Bone mesenchymal stem cells derived extracellular vesicles promotes TRAIL-related apoptosis of hepatocellular carcinoma cells via the delivery of microRNA-20a-3p

2020 ◽  
pp. 1-13
Author(s):  
Lu Deng ◽  
Chang Wang ◽  
Chao He ◽  
Li Chen
Keyword(s):  
Hepatocellular Carcinoma ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Conditioned Medium ◽  
Extracellular Vesicles ◽  
Cell Apoptosis ◽  
Bone Mesenchymal Stem Cells ◽  
Hcc Cells

OBJECTIVE: Bone mesenchymal stem cells (BMSCs) have been widely researched in cancer treatment, including hepatocellular carcinoma (HCC). This study intended to discuss the mechanism of miR-20a-3p in BMSCs-extracellular vesicles (EVs) in HCC apoptosis. METHODS: BMSCs were isolated and identified. EVs derived from BMSCs were extracted and identified. After overexpressing or inhibiting miR-20a-3p expression in BMSCs, EVs were extracted and acted on HCC cells and transplanted tumors. HCC cell apoptosis in the treatment of BMSCs-conditioned medium, BMSCs-EVs and/or miR-20a-3p mimic/inhibitor were evaluated, with the detection of levels of TRAIL and TRAIL-related proteins. A functional rescue experiment about c-FLIP was carried out in HCC cells. The target binding relationship between miR-20a-3p and c-FLIP was detected. The subcutaneous tumorigenesis model of mice was established and injected with BMSCs-EVs to estimate the effect of BMSCs-EVs-miR-20a-3p on HCC growth. RESULTS: EVs isolated from BMSCs conditioned medium promoted the apoptosis of HCC cells. After BMSCs-EVs treatment, TRAIL levels, downstream proteins and miR-20a-3p were increased significantly, but the expression of c-FLIP was decreased. miR-20a-3p could target c-FLIP. BMSCs-EVs inhibited the growth of HCC cells, decreased c-FLIP expression, increased TRAIL levels, and promote the of HCC cell apoptosis. BMSCs-EVs with overexpressing miR-20a-3p further enhanced the apoptotic effect of HCC cells in vitro and in vivo. CONCLUSION: BMSCs-EVs-carried miR-20a-3p targets c-FLIP and increases TRAIL levels in HCC cells, thus promoting TRAIL-related apoptosis.

scholarly journals Tenuigenin promotes the osteogenic differentiation of bone mesenchymal stem cells in vitro and in vivo

2016 ◽  
Vol 367 (2) ◽  
pp. 257-267 ◽  
Author(s):  
Hua-ji Jiang ◽  
Xing-gui Tian ◽  
Shou-bin Huang ◽  
Guo-rong Chen ◽  
Min-jun Huang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Osteogenic Differentiation ◽  
Bone Mesenchymal Stem Cells

scholarly journals Adipose-Derived Mesenchymal Stem Cells Migrate and Rescue RPE in the Setting of Oxidative Stress

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Aya Barzelay ◽  
Shira Weisthal Algor ◽  
Anat Niztan ◽  
Sebastian Katz ◽  
Moshe Benhamou ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stem Cells ◽  
Cell Death ◽  
Mesenchymal Stem Cells ◽  
Conditioned Medium ◽  
Early Passage ◽  
Systemic Injection ◽  
Rpe Cells

