Doping the Bone Marrow

Abstract

Repopulation of the bone marrow (BM) with transplanted hematopoietic stem cells is crucial for treatment of immunodeficiencies and malignancies. BM stem cells, which express CD34, are mobilized by treatment with the myeloid cytokines granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF). The bone marrow is a highly innervated tissue containing stores of dopamine, so Spiegel et al . studied the effects of dopamine on hematopoiesis. Flow cytometry revealed that treatment of human CD34 + cells with G-CSF increased the abundance of the dopamine receptors DR3 and DR5. In vitro migration assays demonstrated that GM-CSF treatment led to an increase in the number of CD34 + cells that migrated to dopamine. By measuring colony formation, the authors found that dopamine treatment increased the proliferation of CD34 + cells. Moreover, engraftment of human G-CSF-mobilized CD34 + cells in susceptible mouse BM was increased by pretreatment with dopamine agonists. Similar results were found with the β 2 -adrenergic receptor (β 2 -AR) agonist epinephrine. Flow cytometry demonstrated that treatment of CD34 + cells with GM-CSF and epinephrine resulted in the accumulation of β-catenin, a downstream mediator of the Wnt signaling pathway, which is known to play a role in stem cell proliferation. Engraftment of mouse BM by GM-CSF and epinephrine-treated human CD34 + cells was inhibited by blocking Wnt signaling. This study illustrates an important role for neurotransmitters in regulating the functions of hematopoietic progenitor cells and suggests that combining neurotransmitters with myeloid cytokines may be clinically relevant in enhancing the effectiveness of stem cell transplantation. A. Spiegel, S. Shivtiel, A. Kalinkovich, A. Ludin, N. Netzer, P. Goichberg, Y. Azaria, I. Resnick, I. Hardan, H. Ben-Hur, A. Nagler, M. Rubinstein, T. Lapidot, Catecholaminergic neurotransmitters regulate migration and repopulation of immature human CD34 + cells through Wnt signaling. Nat. Immunol. 8 , 1123-1131 (2007). [PubMed]