Exosomes from human umbilical cord mesenchymal stem cells (hucMSC-Ex) have been suggested as novel nanomaterials for regenerative medicine. Here we explored the roles of hucMSC-Ex through regulating Yes-associated protein (YAP) in renal injury repair by using rat unilateral ureteral obstruction (UUO) models. Our study identified mechanical stress induced YAP nucleus expression and stimulated collagen deposition and interstitial fibrosis in the kidney. Then, infusion with hucMSC-Ex promoted YAP nuclear cytoplasmic shuttling and ameliorated renal fibrosis in UUO model. Interestingly, hucMSC-Ex delivered casein kinase 1δ (CK1δ) and E3 ubiquitin ligase β-TRCP to boost YAP ubiquitination and degradation. Knockdown of CK1δ and β-TRCP in hucMSC decreased the repairing effects of hucMSC-Ex on renal fibrosis. Our results suggest that hucMSC-Ex attenuates renal fibrosis through CK1δ/β-TRCP inhibited YAP activity, unveiling a new mechanism for the therapeutic effects of hucMSC-Ex on tissue injury and offering a potential approach for renal fibrosis treatment.

The administration of cisplatin is limited due to its nephrotoxic side effects, and prevention of this nephrotoxicity of cisplatin is difficult. Mesenchymal stem cell (MSC)-derived exosomes have been implicated as a novel therapeutic approach for tissue injury. In this study, we demonstrated that the pretreatment of human umbilical cord MSC-derived exosomes (hucMSC-Ex) can prevent the development of cisplatin-induced renal toxicity by activation of autophagy in vitro and in vivo.

Our and other groups have discovered that mesenchymal stem cells (MSCs) derived exosomes are a novel therapeutical modality for many diseases. In this study, we summarized a method to extract and purify hucMSCs-exosomes using ultrafiltration and gradient centrifugation in our laboratory and proved that hucMSCs-exosomes prepared according to our procedure were stable and bioactive. Results showed that exosomes derived from hucMSC were 40~100 nm and CD9 and CD81 positive. Functionally, hucMSCs-exosomes promoted cell proliferation and protected against oxidative stress-induced cell apoptosis in vitro by activation of ERK1/2 and p38. Interestingly, UV exposure abrogated the regulatory roles of exosomes under oxidative stress, indicating that hucMSCs-exosomes may regulate cell growth and apoptosis by exosomal shuttle of RNA. Furthermore, cytokine profile analysis revealed that hucMSCs-exosomes contained high dose of IL-6, IL-8, and other cytokines. The established method is practical and efficient, which provides a basis for further evaluating the potential of hucMSCs-exosomes as therapeutic agents.

This study is aimed at investigating whether human umbilical cord mesenchymal stem cell- (hucMSC-) derived exosomes (hucMSC-exosomes) have a protective effect on acute myocardial infarction (AMI). Exosomes were characterized under transmission electron microscopy and the particles of exosomes were further examined through nanoparticle tracking analysis. Exosomes (400 μg protein) were intravenously administrated immediately following ligation of the left anterior descending (LAD) coronary artery in rats. Cardiac function was evaluated by echocardiography and apoptotic cells were counted using TUNEL staining. The cardiac fibrosis was assessed using Masson's trichrome staining. The Ki67 positive cells in ischemic myocardium were determined using immunohistochemistry. The effect of hucMSC-exosomes on blood vessel formation was evaluated through tube formation and migration of human umbilical vein endothelial cells (EA.hy926 cells). The results indicated that ligation of the LAD coronary artery reduced cardiac function and induced cardiomyocyte apoptosis. Administration of hucMSC-exosomes significantly improved cardiac systolic function and reduced cardiac fibrosis. Moreover, hucMSC-exosomes protected myocardial cells from apoptosis and promoted the tube formation and migration of EA.hy926 cells. It is concluded that hucMSC-exosomes improved cardiac systolic function by protecting myocardial cells from apoptosis and promoting angiogenesis. These effects of hucMSC-exosomes might be associated with regulating the expression of Bcl-2 family.

