Enhancing Stem Cell Mobility: New Hope for Treatment of Cardiovascular Complications in Patients With Diabetes?

Local healing processes, including reparative angiogenesis mounted by resident vascular cells, are remarkably deteriorated in patients with diabetes. Vascular problems are worsened by the scarcity and dysfunction of circulating proangiogenic cells. Stem cell depauperization in bone marrow (BM), disruption of BM microvasculature, and alteration in chemokine signaling mechanisms concur in reducing the mobilization of proangiogenic cells in patients with diabetes (1–4). Diabetic mobilopathy has relevant implications for risk stratification. In fact, the abundance and migratory activity of circulating mononuclear cells (MNCs) expressing the antigenic markers CD34 and vascular endothelial growth factor receptor 2 (VEGFR2)/KDR has been proposed as a new biomarker for prediction of cardiovascular morbidity and mortality (5–9). Moreover, forcing stem cell release with mobilizing agents, a modality initially introduced for harvesting cells in view of autologous or allogeneic transplantation for treatment of hematologic diseases, may help improve the outcome of ischemic complications (10). Currently, granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage colony-stimulating factor (GM-CSF) remain the standard mobilizing agents. Both require repeated administrations to achieve the target (usually 4 3 10 CD34 cells/kg), with success being influenced by basal CD34 cell levels and donor age (11). Additionally, patients with diabetes are often unresponsive to G-CSF (12,13). Plerixafor (AMD3100) represents a promising new mobilizing agent with the potential to overcome the limits of indirect mobilizers. It acts as a direct antagonist of the interaction between the chemokine stromal-derived factor-1 (SDF-1)/CXCL12 and its receptor CXCR4, does not show residual agonistic activity or cross-reactivity with other chemokine receptors, mobilizes stem cells within hours, and is well tolerated (14). In this issue of Diabetes, a new study from Fadini et al. (15) provides evidence that plerixafor may be preferred to G-CSF as a mobilizing agent in patients with diabetes. This investigation comprises a retrospective analysis of 803 patients with hematologic disease who received G-CSF or G-CSF plus plerixafor in view of autologous hematopoietic stem cell (HSC) transplantation and 488 consecutive adult patients who underwent apheresis for allogeneic HSC donation to a family member. In both cohorts, diabetes was associated with poorer mobilization in patients given G-CSF, whereas this was not the case in patients who received G-CSF plus plerixafor. Additional analyses were performed by comparing results of a prospective study in individuals with and without diabetes (n = 10/group) given a single dose of plerixafor and historical data from a previous study in which patients received a single 5 mg/kg dose of subcutaneous G-CSF to test rapid (24 h) HSC mobilization response. Results indicate plerixafor was equally able to mobilize CD34 HSCs in the two groups, whereas in the historical study G-CSF was less effective in patients with diabetes. In addition, plerixafor seems to improve the clonogenic activity of released cells. Merging the results of two studies performed at different occasions is considered a valid approach to generate hypotheses, but not to make conclusive scientific statements. Nevertheless, in our opinion, the effect of plerixafor versus G-CSF on the primary outcome was strong enough to draw valid conclusions, considering that the two studies are coming from the same research group using the same methods. These new exciting data revitalize the interest on mobilization strategies in cardiovascular medicine. Initial excitement from preclinical studies using G-CSF in preclinical models of myocardial infarction (MI) has been tempered following translation to the clinical setting. In mice, G-CSF markedly improves cardiac function and