Function of oxidative stress in the regulation of hematopoietic stem cell-niche interaction.
During postnatal life, the bone marrow (BM) supports both self-renewal and differentiation of hematopoietic stem cells (HSCs) in specialized niches, such as osteoblastic niche and vascular niche. A cell adhesion molecule, N-cadherin expressed in the HSCs and osteoblasts, suggesting that homophylic binding of N-cadherin induce the adhesion of HSCs to the niche cells. Here we demonstrate that an anti-cancer drug, 5-fuluorouracil induces reactive oxygen species (ROS) in HSCs, which suppressed N-cadherin expression. These events result in the shift of side population (SP) cells to non-SP cells, indicating that quiescent HSCs are detached from the niche. Administration of a potent anti-oxidant, N-acetyl cystein (NAC) suppressed the shift from SP cells. These data suggest that ROS suppressed the N-cadherin-mediated cell adhesion, and induce the exit of HSCs from the niche.
Hosokawa
Kentaro
K
Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
Arai
Fumio
F
Yoshihara
Hiroki
H
Nakamura
Yuka
Y
Gomei
Yumiko
Y
Iwasaki
Hiroko
H
Miyamoto
Kana
K
Shima
Haruko
H
Ito
Keisuke
K
Suda
Toshio
T
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002452:Cell Count; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
D015820:Cadherins; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D007093:Imidazoles; D011725:Pyridines; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; D005472:Fluorouracil; D000111:Acetylcysteine