Oxidative stress leads to the degeneration of retinal pigment epithelial (RPE) and photoreceptor cells. We evaluated the potential of adipose-derived mesenchymal stem cells (ASCs) as a therapeutic tool by studying the migration capacity of ASCs in vitro and their protective effect against RPE cell death under oxidative stress in vitro and in vivo. ASCs exhibited enhanced migration when exposed to conditioned medium of oxidative stressed RPE cells obtained by hydrogen peroxide. Migration-related axis SDF-1/CXCR4 was studied, and upregulation of SDF-1 in stressed RPE and of CXCR4 in ASCs was detected. Moreover, ASCs’ conditioned medium prevented H2O2-induced cell death of RPE cells. Early passage ASCs had high expression level of HGF, low VEGF levels, and unmodulated IL-1β levels, compared to late passage ASCs. Thus, early passage ASCs show the potential to migrate towards damaged RPE cells and protect them in a paracrine manner from cell death induced by oxidative stress. In vivo, mice received systemic injection of NaIO3, and 72 h later, ASCs were transplanted in the subretinal space. Seven days after ASC transplantation, the eyes were enucleated fixed and frozen for immunohistochemical analysis. Under such conditions, ASC-treated mice showed preservation of nuclear layers in the outer nuclear layer and stronger staining of RPE and photoreceptor layer, compared to PBS-treated mice. Taken together, our results indicate that ASCs are able to home in on damaged RPE cells and protect against damage to the RPE and PR layers caused by oxidative stress. These data imply the potential that ASCs have in regenerating RPE under oxidative stress, providing the basis for a therapeutic approach to retinal degeneration diseases related to oxidative stress that could help save the eyesight of millions of people worldwide.

scholarly journals Hypoxia Inducible Factor-1α Overexpression Enhances the Efficacy of Mesenchymal Stem Cells Derived Extracellular Vesicles for Cardiac Repair After Myocardial Infarction

2021 ◽  
Author(s):  
Qingjie Wang ◽  
Le Zhang ◽  
Zhiqin Sun ◽  
Boyu Chi ◽  
Ailin Zou ◽  
...  
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Mesenchymal Stem Cells ◽  
Cardiac Function ◽  
Extracellular Vesicles ◽  
Biological Effects ◽  
Hypoxia Inducible Factor ◽  
Sprague Dawley

Abstract Aims Naturally secreted extracellular vesicles (EVs) play important roles in stem-mediated cardioprotection. This study aimed to investigate the cardioprotective function and underlying mechanisms of EVs derived from HIF-1a engineered mesenchymal stem cells (MSCs) in a rat model of AMI.Methods and Results EVs isolated from HIF-1a engineered MSCs (HIF-1a-EVs) and control MSCs (MSCs-EVs) were prepared. In in vitro experiments, the EVs were incubated with cardiomyocytes and endothelial cells exposed to hypoxia and serum deprivation (H/SD); in in vivo experiments, the EVs were injected in the acutely infarcted hearts of Sprague-Dawley rats. Compared with MSCs-EVs, HIF-1a-EVs significantly inhibited the apoptosis of cardiomyocytes and enhanced angiogenesis of endothelial cells; meanwhile, HIF-1a-EVs also significantly shrunk fibrotic area and strengthened cardiac function in infarcted rats. After treatment with EVs/RGD-biotin hydrogels, we observed longer retention, higher stability in HIF-1a-EVs, and stronger cardiac function in the rats. Quantitative real-time PCR (qRT-PCR) displayed that miRNA-221-3p was highly expressed in HIF-1a-EVs. After miR-221-3p was inhibited in HIF-1a-EVs, the biological effects of HIF-1a EVs on apoptosis and angiogenesis were attenuated.Conclusion EVs released by MSCs with HIF-1a overexpression can promote the angiogenesis of endothelial cells and the apoptosis of cardiomyocytes via upregulating the expression of miR-221-3p. RGD hydrogels can enhance the therapeutic efficacy of HIF-1a engineered MSC-derived EVs.

scholarly journals The Effects of Conditioned Medium Derived from Mesenchymal Stem Cells Cocultured with Hepatocytes on Damaged Hepatocytes and Acute Liver Failure in Rats

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Li Chen ◽  
Jiexin Zhang ◽  
Lu Yang ◽  
Guoying Zhang ◽  
Yingjie Wang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Liver Failure ◽  
Acute Liver Failure ◽  
Conditioned Medium ◽  
Therapeutic Potential ◽  
L02 Cells ◽  
Cells Cultured

