The endothelial antigen ESAM monitors hematopoietic stem cell status between quiescence and self-renewal.
Whereas most hematopoietic stem cells (HSC) are quiescent in homeostasis, they actively proliferate in response to bone marrow (BM) injury. Signals from the BM microenvironment are thought to promote entry of HSC into the cell cycle. However, it has been cumbersome to assess cycle status of viable HSC and thus explore unique features associated with division. In this study, we show that expression of endothelial cell-selective adhesion molecule (ESAM) can be a powerful indicator of HSC activation. ESAM levels clearly mirrored the shift of HSC between quiescence and activation, and it was prominent in comparison with other HSC-related Ags. ESAM(hi) HSC were actively dividing, but had surprisingly high long-term reconstituting capacity. Immunohistochemical analyses showed that most ESAM(hi) HSC were located near vascular endothelium in the BM after 5-fluorouracil treatment. To determine the importance of ESAM in the process of BM recovery, ESAM knockout mice were treated with 5-fluorouracil and their hematopoietic reconstruction was examined. The ESAM deficiency caused severe and prolonged BM suppression, suggesting that ESAM is functionally indispensable for HSC to re-establish homeostatic hematopoiesis. With respect to intracellular regulators, NF-κB and topoisomerase II levels correlated with the ESAM upregulation. Thus, our data demonstrate that the intensity of ESAM expression is useful to trace activated HSC and to understand molecular events involved in stem cell states.
Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
Takao
T
Sudo
Takafumi
T
Yokota
Kenji
K
Oritani
Yusuke
Y
Satoh
Tatsuki
T
Sugiyama
Tatsuro
T
Ishida
Hirohiko
H
Shibayama
Sachiko
S
Ezoe
Natsuko
N
Fujita
Hirokazu
H
Tanaka
Tetsuo
T
Maeda
Takashi
T
Nagasawa
Yuzuru
Y
Kanakura
D000818:Animals; D000941:Antigens / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015415:Biomarkers / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D016192:Resting Phase, Cell Cycle / Q000235:genetics / Q000276:immunology*
D000941:Antigens; D015415:Biomarkers; D015815:Cell Adhesion Molecules; C428190:Esam protein, mouse