We demonstrated previously that extracellular vesicles (EVs) released from mesenchymal stem cells (MSCs) play a critical role in angiogenesis. Here, we examine whether this pro-angiogenic efficacy is enhanced in EVs derived from MSCs overexpressing GATA-4 (MSCGATA−4). Methods and Results. EVs were isolated from MSCGATA-4 (EVGATA-4) and control MSCs transduced with an empty vector (EVnull). EVs from both cell types were of the same size and displayed similar molecular markers. Compared with EVnull, EVGATA-4 increased both a tube-like structure formation and spheroid-based sprouting of human umbilical vein endothelial cells (HUVECs). The EVGATA-4 increased the numbers of CD31-positive cells and hemoglobin content inside Matrigel plugs subcutaneously transplanted into mice for 2 weeks. Moreover, EVGATA-4 encapsulated higher levels of let-7 family miRs compared to EVnull. The transfer of exosomal let-7 miRs into HUVECs was recorded with an accompanied down-regulation of thrombospondin-1 (THBS1) expression, a major endogenous angiogenesis inhibitor. The loss-and-gain of function studies of let-7 miRs showed that let-7f knockdown significantly decreased EVGATA-4-mediated vascularization inside Matrigel plugs. In contrast, let-7f overexpression promoted HUVEC migration and tube formation. Conclusion. Our results indicate that EVs derived from genetically modified MSCs with GATA-4 overexpression had increased pro-angiogenic capacity due to the delivery of let-7 miRs that targeted THBS1 in endothelial cells.
Background Patients undergoing cancer treatment often experience chemotherapy-induced neuropathic pain at their extremities, for which there is no U.S. Food and Drug Administration–approved drug. The authors hypothesized that local sympathetic blockade, which is used in the clinic to treat various pain conditions, can also be effective to treat chemotherapy-induced neuropathic pain. Methods A local sympathectomy (i.e., cutting the ipsilateral gray rami entering the spinal nerves near the L3 and L4 dorsal root ganglia) was performed in mice receiving intraperitoneal injections every other day of the chemotherapeutic drug paclitaxel. Sympathectomy effects were then assessed in chemotherapy-induced pain-like behaviors (i.e., mechanical and cold allodynia) and neuroimmune and electrophysiologic responses. Results Local microsympathectomy produced a fast recovery from mechanical allodynia (mean ± SD: sympathectomy vs. sham at day 5, 1.07 ± 0.34 g vs. 0.51 ± 0.17g, n = 5, P = 0.030 in male mice, and 1.08 ± 0.28 g vs. 0.62 ± 0.16 g, n = 5, P = 0.036 in female mice) and prevented the development of cold allodynia in both male and female mice after paclitaxel. Mechanistically, microsympathectomy induced transcriptional increases in dorsal root ganglia of macrophage markers and anti-inflammatory cytokines, such as the transforming growth factor-β. Accordingly, depletion of monocytes/macrophages and blockade of transforming growth factor-β signaling reversed the relief of mechanical allodynia by microsympathectomy. In particular, exogenous transforming growth factor-β was sufficient to relieve mechanical allodynia after paclitaxel (transforming growth factor-β 100 ng/site vs. vehicle at 3 h, 1.21 ± 0.34g vs. 0.53 ± 0.14 g, n = 5, P = 0.001 in male mice), and transforming growth factor-β signaling regulated neuronal activity in dorsal root ganglia. Conclusions Local sympathetic nerves control the progression of immune responses in dorsal root ganglia and pain-like behaviors in mice after paclitaxel, raising the possibility that clinical strategies already in use for local sympathetic blockade may also offer an effective treatment for patients experiencing chemotherapy-induced neuropathic pain. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New
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