Mesenchymal stem cells (MSCs) and hepatocytes are two attractive sources of cell-based therapies for acute liver failure (ALF). The cotransplantation of hepatocytes with MSCs can improve the therapeutic performance for the treatment of ALF. However, the therapeutic potential of conditioned medium (CM) derived from MSCs cocultured with hepatocytes (MSC-H-CM) remains unclear. The purpose of this study was to investigate the effects of MSC-H-CM on damaged hepatocytes in vitro and on D-galactosamine-induced ALF in vivo. D-Galactosamine-treated L02 cells cultured in MSC-H-CM exhibited higher of cell viability and total protein synthesis than L02 cells cultured in MSC-CM, CM derived from hepatocytes (H-CM), MSC-CM + H-CM, or with nonconditioned medium (NCM). Lactate dehydrogenase and aspartate aminotransferase levels were lower in the supernatant of damaged L02 cells cultured in MSC-H-CM than in that of L02 cells cultured in other types of CM. The lowest percentage of apoptotic cells was observed after the MSC-H-CM treatment. When CM was injected into the tail vein of rats with ALF, MSC-H-CM was the most successful at preventing the release of liver injury biomarkers and in promoting the recovery of liver structure. The greatest survival rate 7 days after the first treatment was observed in the MSC-H-CM-treated rats. Our results reveal that the delivery of MSC-H-CM could be a novel strategy for integrating the therapeutic potentials of hepatocytes and MSCs for the treatment of ALF.

scholarly journals The Healing Effects of Conditioned Medium Derived from Mesenchymal Stem Cells on Radiation-Induced Skin Wounds in Rats

2018 ◽  
Vol 28 (1) ◽  
pp. 105-115 ◽  
Author(s):  
JiaYang Sun ◽  
YunFeng Zhang ◽  
XianJi Song ◽  
Jiajing Zhu ◽  
QingSan Zhu
Keyword(s):  
Stem Cells ◽  
Wound Healing ◽  
Mesenchymal Stem Cells ◽  
Conditioned Medium ◽  
Radiation Dermatitis ◽  
Skin Wounds ◽  
Cutaneous Injury ◽  
Radiation Induced

Radioactive dermatitis is caused by the exposure of skin and mucous membranes to radiation fields. The pathogenesis of radioactive dermatitis is complex and difficult to cure. Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) may serve as a promising candidate for the therapy of cutaneous wounds. The aim of this study was to investigate whether a WJ-MSC-derived conditioned medium (MSC-CM) could be used to treat radiation-induced skin wounds in rats using a radiation-induced cutaneous injury model. The present study was designed to examine MSC-CM therapy in the recovery of radiation-induced skin wounds in vitro and in vivo. Firstly, we prepared the MSC-CM and tested the effects of the MSC-CM on human umbilical vein endothelial cell proliferation in vitro. After that, we used a β-ray beam to make skin wounds in rats and tested the effects of MSC-CM on cutaneous wound healing in vivo. Our results indicated that MSC-CM secreted factors that promoted HUVEC proliferation, regeneration of sebaceous glands, and angiogenesis. Importantly, MSC-CM promoted wound healing in excess of the positive control (epidermal growth factor), with no, or smaller, scar formation. In conclusion, MSC-CM significantly accelerated wound closure and enhanced the wound healing quality. MSC-CM has a beneficial therapeutic effect on radiation-induced cutaneous injury skin in rats and in this way MSC-CM may serve as a basis of a novel cell-free therapeutic approach for radiation dermatitis.

scholarly journals Neurobiological Observations of Bone Mesenchymal Stem Cells in vitro and in vivo of Injured Sciatic Nerve in Rabbit

2011 ◽  
Vol 10 (6) ◽  
pp. 686-691 ◽  
Author(s):  
Al-Timmemi Hameed ◽  
R. Ibrahim ◽  
Al-Jashamy Karim ◽  
Abz Zuki ◽  
Ti. Azmi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Sciatic Nerve ◽  
Bone Mesenchymal Stem Cells