Mesenchymal stem cells (MSCs) can promote tumor growth in a mouse xenograft model, but the exact mechanism remains unclear. In this study, we investigated the effects of bone marrow MSC-derived exosomes (MSC-exosomes) on tumor growth in vitro and in vivo. Our results showed that MSC-exosomes promoted tumor growth in vivo. MSC-exosomes enhanced vascular endothelial growth factor (VEGF) expression in tumor cells by activating extracellular signal-regulated kinase1/2 (ERK1/2) pathway. Inhibition of ERK1/2 activation reserved the increase of VEGF level by MSC-exosomes. Our findings demonstrate a new mechanism through which MSC-exosome-mediated cell-cell interactions may contribute to tumor progression.

Exosomes are extracellular vesicles that mediate cellular communication in health and diseases. Neutrophils could be polarized to a pro-tumor phenotype by tumor. The function of tumor-derived exosomes in neutrophil regulation remains unclear.

Inflammatory bowel disease (IBD) is a group of chronic intestinal inflammation that is a risk factor for many gastrointestinal cancers. Exosomes are gradually gaining attention as an emerging treatment method for IBD due to their important biological characteristics. NF-κB is an important pro-inflammatory transcription factor kept inactive by IκB protein in the cytoplasm by masking the nuclear localization signal of NF-κB. The deterioration of IκB is mainly ubiquitination, and this depends on neddylation.

Exosomes secreted by mesenchymal stem cells (MSCs) have shown repairing effects on several tissue injury diseases. In this study, we aimed to investigate the effects of exosomes released from human umbilical cord mesenchymal stem cells (hucMSCs) on the treatment of dextran sulfate sodium- (DSS-) induced inflammatory bowel disease (IBD) and to explore the underlying mechanism. We found that indocyanine green (ICG) labeled exosomes homed to colon tissues of IBD mice at 12 hours after injection. Exosomes significantly relieved the severity of IBD in mice as hucMSCs. The expression of IL-10 gene was increased while that of TNF-α, IL-1β, IL-6, iNOS, and IL-7 genes was decreased in the colon tissues and spleens of exosomes-treated mice. Furthermore, the infiltration of macrophages into the colon tissues was decreased by exosome treatment in IBD mice. In addition, we provided evidence that in vitro coculture with exosomes inhibited the expression of iNOS and IL-7 in mouse enterocoelia macrophages. Moreover, we found that the expression of IL-7 was higher in the colon tissues of colitis patients than that of healthy controls. Our findings suggest that exosomes from hucMSCs have profound effects on alleviating DSS-induced IBD and may exert their impact through the modulation of IL-7 expression in macrophages.

Human umbilical cord mesenchymal stem cell (hucMSC)-derived exosomes are recognized as novel cell-free therapeutic agents for inflammatory bowel disease (IBD), a condition caused by dysregulated intestinal mucosal immunity. In this event, macrophage pyroptosis, a process of cell death following the activation of NLRP3 (NOD-like receptor family, pyrin domain-containing 3) inflammasomes, is believed to partially account for inflammatory reactions. However, the role of macrophage pyroptosis in the process of hucMSC-derived exosomes alleviating colitis remains unknown. This study aimed at exploring the therapeutic effect and mechanism of hucMSC-derived exosomes on colitis repair.

Mesenchymal stem cells (MSCs) have been increasingly applied into clinical therapy. Exosomes are small (30-100 nm in diameter) membrane vesicles released by different cell types and possess the similar functions with their derived cells. Human umbilical cord MSC-derived exosomes (hucMSC-Ex) play important roles in liver repair. However, the effects and mechanisms of hucMSC-Ex on liver injury development remain elusive. Mouse models of acute and chronic liver injury and liver tumor were induced by carbon tetrachloride (CCl4) injection, followed by administration of hucMSC-Ex via the tail vein. Alleviation of liver injury by hucMSC-Ex was determined. We further explored the production of oxidative stress and apoptosis in the development of liver injury and compared the antioxidant effects of hucMSC-Ex with frequently used hepatic protectant, bifendate (DDB) in liver injury. hucMSC-Ex alleviated CCl4-induced acute liver injury and liver fibrosis and restrained the growth of liver tumors. Decreased oxidative stress and apoptosis were found in hucMSC-Ex-treated mouse models and liver cells. Compared to bifendate (DDB) treatment, hucMSC-Ex presented more distinct antioxidant and hepatoprotective effects. hucMSC-Ex may suppress CCl4-induced liver injury development via antioxidant potentials and could be a more effective antioxidant than DDB in CCl4-induced liver tumor development.

