The Role of Adenosine Receptor Agonists in Regulation of Hematopoiesis

Abstract

The review summarizes data evaluating the role of adenosine receptor signaling in murine hematopoietic functions. The studies carried out utilized either non-selective activation of adenosine receptors induced by elevation of extracellular adenosine or by administration of synthetic adenosine analogs having various proportions of selectivity for a particular receptor. Numerous studies have described stimulatory effects of non-selective activation of adenosine receptors, manifested as enhancement of proliferation of cells at various levels of the hematopoietic hierarchy. Subsequent experimental approaches, considering the hematopoiesis-modulating action of adenosine receptor agonists with a high level of selectivity to individual adenosine receptor subtypes, have revealed differential effects of various adenosine analogs. Whereas selective activation of A1 receptors has resulted in suppression of proliferation of hematopoietic progenitor and precursor cells, that of A3 receptors has led to stimulated cell proliferation in these cell compartments. Thus, A1 and A3 receptors have been found to play a homeostatic role in suppressed and regenerating hematopoiesis. Selective activation of adenosine A3 receptors has been found to act curatively under conditions of drug- and radiation-induced myelosuppression. The findings in these and further research areas will be summarized and mechanisms of hematopoiesis-modulating action of adenosine receptor agonists will be discussed.

Lack of adenosine A3 receptors causes defects in mouse peripheral blood parameters

“…We have shown that pharmacologically induced elevation of extracellular adenosine, i.e., nonselective activation of adenosine receptors, stimulates hematopoiesis in mice (e.g., [4][5][6], for review, see [7]). In a subsequent study using adenosine receptor agonists selective for individual receptor subtypes, it was revealed that activation of adenosine A 3 receptors by their selective agonist, N 6 -(3-iodobenzyl)adenosine-5′-N-methyluronadenosine (IB-MECA), stimulated proliferation of hematopoietic progenitor cells for granulocytes/macrophages (granulocyte/macrophage colony-forming cells (GM-CFC)) and erythrocytes (burst-forming unit erythroid (BFU-E)) [8].…”

The pharmacological activation of adenosine A1 and A3 receptors does not modulate the long- or short-term repopulating ability of hematopoietic stem and multipotent progenitor cells in mice

“…The system of adenosine receptors and their agonists has been shown to play a distinct regulatory role in the processes of cell proliferation and differentiation in normal, as well as suppressed hematopoiesis [for a review, see 8,9]. Numerous studies have revealed the significant role of the nonselective activation of adenosine receptors in stimulating hematopoiesis [e.g., [10][11][12][13][14].…”

Pharmacological Modulation of Radiation Damage. Does It Exist a Chance for Other Substances than Hematopoietic Growth Factors and Cytokines?

“…Further experimentation, using agonists selected for the individual subtypes, has been aimed at finding out whether stimulation of one of the four subtypes is responsible for the previously observed hematopoiesis-stimulating and radioprotective effects. These experiments are described in detail in a separate review [ 161 ]. It follows from the findings that IB-MECA ( N 6 -(3-iodobenzyl)adenosine-5′- N -methyluronamide) stimulates the cycling of hematopoietic progenitor cells [ 162 ].…”