JOURNAL ARTICLE

Diabetes impairs hematopoietic stem cell mobilization by altering niche function

Francesca Ferraro, Stefania Lymperi, Simón Méndez-Ferrer, Borja Saez, Joel A Spencer, Beow Y Yeap, Elena Masselli, Gallia Graiani, Lucia Prezioso, Elisa Lodi Rizzini, Marcellina Mangoni, Vittorio Rizzoli, Stephen M Sykes, Charles P Lin, Paul S Frenette, Federico Quaini, David T Scadden
Science Translational Medicine 2011 October 12, 3 (104): 104ra101
21998408
Success with transplantation of autologous hematopoietic stem and progenitor cells (HSPCs) in patients depends on adequate collection of these cells after mobilization from the bone marrow niche by the cytokine granulocyte colony-stimulating factor (G-CSF). However, some patients fail to achieve sufficient HSPC mobilization. Retrospective analysis of bone marrow transplant patient records revealed that diabetes correlated with poor mobilization of CD34+ HSPCs. In mouse models of type 1 and type 2 diabetes (streptozotocin-induced and db/db mice, respectively), we found impaired egress of murine HSPCs from the bone marrow after G-CSF treatment. Furthermore, HSPCs were aberrantly localized in the marrow niche of the diabetic mice, and abnormalities in the number and function of sympathetic nerve termini were associated with this mislocalization. Aberrant responses to β-adrenergic stimulation of the bone marrow included an inability of marrow mesenchymal stem cells expressing the marker nestin to down-modulate the chemokine CXCL12 in response to G-CSF treatment (mesenchymal stem cells are reported to be critical for HSPC mobilization). The HSPC mobilization defect was rescued by direct pharmacological inhibition of the interaction of CXCL12 with its receptor CXCR4 using the drug AMD3100. These data suggest that there are diabetes-induced changes in bone marrow physiology and microanatomy and point to a potential intervention to overcome poor HSPC mobilization in diabetic patients.

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