Activated hepatic stellate cells (HSCs) are significant in liver fibrosis. Our past investigations have shown that human umbilical cord mesenchymal stem cells (hucMSCs) and their secreted exosomes (MSC-ex) could alleviate liver fibrosis via restraining HSCs activation. However, the mechanisms underlying the efficacy were not clear. Ferroptosis is a regulatory cell death caused by excessive lipid peroxidation, and it plays a vital role in the occurrence and development of liver fibrosis. In the present study, we aimed to study the proferroptosis effect and mechanism of MSC-ex in HSCs. MSC-ex were collected and purified from human umbilical cord MSCs. Proferroptosis effect of MSC-ex was examined in HSCs line LX-2 and CCl4 induced liver fibrosis in mice. Gene knockdown or overexpression approaches were used to investigate the biofactors in MSC-ex-mediated ferroptosis regulation. Results: MSC-ex could trigger HSCs ferroptosis by promoting ferroptosis-like cell death, ROS formation, mitochondrial dysfunction, Fe2+ release, and lipid peroxidation in human HSCs line LX-2. Glutathione peroxidase 4 (GPX4) is a crucial regulator of ferroptosis. We found that intravenous injection of MSC-ex significantly decreased glutathione peroxidase 4 (GPX4) expression in activated HSCs and collagen deposition in experimental mouse fibrotic livers. Mechanistically, MSC-ex derived BECN1 promoted HSCs ferroptosis by suppressing xCT-driven GPX4 expression. In addition, ferritinophagy and necroptosis might also play a role in MSC-ex-promoted LX-2 cell death. Knockdown of BECN1 in MSC diminished proferroptosis and anti-fibrosis effects of MSC-ex in LX-2 and fibrotic livers. MSC-ex may promote xCT/GPX4 mediated HSCs ferroptosis through the delivery of BECN1 and highlights BECN1 as a potential biofactor for alleviating liver fibrosis.

Mesenchymal stem cells (MSCs) promote tumor growth by differentiating into carcinoma-associated fibroblasts (CAFs) and composing the tumor microenvironment. However, the mechanisms responsible for the transition of MSCs to CAFs are not well understood. Exosomes regulate cellular activities by mediating cell-cell communication. In this study, we aimed to investigate whether cancer cell-derived exosomes were involved in regulating the differentiation of human umbilical cord-derived MSCs (hucMSCs) to CAFs.

Cigarette smoke is a major risk factor for gastric cancer. Exosomes are an important part of intercellular and intra-organ communication systems and can carry circRNA and other components to play a regulatory role in the occurrence and development of gastric cancer. However, it is unclear whether cigarette smoke can affect exosomes and exosomal circRNA to promote the development of gastric cancer. Exosomes secreted by cancer cells promote cancer development by affecting surrounding normal cells. Herein, we aimed to clarify whether the exosomes secreted by cigarette smoke-induced gastric cancer cells can promote the development of gastric cancer by affecting the surrounding gastric mucosal epithelial cells (GES-1). In the present study, we treated gastric cancer cells with cigarette smoke extract for 4 days and demonstrated that cigarette smoke promotes the stemness and EMT of gastric cancer cells and cigarette smoke-induced exosomes promote stemness gene expression, EMT processes and the proliferation of GES-1 cells. We further found that circ0000670 was up-regulated in tissues of gastric cancer patients with smoking history, cigarette smoke-induced gastric cancer cells and their exosomes. Functional assays showed that circ0000670 knockdown inhibited the promoting effects of cigarette smoke-induced exosomes on the stemness and EMT characteristic of GES-1 cells, whereas its overexpression had the opposite effect. In addition, exosomal circ0000670 was found to promote the development of gastric cancer by regulating the Wnt/β-catenin pathway. Our findings indicated that exosomal circ0000670 promotes cigarette smoke-induced gastric cancer development, which might provide a new basis for the treatment of cigarette smoke-related gastric cancer.

