Dual angiogenic and neurotrophic effects of bone marrow-derived endothelial progenitor cells on diabetic neuropathy

Abstract

Endothelial progenitor cells (EPCs) are known to promote neovascularization in ischemic diseases.  Recent evidence suggested that diabetic neuropathy (DN) is causally related to impaired angiogenesis and deficient growth factors. Accordingly, we investigated whether DN could be reversed by local transplantation of EPCs. We found that motor and sensory nerve conduction velocities, blood flow, and capillary density were reduced in sciatic nerves of streptozotocin-induced diabetic mice, but recovered to normal levels after injection of bone marrow (BM)-derived EPCs into hindlimb. Injected EPCs were preferentially and durably engrafted in sciatic nerves. A portion of engrafted EPCs were uniquely localized in close proximity to vasa nervorum and a smaller portion of these EPCs were colocalized with endothelial cells. Multiple angiogenic and neurotrophic factors were significantly increased in the EPC-injected nerves. These dual angiogenic and neurotrophic effects of EPCs were confirmed by higher proliferation of Schwann cells and endothelial cells cultured in EPC conditioned media. We for the first time demonstrated that BM-derived EPCs could reverse various manifestations of DN. These therapeutic effects were mediated by direct augmentation of neovascularization in peripheral nerves through long-term and preferential engraftment of EPCs in nerves and particularly vasa nervorum, and their paracrine effects. These findings suggest that EPC transplantation could represent an innovative therapeutic option for treating diabetic neuropathy.