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

Diabetic foot ulcers are a major health‐care burden worldwide. One primary cause of the delayed wound healing in diabetic patients is impaired function of the hypoxia‐inducible factor‐1α/vascular endothelial growth factor (HIF‐1α/VEGF) axis, which results in compromised neovascularization in response to hypoxia. In the present study, we aimed to investigate the effect of roxadustat, a novel HIF prolyl‐4‐hydroxylase inhibitor, on angiogenesis and its therapeutic effect on cutaneous wound healing in diabetic rats. In vitro, we found that roxadustat could promote the angiogenic activity of human umbilical vein endothelial cells, accompanied by up‐regulation of HIF‐1α/VEGF/VEGFR2 signaling. Next, we demonstrated that Ki8751, a VEGFR2‐specific inhibitor, could inhibit the increased angiogenic activity of human umbilical vein endothelial cells induced by roxadustat. In vivo, we performed a Matrigel plug assay and demonstrated that roxadustat induced vascularization of the Matrigel plugs, and this effect could be partially inhibited by Ki8751. Finally, we utilized a streptozotocin‐induced diabetic rat model and found that roxadustat could accelerate cutaneous wound healing and promote angiogenesis in the wound sites. In conclusion, roxadustat promotes angiogenesis via activation of the HIF‐1α/VEGF/VEGFR2 pathway and exhibits therapeutic effects on diabetic wound healing by increasing angiogenesis. Our findings suggest that roxadustat can be a promising strategy to promote diabetic cutaneous wound healing.

Objective: Nonalcoholic fatty liver disease (NAFLD) is related to several inflammatory or metabolic diseases. However, findings of previous studies investigating the association between NAFLD and BMD are inconsistent. Only one study reported a potential association between NAFLD and osteoporotic fracture. This study investigated whether NAFLD in older participants (>55 years) was associated with osteoporotic fracture risk.Materials and Methods: This cross-sectional, observational study included 2,695 participants (35.7% men, 614 cases of NAFLD, and 383 fractures). Standardized questionnaires, laboratory tests, and physical and ultrasonic examinations were completed.Results: After adjusting for various factors including serum triglycerides (TG), high-density cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), multivariate logistic regression models revealed a marginal association between NAFLD and osteoporotic fracture risk in men (odds ratio [OR], 1.86; 95% confidence interval [CI], 1.06–3.27; P = 0.030) but no association in women (OR, 1.05; 95% CI, 0.74–1.48; P = 0.800). Further stratified analyses showed a significant association between NAFLD and osteoporotic fracture risk in men without high TG, low HDL-C, and high LDL-C.Conclusions: There was a significant association between NAFLD and osteoporotic fracture risk in older Chinese men, particularly men without dyslipidemia.