Administration of bone marrow mesenchymal stem cells (MSCs) or secreted microvesicles improves recovery from acute kidney injury (AKI). However, the potential roles and mechanisms are not well understood. In the current study, we focused on the protective effect of exosomes derived from human umbilical cord mesenchymal stem cells (hucMSC-ex) on cisplatin-induced nephrotoxicity in vivo and in vitro.

We have previously demonstrated the cardioprotective effects of exosomes derived from mesenchymal stem cells (MSCs). It is well known that the activation of Akt is involved in stem cell-induced cardioprotection. In the present study, we investigated whether exosomes released from Akt-overexpressing MSCs showed a beneficial effect on cardioprotection and angiogenesis. MSCs were collected from human umbilical cord (hucMSCs), and Akt was transfected into hucMSCs (Akt-hucMSCs) by using an adenovirus transfection system. Exosomes were isolated from control hucMSCs (Exo) and Akt-hucMSCs (Akt-Exo). An acute myocardial infarction model was created by ligation of the left anterior decedent coronary artery (LAD) in rats. Various source exosomes (400 µg of protein) were infused via the tail vein immediately after LAD ligation. The cardiac function was evaluated by using echocardiography after different treatments for 1 and 5 weeks, respectively. Endothelial cell proliferation, migration, and tube-like structure formation, as well as chick allantoic membrane assay, were used to evaluate the angiogenetic effects of Akt-Exo. The results indicated that cardiac function was significantly improved in the animals treated with Akt-Exo. In addition, Akt-Exo significantly accelerated endothelial cell proliferation and migration, tube-like structure formation in vitro, and blood vessel formation in vivo. The expression of platelet-derived growth factor D (PDGF-D) was significantly upregulated in Akt-Exo. However, the angiogenesis was abrogated in endothelial cells treated with the exosomes obtained from MSCs transfected with PDGF-D-siRNA. Our studies suggest that exosomes obtained from Akt-modified hucMSCs are more effective in myocardial infarction therapy through promoting angiogenesis. PDGF-D plays an important role in Akt-Exo-mediated angiogenesis. Stem Cells Translational Medicine 2017;6:51-59.

Human umbilical cord-derived mesenchymal stem cells (hucMSCs) are a promising tool for damaged tissues repair, especially for the kidney. However, their efficacy requires improvement. In order to optimize the clinical utility of hucMSCs, we adopted a strategy of treating hucMSCs with 20 μmol/L of resveratrol (Res-hucMSCs), applying it in a cisplatin-induced acute kidney injury model. Interestingly, we found that Res-hucMSCs exhibited a more efficient repairing effect than did hucMSCs. Resveratrol-promoted hucMSCs secreted platelet-derived growth factor-DD (PDGF-DD) into renal tubular cells resulting in downstream phosphorylation of extracellular signal-regulated kinase (ERK), which inhibited renal tubular cells apoptosis. In contrast, PDGF-DD knockdown impaired the renal protection of Res-hucMSCs. In addition, angiogenesis induced by PDGF-DD in endothelial cells was also involved in the renal protection of Res-hucMSCs. The conditioned medium of Res-hucMSCs accelerated proliferation and migration of vascular endothelial cells in vitro and CD31 was in a high-level expression in Res-hucMSCs group in vivo. Nevertheless, the angiogenesis was abrogated when Res-hucMSCs were treated with PDGF-DD siRNA. In conclusion, our findings showed that resveratrol-modified hucMSCs activated ERK pathway in renal tubular cells and promoted angiogenesis in endothelial cells via paracrine PDGF-DD, which could be a novel strategy for enhancing the therapy efficacy of hucMSCs in cisplatin-induced kidney injury.

