Departamento de Biofísica, Universidade Federal de São Paulo, Rua Botucatu 862, 2° Andar, 04023-062 São Paulo, Brazil.
Cell Death Dis. 2011 Jun 2;2(6):e165. doi: 10.1038/cddis.2011.49.
Extracellular nucleotides are emerging as important regulators of inflammation, cell proliferation and differentiation in a variety of tissues, including the hematopoietic system. In this study, the role of ATP was investigated during murine hematopoiesis. ATP was able to reduce the percentage of hematopoietic stem cells (HSCs), common myeloid progenitors and granulocyte-macrophage progenitors (GMPs), whereas differentiation into megakaryocyte-erythroid progenitors was not affected. In addition, in vivo administration of ATP to mice reduced the number of GMPs, but increased the number of Gr-1(+)Mac-1(+) myeloid cells. ATP also induced an increased proliferation rate and reduced Notch expression in HSCs and impaired HSC-mediated bone marrow reconstitution in sublethally irradiated mice. Moreover, the effects elicited by ATP were inhibited by suramin, a P2 receptor antagonist, and BAPTA, an intracellular Ca(2+) chelator. We further investigated whether the presence of cytokines might modulate the observed ATP-induced differentiation. Treatment of cells with cytokines (stem cell factor, interleukin-3 and granulocyte-monocyte colony stimulator factor) before ATP stimulation led to reduced ATP-dependent differentiation in long-term bone marrow cultures, thereby restoring the ability of HSCs to reconstitute hematopoiesis. Thus, our data suggest that ATP induces the differentiation of murine HSCs into the myeloid lineage and that this effect can be modulated by cytokines.
细胞外核苷酸在多种组织中作为炎症、细胞增殖和分化的重要调节剂而出现，包括造血系统。在这项研究中，研究了 ATP 在小鼠造血过程中的作用。ATP 能够降低造血干细胞 (HSCs)、普通髓系祖细胞和粒细胞-巨噬细胞祖细胞 (GMP) 的百分比，而对巨核细胞-红细胞祖细胞的分化没有影响。此外，体内给予 ATP 可减少 GMP 的数量，但增加 Gr-1(+)Mac-1(+)髓系细胞的数量。ATP 还诱导 HSCs 增殖率增加和 Notch 表达减少，并损害亚致死照射小鼠的 HSC 介导的骨髓重建。此外，P2 受体拮抗剂苏拉明和细胞内 Ca(2+)螯合剂 BAPTA 抑制了 ATP 引起的作用。我们进一步研究了细胞因子的存在是否可能调节观察到的 ATP 诱导的分化。在用细胞因子（干细胞因子、白细胞介素 3 和粒细胞-巨噬细胞集落刺激因子）处理细胞后再用 ATP 刺激，导致长期骨髓培养中 ATP 依赖性分化减少，从而恢复 HSCs 重建造血的能力。因此，我们的数据表明，ATP 诱导小鼠 HSCs 分化为髓系，并且这种效应可以被细胞因子调节。
