Abstract
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 Ca2+ 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.
Highlights
The cells present in hematopoietic niches regulate hematopoiesis through the release of different cytokines, which activate distinct cytokine receptors with intrinsic kinase activity or Janus kinase-dependent receptors
Because ATP induces the differentiation of primitive cells in long-term bone marrow cultures (LTBMCs), we determined whether ATP stimulation could alter the percentages of the hematopoietic stem cells (HSCs) and MP populations, including the common myeloid progenitors (CMPs), granulocyte– macrophage progenitors (GMPs) and megakaryocytic– erythroid progenitors (MEPs)
Our results showed a significant decrease in the percentage of the HSC, CMP and GMP populations after stimulation with ATP for 4 h in vitro (Figure 1a), whereas the MEP population was not affected
Summary
The cells present in hematopoietic niches regulate hematopoiesis through the release of different cytokines, which activate distinct cytokine receptors with intrinsic kinase activity or Janus kinase-dependent receptors. Received 24.1.11; revised 05.4.11; accepted 28.4.11; Edited by A Stephanou death,[17,18] platelet aggregation,[14] and cellular proliferation and differentiation.[6,7] Studies in promyelocytic leukemia HL-60 cells have shown that the expression levels of P2 receptors change significantly during myeloid differentiation.[19,20] Nucleotides such as ATP and UTP enhance the response of HSCs to several cytokines.[7] For example, UTP was able to significantly improve chemokine receptor 4-mediated (CxC4R) HSC migration.[21] In addition, we have shown that large increases in ATP-induced Ca2i þ promote transient proliferation and induce the differentiation of primitive hematopoietic cells in long-term bone marrow cultures (LTBMCs).[6] Recently, the functional presence of P2X receptors was described in an HSC subset, which is probably related to proliferation.[22]
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