Bone marrow as a target and accomplice of vascular complications in diabetes

Peripheral vascular complications are common in diabetic patients. While pathogenic mechanisms have received much consideration, only recently regenerative processes captured attention. There is now a consensus that the bone marrow is a source of reparative cells and that this healing mechanism is lost in people with diabetes, especially in those suffering from ischemic complications. This failure was thought to occur due to a negative impact of diabetes on the mobilization of stem/progenitor cells with angiogenic properties from the bone marrow to the circulation. Moreover, those patients showing severely reduced bone marrow cell mobilization also bared a very high risk for adverse cardiovascular events. More recently, the structural integrity of the bone marrow was recognized to be altered because of the rarefaction of local microvasculature and innervation, thus mirroring anatomical features that typically occur in peripheral tissues. Ensuing hypoxia, nutrient starvation, and creation of an acidic and oxidative environment concur in causing the depletion of stem/progenitor cells in the endosteal niche and in forcing stromal cells to activate an adipogenesis program. Moreover, stem/progenitor cells acquire a pathogenic phenotype and, once mobilized, can pass harmful signalling molecules to vascular cells of peripheral tissues thereby contributing to ischemic complications. These new pieces of evidence indicate that the bone marrow should deserve more attention in the current care of critical limb ischemia and diabetic foot. Owing to powerful reserve capacities, the bone marrow integrity could be preserved and even rescued using rehabilitation programs and pharmacological treatments with consequent benefit for local and whole-organism homeostasis.