Bone Marrow Microenvironmental Control Of Hematopoietic Stem Cell Trafficking

Autologous hematopoietic stem/progenitor cells (HSPC) transplantation success depends upon adequate cell collection after G-CSF-administration that a substantial fraction of patients fails to achieve. Retrospective analysis of patient records demonstrated that diabetes correlated with lower CD34+ cell mobilization. Using mouse models, we found impaired HSPC egress from the bone marrow in either streptozotocin-induced or db/db diabetic animals. HSPC aberrantly localized within the marrow microenvironment of diabetic animals in association with abnormalities in sympathetic neuron number and function. Markedly increased sympathetic neuron density was accompanied by abnormal response to -adrenergic stimulation and a failure to generate the G-CSF-induced CXCL12 gradient in nestin-expressing mesenchymal cells associated with HSPC mobilization. Alternative mobilization by direct pharmacologic inhibition of CXCL12-CXCR4 interaction rescued the defect. These data reveal diabetes-induced changes in bone marrow physiology and microanatomy and point to a pathophysiologically based approach to overcome HSPC mobilization defects in diabetic patients.