Impaired Bone Regenerative Effect of Exosomes Derived from Bone Marrow Mesenchymal Stem Cells in Type 1 Diabetes

Abstract

Stem cell-derived exosomes have exhibited promise for applications in tissue regeneration. However, one major problem for stem cell-derived exosome therapies is identifying appropriate source cells. In the present study, we aimed to compare the bone regenerative effect of exosomes secreted by bone marrow mesenchymal stem cells (BMSCs) derived from type 1 diabetes rats (dBMSC-exos) and exosomes secreted by BMSCs derived from normal rats (nBMSC-exos). BMSCs were isolated from rats with streptozotocin-induced diabetes and normal rats. dBMSC-exos and nBMSC-exos were isolated by an ultracentrifugation method and identified. The effects of dBMSC-exos and nBMSC-exos on the proliferation and migration of BMSCs and human umbilical vein endothelial cells (HUVECs) were investigated. The effects of exosomes on the osteogenic differentiation of BMSCs and the angiogenic activity of HUVECs were compared. Finally, a rat calvarial defect model was used to compare the effects of exosomes on bone regeneration and neovascularization in vivo. In vitro, dBMSC-exos and nBMSC-exos both enhanced the osteogenic differentiation of BMSCs and promoted the angiogenic activity of HUVECs, but nBMSC-exos had a greater effect than dBMSC-exos. Similarly, in vivo, both dBMSC-exos and nBMSC-exos promoted bone regeneration and neovascularization in rat calvarial defects, but the therapeutic effect of nBMSC-exos was superior to that of dBMSC-exos. The present study demonstrates for the first time that the bone regenerative effect of exosomes derived from BMSCs is impaired in type 1 diabetes, indicating that for patients with type 1 diabetes, the autologous transplantation of BMSC-exos to promote bone regeneration may be inappropriate. Stem Cells Translational Medicine 2019;8:593-605.