Autophagy of umbilical cord mesenchymal stem cells conduces to pro-angiogenic function of conditioned medium

2021 ◽  
Author(s):  
Wenya Wang ◽  
Xiao Li ◽  
Chaochu Cui ◽  
Dongling Liu ◽  
Guotian Yin ◽  
...  
Keyword(s):  
Stem Cells ◽  
Wound Healing ◽  
Mesenchymal Stem Cells ◽  
Conditioned Medium ◽  
Umbilical Cord ◽  
Tube Formation ◽  
Dependent Manner ◽  
And Control

Abstract BackgroundAngiogenesis is a key prerequisite for wound healing. The conditioned medium following culture of umbilical cord mesenchymal stem cells (UCMSCs) has a potential to promote angiogenesis, but the efficacy is very low. Autophagy is an important process in protein recycling and a contributor for cell exocrine, which maybe stimulate the release of cytokines from UCMSCs to the medium and enhance the pro-angiogenic efficacy of the conditioned medium.MethodsAutophagy in UCMSCs was induced by 100 nM, 1 µM and 10 µM rapamycin for 6-hour and then detected by LC-3 immunofluorescence staining. After induction, the cells were washed with PBS for 3 times and cultured in fresh medium without rapamycin for additional 24-hour. And then, the conditioned medium was collected for the following experiments. The angiogenic effects of different groups of conditioned medium were verified by in vitro and in vivo tube formation assays in the matrigel-coated plates and matrigel plaques injected in mouse inguinal areas. Finally, the expressions of angiogenic factors including VEGF, FGF-1, FGF-2, TGF-α, MMP-3, MMP-9, PDGF-α, PDGF-β, HIF-1α and Ang II in the autophagic and control UCMSCs were measured by q-PCR assay.ResultsRapamycin induced autophagy of UCMSCs in a dose dependent manner, but the conditioned medium in 100 nM rapamycin-induced group was with the best pro-angiogenic efficacy. Thus, this group of medium was viewed as the optimal conditioned medium. The in vivo tube formation assay showed that angiogenesis in matrigel plaques injected daily with the optimal conditioned medium was more obvious than that injected with the control conditioned medium. Further, the expressions of VEGF, FGF-2, PDGF-α, MMP-9 and HIF-1α were markedly increased in UCMSCs following treatment with 100 nM rapamycin.ConclusionAppropriate autophagy improves the pro-angiogenic efficacy of the conditioned medium, which might be utilized to optimize the applications of UCMSCs-derived conditioned medium in wound healing and tissue repair.Trial registrationNot applicable.

scholarly journals Synergistic Anti-Proliferation and Anti-Angiogenesis Effects of Sevacizumab on Hepatocellular Carcinoma Cells in Combination with Chemotherapy

2021 ◽  
Author(s):  
Lin Liu ◽  
Shukui Qin ◽  
Zhengcao Liu ◽  
Yinghui Zheng ◽  
Li Han ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Endothelial Cell ◽  
Combination Therapy ◽  
Blood Vessels ◽  
Signaling Pathway ◽  
Cell Apoptosis ◽  
Tube Formation ◽  
Hcc Cells

