Abstract
BackgroundCirculating Endothelial Progenitor Cell (EPC) levels are reduced in diabetes mellitus. This may be a consequence of impaired mobilization of EPC from the bone marrow. We hypothesized that under diabetic conditions, mobilization of EPC from the bone marrow to the circulation is impaired –at least partly– due to dysfunction of the bone marrow stromal compartment.MethodsDiabetes was induced in mice by streptozotocin injection. Circulating Sca-1+Flk-1+ EPC were characterized and quantified by flow cytometry at baseline and after mobilization with G-CSF/SCF injections. In vivo hemangiogenic recovery was tested by 5-FU challenge. Interaction within the bone marrow environment between CD34+ hematopoietic progenitor cells (HPC) and supporting stroma was assessed by co-cultures. To study progenitor cell–endothelial cell interaction under normoglycemic and hyperglycemic conditions, a co-culture model using E4Orf1-transfected human endothelial cells was employed.ResultsIn diabetic mice, bone marrow EPC levels were unaffected. However, circulating EPC levels in blood were lower at baseline and mobilization was attenuated. Diabetic mice failed to recover and repopulate from 5-FU injection. In vitro, primary cultured bone marrow stroma from diabetic mice was impaired in its capacity to support human CFU-forming HPC. Finally, hyperglycemia hampered the HPC supportive function of endothelial cells in vitro.ConclusionEPC mobilization is impaired under experimental diabetic conditions and our data suggest that diabetes induces alterations in the progenitor cell supportive capacity of the bone marrow stroma, which could be partially responsible for the attenuated EPC mobilization and reduced EPC levels observed in diabetic patients.
Highlights
Premature atherosclerosis is a major complication in diabetes [1], which is at least in part attributable to an impaired vascular regenerative potential of bone marrow-derived progenitor cells [2]
Similar to hematopoietic progenitor cells (HPC), Endothelial Progenitor Cell (EPC) originate from the bone marrow, from which they are mobilized in response to mobilizing cytokines, such as vascular endothelial growth factor (VEGF) [12], granulocyte colony-stimulating factor (G-CSF) [13], [14], and stromal-derived factor-1a (SDF-1a) [15], and neuronal impulses [16], [17]
Diabetic mice have normal bone marrow EPC levels, but EPC mobilization is impaired The number of Sca-1+Flk-1+ EPC isolated per femur did not differ between diabetic and control mice
Summary
Premature atherosclerosis is a major complication in diabetes [1], which is at least in part attributable to an impaired vascular regenerative potential of bone marrow-derived progenitor cells [2]. Similar to HPC, EPC originate from the bone marrow, from which they are mobilized in response to mobilizing cytokines, such as vascular endothelial growth factor (VEGF) [12], granulocyte colony-stimulating factor (G-CSF) [13], [14], and stromal-derived factor-1a (SDF-1a) [15], and neuronal impulses [16], [17]. The sinusoidal endothelium is the essential component of the ‘vascular niche’ and plays a pivotal role in progenitor cell egress from the bone marrow to the circulation [18,19,20], a process that requires nitric oxide (NO) [21]. Circulating Endothelial Progenitor Cell (EPC) levels are reduced in diabetes mellitus This may be a consequence of impaired mobilization of EPC from the bone marrow. We hypothesized that under diabetic conditions, mobilization of EPC from the bone marrow to the circulation is impaired –at least partly– due to dysfunction of the bone marrow stromal compartment
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