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Blood, 15 October 2007, Vol. 110, No. 8, pp. 3056-3063.
Prepublished online as a Blood First Edition Paper on June 26, 2007; DOI 10.1182/blood-2007-05-087759.
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Submitted May 1, 2007
Accepted June 22, 2007
A low level of reactive oxygen species selects for primitive hematopoietic stem cells that may reside in the low-oxygenic niche
Yoon-Young Jang and Saul J Sharkis*
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States
* Corresponding author; email: ssharkis{at}jhmi.edu.
A low-oxygenic niche in bone marrow limits reactive oxygen species (ROS) production, thus providing long-term protection for hematopoietic stem cells (HSCs) from ROS stress. Although many approaches have been used to enrich HSCs, none has been designed to isolate primitive HSCs located within the low-oxygenic niche due to difficulties of direct physical access. Here we show that an early HSC population which might reside in the niche can be functionally isolated by taking advantage of the relative intracellular ROS activity. Many attributes of primitive HSCs in the low-oxygenic osteoblastic-niche such as quiescence, and calcium receptor, N-cadherin, Notch1, and p21 are higher in the ROSlow population. Intriguingly, the ROSlow population has a higher self-renewal potential. In contrast, significant HSC exhaustion in the ROShigh population was observed following serial transplantation, and expression of activated p38 MAPK and mTOR was higher in this population. Importantly, treatment with an antioxidant, a p38 inhibitor, or rapamycin was able to restore HSC function in the ROShigh population. Thus, more potent HSCs associated with the low-oxygenic niche can be indirectly isolated by selecting for the low-level of ROS expression. The ROS related signalling pathways together with specific characteristics of niche-HSCs may serve as targets for beneficial therapies.
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