Eliasson Pernilla, Jönsson Jan-Ingvar
Department of Clinical and Experimental Medicine, Experimental Hematology Unit, Linköping University, Linköping, Sweden.
J Cell Physiol. 2010 Jan;222(1):17-22. doi: 10.1002/jcp.21908.
The enormous regenerative capacity of the blood system to sustain functionally mature cells are generated from highly proliferative, short-lived progenitors, which in turn arise from a rare population of pluripotent and self-renewing hematopoietic stem cells (HSC). In the bone marrow, these stem cells are kept in a low proliferative, relatively quiescent state in close proximity to stromal cells and osteoblasts, forming specialized niches. The interaction in particular to bone is crucial to prevent exhaustion of HSCs from uncontrolled cell-cycle entry and to excessive proliferation. In addition, the niche and its components protect stem cells from stress, such as accumulation of reactive oxygen species and DNA damage. One of the key issues is to identify conditions to increase the number of HSCs, either in vivo or during ex vivo growth cultures. This task has been very difficult to resolve and most attempts have been unsuccessful. However, the mechanistic insights to HSC self-renewal and preservation are gradually increasing and there is now hope that future research will enable scientists and clinicians to modulate the process. In this review, we will focus on the molecular mechanisms of self-renewal and HSC maintenance in the light of novel findings that HSCs reside at the lowest end of an oxygen gradient. Hypoxia appears to regulate hematopoiesis in the bone marrow by maintaining important HSC functions, such as cell cycle control, survival, metabolism, and protection against oxidative stress. To improve the therapeutic expansion of HSCs we need to learn more about the molecular mechanisms of hypoxia-mediated regulation.
血液系统具有巨大的再生能力，能够维持功能成熟的细胞，这些细胞由高度增殖、寿命短暂的祖细胞产生，而祖细胞又源自罕见的多能且自我更新的造血干细胞（HSC）。在骨髓中，这些干细胞与基质细胞和成骨细胞紧密相邻，处于低增殖、相对静止的状态，形成了特殊的微环境。尤其是与骨骼的相互作用对于防止造血干细胞因不受控制地进入细胞周期和过度增殖而耗竭至关重要。此外，微环境及其组成部分可保护干细胞免受应激影响，如活性氧的积累和DNA损伤。关键问题之一是确定在体内或体外生长培养过程中增加造血干细胞数量的条件。这项任务一直很难解决，大多数尝试都未成功。然而，对造血干细胞自我更新和维持的机制性认识正在逐渐增加，现在有望未来的研究能使科学家和临床医生调节这一过程。在这篇综述中，鉴于造血干细胞位于氧梯度最低端这一新发现，我们将聚焦于自我更新和造血干细胞维持的分子机制。缺氧似乎通过维持重要的造血干细胞功能，如细胞周期控制、存活、代谢以及抵御氧化应激，来调节骨髓中的造血作用。为了改善造血干细胞的治疗性扩增，我们需要更多地了解缺氧介导调节的分子机制。
