; D001402:B-Lymphocytes / Q000187:drug effects / Q000502:physiology*; D001773:Blood Cells / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects; D003114:Colony-Forming Units Assay; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004777:Environment; D005472:Fluorouracil / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000502:physiology; D006410:Hematopoiesis / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D025341:Principal Component Analysis; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D012038:Regeneration / Q000187:drug effects / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000187:drug effects / Q000502:physiology*
chemical_list: D000963:Antimetabolites; D016207:Cytokines; D012313:RNA; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D005472:Fluorouracil