Mesenchymal stem cell-secreted extracellular vesicles carrying TGF-β1 up-regulate miR-132 and promote mouse M2 macrophage polarization.

The effects of mesenchymal stem cells (MSCs) on different types of diseases are controversial, and the inner mechanisms remain unknown, which retards the utilization of MSCs in disease therapy. In this study, we aimed to elucidate the mechanisms of MSCs-extracellular vesicles (EVs) carrying transforming growth factor-beta 1 (TGF-β1) in M2 polarization in mouse macrophages via the microRNA-132 (miR-132)/E3 ubiquitin ligase myc binding protein 2 (Mycbp2)/tuberous sclerosis complex 2 (TSC2) axis. Mouse MSCs were isolated for adipogenic and osteogenic induction, followed by co-culture with mouse macrophages RAW264.7. Besides, mouse macrophages RAW264.7 were co-cultured with MSCs-EVs in vitro, where the proportion of macrophages and inflammation were detected by flow cytometry and ELISA. The experimental data revealed that MSCs-EVs promoted M2 polarization of macrophages, and elevated interleukin (IL)-10 expression and inhibited levels of IL-1β, tumour necrosis factor (TNF)-α and IL-6. MSC-EV-treated macrophages RAW264.7 increased TGF-β1 expression, thus elevating miR-132 expression. MiR-132 directly bound to Mycbp2, as confirmed by luciferase activity assay. Meanwhile, E3 ubiquitin ligase Mycbp2 could ubiquitinate TSC2 protein. Furthermore, silencing TGF-β1 inhibited M2 polarization of MSC-EV-treated macrophages. Taken conjointly, this study provides evidence reporting that MSC-secreted EVs carry TGF-β1 to promote M2 polarization of macrophages via modulation of the miR-132/Mycbp2/TSC2 axis.

Wang Y ，Han B ，Wang Y ，Wang C ，Zhang H ，Xue J ，Wang X ，Niu T ，Niu Z ，Chen Y ... -  《-》

Mesenchymal stem cell-derived extracellular vesicles prevent glioma by blocking M2 polarization of macrophages through a miR-744-5p/TGFB1-dependent mechanism.

Our current study is conducted with intention to explore the regulatory mechanism of mesenchymal stem cell (MSC)-derived extracellular vesicle (EV)-miR-744-5p in glioma. Expression patterns of TGFB1, TGFBR1, and miR-744-5p were determined. EVs were isolated from human MSCs, which were characterized. Then, macrophages were co-cultured with MSCs with ectopic miR-744-5p expression to explore its role in cell proliferation, invasion, and migration capabilities. A nude mouse model of glioma xenograft was developed to observe the tumorigenesis and metastasis ability of glioma in vivo. TGFB1 and TGFBR1 were upregulated in glioma. TGFB1 promoted M2 polarization of macrophages through theMAPK signaling, thereby promoting the progression of glioma. MSC-EVs suppressed TGFB1 expression in macrophages and inhibited M2 polarization of macrophages. MSC-EVs-miR-744-5p/TGFB1/MAPK axis inhibited M2 polarization of macrophages and reduced the malignant phenotypes of glioma cells. In vivo experiments verified that MSC-EVs-miR-744-5p inhibited the polarization of macrophage M2 and prevented glioma progression. Taken together, MSC-EVs-miR-744-5p may suppress the MAPK signaling activity by downregulating TGFB1, and then inhibit polarization of macrophages M2, thereby preventing the progression of glioma. Graphical Headlights 1. TGFB1 promotes the M2 polarization of macrophages via the MAPK signaling. 2. miR-744-5p carried by MSC-EVs targets and inhibits TGFB1. 3. MSC-EV-miR-744-5p inhibits M2 polarization of macrophages to prevent glioma progression. 4. miR-744-5p loaded by MSC-EVs may be a preventive strategy against glioma.

Liu L ，Cheng M ，Zhang T ，Chen Y ，Wu Y ，Wang Q ... -  《-》

Extracellular vesicles secreted by hypoxia pre-challenged mesenchymal stem cells promote non-small cell lung cancer cell growth and mobility as well as macrophage M2 polarization via miR-21-5p delivery.

Ren W ，Hou J ，Yang C ，Wang H ，Wu S ，Wu Y ，Zhao X ，Lu C ... -  《JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH》

Extracellular vesicle-carried microRNA-27b derived from mesenchymal stem cells accelerates cutaneous wound healing via E3 ubiquitin ligase ITCH.

Mesenchymal stem cells (MSCs) have been highlighted as promising candidate cells in relation to cutaneous wound healing. The current study aimed to investigate whether MSC-derived extracellular vesicles (EVs) could transfer microRNA-27b (miR-27b) to influence cutaneous wound healing. The miR-27b expression was examined in the established cutaneous wound mouse model, and its correlation with the wound healing rate was evaluated by Pearson's correlation analysis. The identified human umbilical cord MSC-derived EVs were co-cultured with human immortal keratinocyte line HaCaT and human skin fibroblasts (HSFs). The mice with cutaneous wound received injections of MSC-derived EVs. The effects of EVs or miR-27b loaded on wound healing and cellular functions were analysed via gain- and loss-of-function approaches in the co-culture system. Dual-luciferase reporter gene assay was employed to verify the relationship between miR-27b and Itchy E3 ubiquitin protein ligase (ITCH). Rescue experiments were conducted to investigate the underlying mechanisms associated with the ITCH/JUNB/inositol-requiring enzyme 1α (IRE1α) axis. miR-27b was down-regulated in the mouse model, with its expression found to be positively correlated with the wound healing rate. Abundant miR-27b was detected in the MSC-derived EVs, while EV-transferred miR-27b improved cutaneous wound healing in mice and improved proliferation and migration of HaCaT cells and HSFs in vitro. As a target of miR-27b, ITCH was found to repress cell proliferation and migration. ITCH enhanced the JUNB ubiquitination and degradation, ultimately inhibiting JUNB and IRE1α expressions and restraining wound healing. Collectively, MSC-derived EVs transferring miR-27b can promote cutaneous wound healing via ITCH/JUNB/IRE1α signalling, providing insight with clinical implications.

Cheng S ，Xi Z ，Chen G ，Liu K ，Ma R ，Zhou C ... -  《-》

MSC-secreted TGF-β regulates lipopolysaccharide-stimulated macrophage M2-like polarization via the Akt/FoxO1 pathway.

Liu F ，Qiu H ，Xue M ，Zhang S ，Zhang X ，Xu J ，Chen J ，Yang Y ，Xie J ... -  《Stem Cell Research & Therapy》