Human umbilical cord mesenchymal stem cells-derived small extracellular vesicles (hucMSC-sEVs) have been demonstrated as a therapeutic agent to prevent and treat cisplatin-induced acute kidney injury (AKI). However, hucMSC-sEVs still face many problems and challenges in the repair and treatment of tissue injury, including short circulation time, insufficient targeting, and low therapeutic efficacy. Therefore, we constructed engineered hybrid vesicles fused with nanovesicles derived from human neutrophil membranes and hucMSC-sEVs, named neutrophil membrane engineered hucMSC-sEVs (NEX). NEX significantly enhanced the targeting of hucMSC-sEVs to injured kidney tissues, improved the impaired renal function via reducing pro-inflammatory cytokines expression, promoted the proliferation of renal tissue cells, and inhibited renal cell apoptosis in vivo. In addition, NEX enhanced hucMSC-sEVs uptake by NRK52E cells, but inhibited its uptake by RAW264.7 cells. Moreover, administration of NEX reduced cellular oxidative stress and promoted proliferation of NRK52E cells treated with cisplatin in vitro. In summary, our findings indicate that this design of a universal approach enhances the targeting and therapeutic efficacy of hucMSC-sEVs in kidney tissue regeneration, and provides new evidence promoting its clinical application.

Mesenchymal stem cell- (MSC-) derived extracellular vesicles (EVs) serving as delivery system have attracted extensive research interest, especially in cancer therapy. In our previous study, lipocalin-type prostaglandin D2 synthase (L-PGDS) showed inhibitory effects on gastric cancer growth. In this study, we aimed to explore whether MSC-EV-delivered L-PGDS (EVs-L-PGDS) could inhibit gastric cancer progression. EVs-L-PGDS were generated from MSCs transfected with adenovirus encoding L-PGDS. Cell colony-forming, migration, invasion, and flow cytometry assays were used to show the inhibitory effects of EVs on tumor cells in vitro, and the nude mouse subcutaneous tumor model was performed to show the inhibitory effect of EVs on tumor progression in vivo. In vitro, EVs-L-PGDS could be internalized and inhibit the colony-forming, migration, and invasion ability of gastric cancer cell SGC-7901 and promote cell apoptosis. In vivo, EVs-L-PGDS inhibited the tumor growth in nude mouse subcutaneous tumor-bearing model. Compared with the PBS and EVs containing empty vector (EVs-Vector) group, more apoptotic cells and higher L-PGDS expression were detected in tumor tissue of the EVs-L-PGDS treatment group. And these differences are significant. Mechanistically, EVs-L-PGDS reduced the expression of stem cell markers including Oct4, Nanog, and Sox2 and inhibited STAT3 phosphorylation in gastric cancer cell SGC-7901. In conclusion, our results imply that MSC-derived EVs could be utilized as an effective nanovehicle to deliver L-PGDS for gastric cancer treatment, which provides a novel idea for the EV-based cancer therapy.

Mesenchymal stem cells derived from human umbilical cord (hucMSCs) are considered a promising tool for regenerative medicine. circRNAs as newly discovered noncoding RNAs are involved in multiple biological processes. However, little has been known about the function of circRNAs in the proliferation and differentiation of hucMSCs. In this study, we selected several circRNAs expressed in MSCs from circBase and found that CDR1as expression level was markedly significant. We observed that, compared with that of uninduced hucMSCs, the CDR1as expression level of induced hucMSCs decreased with cell induction differentiation. By using siRNA to knock down CDR1as of hucMSCs, we discovered that proliferation was inhibited but the apoptosis increased. In addition, we found that the expression of stemness transcription factors (STFs) was downregulated after CDR1as knockdown and the adipogenesis and osteogenesis potential of hucMSCs was impaired. Our findings suggest that CDR1as takes a part in maintaining proliferation and differentiation of hucMSCs, providing clues for MSC modification and further for stem cell therapy and tissue regeneration.

Circular RNA CDR1as has been demonstrated to participate in various cancer progressions as miRNA sponges. The exact underlying mechanisms of CDR1as on gastric cancer (GC) metastasis remain unknown. Here, we found that CDR1as knockdown facilitated GC cell migration and invasion while its overexpression inhibited the migration and invasion abilities of GC cells in vitro and in vivo. Moreover, epithelial-mesenchymal transition- (EMT-) associated proteins and MMP2 and MMP9 were downregulated by CDR1as. Bioinformatics analysis combined with dual-luciferase reporter gene assays, western blot, RT-qPCR analysis, and functional rescue experiments demonstrated that CDR1as served as a miR-876-5p sponge and upregulated the target gene GNG7 expression to suppress GC metastasis. In summary, our findings indicate that CDR1as suppresses GC metastasis through the CDR1as/miR-876-5p/GNG7 axis.