title: Bmi1 confers resistance to oxidative stress on hematopoietic stem cells.
abstract: BACKGROUND
  The polycomb-group (PcG) proteins function as general regulators of stem cells. We previously reported that retrovirus-mediated overexpression of Bmi1, a gene encoding a core component of polycomb repressive complex (PRC) 1, maintained self-renewing hematopoietic stem cells (HSCs) during long-term culture. However, the effects of overexpression of Bmi1 on HSCs in vivo remained to be precisely addressed.
  
  
  RESULTS
  In this study, we generated a mouse line where Bmi1 can be conditionally overexpressed under the control of the endogenous Rosa26 promoter in a hematopoietic cell-specific fashion (Tie2-Cre;R26Stop(FL)Bmi1). Although overexpression of Bmi1 did not significantly affect steady state hematopoiesis, it promoted expansion of functional HSCs during ex vivo culture and efficiently protected HSCs against loss of self-renewal capacity during serial transplantation. Overexpression of Bmi1 had no effect on DNA damage response triggered by ionizing radiation. In contrast, Tie2-Cre;R26Stop(FL)Bmi1 HSCs under oxidative stress maintained a multipotent state and generally tolerated oxidative stress better than the control. Unexpectedly, overexpression of Bmi1 had no impact on the level of intracellular reactive oxygen species (ROS).
  
  
  CONCLUSIONS
  Our findings demonstrate that overexpression of Bmi1 confers resistance to stresses, particularly oxidative stress, onto HSCs. This thereby enhances their regenerative capacity and suggests that Bmi1 is located downstream of ROS signaling and negatively regulated by it.
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Nakamura
authors.forename: Motohiko
authors.initials: M
authors.lastname: Oshima
authors.forename: Jin
authors.initials: J
authors.lastname: Yuan
authors.forename: Atsunori
authors.initials: A
authors.lastname: Saraya
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyagi
authors.forename: Takaaki
authors.initials: T
authors.lastname: Konuma
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamazaki
authors.forename: Mitsujiro
authors.initials: M
authors.lastname: Osawa
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Nakauchi
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Koseki
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwama
mesh_terms: D000818:Animals; D003114:Colony-Forming Units Assay; D006410:Hematopoiesis / Q000235:genetics / Q000502:physiology / Q000528:radiation effects; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism* / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D039902:Multipotent Stem Cells / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011836:Radiation Tolerance / Q000235:genetics / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: C489421:Bmi1 protein, mouse; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; D063150:Polycomb Repressive Complex 1