Immunology Program, Sloan-Kettering Institute, 3 Department of Pediatrics, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
J Exp Med. 2011 Aug 29;208(9):1757-65. doi: 10.1084/jem.20102170. Epub 2011 Aug 15.
Hematopoietic stem cells (HSCs) self-renew to maintain the lifelong production of all blood populations. Here, we show that the proliferating cell nuclear antigen-associated factor (Paf) is highly expressed in cycling bone marrow HSCs and plays a critical role in hematopoiesis. Mice lacking Paf exhibited reduced bone marrow cellularity; reduced numbers of HSCs and committed progenitors; and leukopenia. These phenotypes are caused by a cell-intrinsic blockage in the development of long-term (LT)-HSCs into multipotent progenitors and preferential loss of lymphoid progenitors caused by markedly increased p53-mediated apoptosis. In addition, LT-HSCs from Paf(-/-) mice had increased levels of reactive oxygen species (ROS), failed to maintain quiescence, and were unable to support LT hematopoiesis. The loss of lymphoid progenitors was likely due the increased levels of ROS in LT-HSCs caused by treatment of Paf(-/-) mice with the anti-oxidant N-acetylcysteine restored lymphoid progenitor numbers to that of Paf(+/+) mice. Collectively, our studies identify Paf as a novel and essential regulator of early hematopoiesis.
造血干细胞 (HSCs) 通过自我更新来维持所有血液群体的终身产生。在这里，我们表明，增殖细胞核抗原相关因子 (Paf) 在循环骨髓 HSCs 中高度表达，并在造血中发挥关键作用。缺乏 Paf 的小鼠表现出骨髓细胞减少；HSCs 和定向祖细胞数量减少；以及白细胞减少症。这些表型是由 LT-HSCs 向多能祖细胞发育的细胞内在阻断以及由于 p53 介导的凋亡显著增加而导致的淋巴祖细胞优先丢失引起的。此外，来自 Paf(-/-) 小鼠的 LT-HSCs 具有更高水平的活性氧 (ROS)，无法维持静止状态，并且无法支持 LT 造血。淋巴祖细胞的丢失可能是由于 LT-HSCs 中 ROS 水平升高所致，用抗氧化剂 N-乙酰半胱氨酸处理 Paf(-/-) 小鼠可将淋巴祖细胞数量恢复到 Paf(+/+) 小鼠的水平。总的来说，我们的研究表明 Paf 是早期造血的一个新的和必需的调节因子。
