Systemic abnormalities cause several complications in diabetes patients. Impaired wound healing is a serious complication that leads to severe foot ulcer and amputation. Mesenchymal stem cells (MSCs) have been considered a promising strategy for promoting wound healing due to their paracrine function. However, their poor survival after transplantation limits their therapeutic effect and applications. Salidroside, a glucopyranoside, has been reported to exert cytoprotective effects. Our previous study revealed that salidroside could promote the paracrine function of skeletal muscle cells. However, whether salidroside could improve MSCs survival under hyperglycemic condition and, subsequently, promote wound healing in diabetic model mice remains unknown. Here, we found that salidroside pretreatment effectively reversed the hyperglycemia‐induced suppression of the expression of crucial wound healing factors in MSCs, such as heme oxygenase‐1 (HO‐1), fibroblast growth factor 2 (FGF2), and hepatocyte growth factor (HGF). Salidroside pretreatment also suppressed the hyperglycemia‐induced intracellular reactive oxygen species (ROS) levels in MSCs, thereby lowering the apoptosis rate and enhancing MSCs survival rate. Furthermore, salidroside improved the MSCs migration potential that was impaired under hyperglycemia. in vivo experiments revealed that salidroside pretreatment prior to transplantation significantly enhanced the effect of MSCs in promoting wound closure in diabetic mice. Collectively, our results suggest that pretreatment with salidroside could be an effective strategy to enhance the survival rate and the therapeutic effect of MSCs. Thus, our article suggested a novel, potential MSC‐based strategy for diabetic wound healing. Stem Cells Translational Medicine 2019;8:404–414

Peripheral artery disease (PAD) poses a great challenge to society, with a growing prevalence in the upcoming years. Patients in the severe stages of PAD are prone to amputation and death, leading to poor quality of life and a great socioeconomic burden. Furthermore, PAD is one of the major complications of diabetic patients, who have higher risk to develop critical limb ischemia, the most severe manifestation of PAD, and thus have a poor prognosis. Hence, there is an urgent need to develop an effective therapeutic strategy to treat this disease. Therapeutic angiogenesis has raised concerns for more than two decades as a potential strategy for treating PAD, especially in patients without option for surgery-based therapies. Since the discovery of gene-based therapy for therapeutic angiogenesis, several approaches have been developed, including cell-, protein-, and small molecule drug-based therapeutic strategies, some of which have progressed into the clinical trial phase. Despite its promising potential, efforts are still needed to improve the efficacy of this strategy, reduce its cost, and promote its worldwide application. In this review, we highlight the current progress of therapeutic angiogenesis and the issues that need to be overcome prior to its clinical application.

Diabetes mellitus is associated with a high risk of hindlimb ischemia (HLI) progression and an inevitably poor prognosis, including worse limb salvage and mortality. Skeletal muscle cells can secrete angiogenic factors, which could promote neovascularization and blood perfusion recovery. Thus, paracrine function of skeletal muscle cells, which is aberrant in diabetic conditions, is crucial for therapeutic angiogenesis in diabetic HLI. Dapagliflozin is a well-known anti-hyperglycemia and anti-obesity drug; however, its role in therapeutic angiogenesis is unknown. Herein, we found that dapagliflozin could act as an angiogenesis stimulator in diabetic HLI. We showed that dapagliflozin enhances the viability, proliferation, and migration potentials of skeletal muscle cells and promotes the secretion of multiple angiogenic factors from skeletal muscle cells, most plausibly through PHD2/HIF-1a axis. Furthermore, we demonstrated that conditioned medium from dapagliflozin-treated skeletal muscle cells enhances the proliferation and migration potentials of vascular endothelial and smooth muscle cells, which are two fundamental cells of functional mature vessels. Finally, an in vivo study demonstrated that intramuscular administration of dapagliflozin effectively enhances the formation of mature blood vessels and, subsequently, blood perfusion recovery in diabetic HLI mice. Hence, our results suggest a novel function of dapagliflozin as a potential therapeutic angiogenesis agent for diabetic HLI.

As one of the most severe manifestations of diabetes, vascular complications are the main causes of diabetes-related morbidity and mortality. Hyperglycemia induces systemic abnormalities, including impaired angiogenesis, causing diabetic patients to be highly susceptible in suffering hindlimb ischemia (HLI). Despite its severe prognosis, there is currently no effective treatment for diabetic HLI. Skeletal muscle cells secrete multiple angiogenic factors, hence, recently are reported to be critical for angiogenesis; however, hyperglycemia disrupted the paracrine function in skeletal muscle cells, leading to the impaired angiogenesis potential observed in diabetic patients. The present study showed that tyrosol, a phenylethanoid compound, suppresses accumulation of intracellular reactive oxygen species (ROS) caused by hyperglycemia, most plausibly by promoting heme oxygenase-1 (HO-1) expression in skeletal muscle cells. Consequently, tyrosol exerts cytoprotective function against hyperglycemia-induced oxidative stress in skeletal muscle cells, increases their proliferation vigorously, and simultaneously suppresses apoptosis. Furthermore, tyrosol grossly increases the secretion of vascular endothelial growth factor-A (VEGF-A) and platelet-derived growth factor-BB (PDGF-BB) from skeletal muscle cells. This leads to enhanced proliferation and migration capabilities of vascular endothelial and smooth muscle cells, two types of cells that are responsible in forming blood vessels, through cell-cell communication. Finally, in vivo experiment using the diabetic HLI mouse model showed that tyrosol injection into the gastrocnemius muscle of the ischemic hindlimb significantly enhances the formation of functional blood vessels and subsequently leads to significant recovery of blood perfusion. Overall, our findings highlight the potential of the pharmacological application of tyrosol as a small molecule drug for therapeutic angiogenesis in diabetic HLI patients.

Therapeutic angiogenesis is a potential therapeutic strategy for hind limb ischemia (HLI); however, currently, there are no small-molecule drugs capable of inducing it at the clinical level. Activating the hypoxia-inducible factor-1 (HIF-1) pathway in skeletal muscle induces the secretion of angiogenic factors and thus is an attractive therapeutic angiogenesis strategy. Using salidroside, a natural glycosidic compound as a lead, we performed a structure–activity relationship (SAR) study for developing a more effective and druggable angiogenesis agent. We found a novel glycoside scaffold compound (C-30) with better efficacy than salidroside in enhancing the accumulation of the HIF-1α protein and stimulating the paracrine functions of skeletal muscle cells. This in turn significantly increased the angiogenic potential of vascular endothelial and smooth muscle cells and, subsequently, induced the formation of mature, functional blood vessels in diabetic and nondiabetic HLI mice. Together, this study offers a novel, promising small-molecule-based therapeutic strategy for treating HLI.