Abstract Background We previously found that (via inhibition of the VEGF/VEGFR signaling pathway) ckgroundSevacizumab (Sev), an anti-VEGF monoclonal antibody, was proven to have a superior inhibitory effect than bevacizumab (Bev) on the growth of hepatocellular carcinoma (HCC) cells. This study aimed to explore the anti-proliferation and anti-angiogenic effects of Sev on HCC cells in combination with oxaliplatin (OXA) or 5-fluorouracil (5-Fu). Methods In vitro HCC/endothelial cell growth in different concentration drug was analyzed by MTT assay, DAPI and flow cytometry assay. Cell scratch test, transwell assay, tube formation assay, zebrafish assay, and CAM assay were used to investigate anti-angiogenesis effect of drugs. VEGF mRNA relative expression changes of zebrafish embryos were detected by RT-PCR.A fluorescence imaging system was applied to observe the growth of transplantation tumor and blood vessels in HCC mouse xenografts. Tissue H-E staining and TEM detection were used to detect the tumor cell apoptosis. MVD was detected by immunohistochemical analysis of CD31. ELISA and western-blots were used to detect the cell VEGF/VEGFR pathway and its downstream target activity both in vitro and in vivo. Results In vitro results showed that the combination of Sev with OXA/5-Fu can synergistically inhibit the proliferation of HCC and endothelial cells. Compared with the corresponding monotherapy group, combination therapy showed a stronger effect on inducing apoptosis and cell cycle arrest. In vivo findings revealed that Sev in combination with chemotherapy can synergistically inhibit tumor growth by inducing cell apoptosis in nude mice with HCC xenografts. In addition, the wound healing and transwell migration assays demonstrated that Sev can inhibit the migration of endothelial cell lines in combination with chemotherapy. In vitro tube formation test, zebrafish and chicken embryonic-angiogenic assay, immunohistochemistry, and in vivo fluorescence imaging consistently verified that Sev and OXA/5-Fu can synergistically inhibit the growth of blood vessels, and the underlying mechanism may be associated with inhibition of the VEGF/VEGFR signaling pathway. Conclusions The combination of Sev and chemotherapy is associated with the inhibition of HCC growth and tumor angiogenesis, which may provide a significant biological rationale for evaluating the efficacy of Sev and OXA/5-Fu combination therapy on HCC.

scholarly journals Nanoscale Modification of Titanium Implants Improves Behaviors of Bone Mesenchymal Stem Cells and Osteogenesis In Vivo

2022 ◽  
Vol 2022 ◽  
pp. 1-13
Author(s):  
Huangdi Li ◽  
Jinghui Huang ◽  
Yanpeng Wang ◽  
Ziyuan Chen ◽  
Xing Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Surface Characteristics ◽  
Titanium Implants ◽  
Bone Mesenchymal Stem Cells ◽  
H2o2 Treatment ◽  
Cell Behaviors ◽  
Rat Bone

The surficial micro/nanotopography and physiochemical properties of titanium implants are essential for osteogenesis. However, these surface characters’ influence on stem cell behaviors and osteogenesis is still not fully understood. In this study, titanium implants with different surface roughness, nanostructure, and wettability were fabricated by further nanoscale modification of sandblasted and acid-etched titanium (SLA: sandblasted and acid-etched) by H2O2 treatment (hSLAs: H2O2 treated SLA). The rat bone mesenchymal stem cells (rBMSCs: rat bone mesenchymal stem cells) are cultured on SLA and hSLA surfaces, and the cell behaviors of attachment, spreading, proliferation, and osteogenic differentiation are further analyzed. Measurements of surface characteristics show hSLA surface is equipped with nanoscale pores on microcavities and appeared to be hydrophilic. In vitro cell studies demonstrated that the hSLA titanium significantly enhances cell response to attachment, spreading, and proliferation. The hSLAs with proper degree of H2O2 etching (h1SLA: treating SLA with H2O2 for 1 hour) harvest the best improvement of differentiation of rBMSCs. Finally, the osteogenesis in beagle dogs was tested, and the h1SLA implants perform much better bone formation than SLA implants. These results indicate that the nanoscale modification of SLA titanium surface endowing nanostructures, roughness, and wettability could significantly improve the behaviors of bone mesenchymal stem cells and osteogenesis on the scaffold surface. These nanoscale modified SLA titanium scaffolds, fabricated in our study with enhanced cell affinity and osteogenesis, had great potential for implant dentistry.

scholarly journals Exosomal microRNA-15a from mesenchymal stem cells impedes hepatocellular carcinoma progression via downregulation of SALL4

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yu-Shui Ma ◽  
Ji-Bin Liu ◽  
Lan Lin ◽  
Hui Zhang ◽  
Jian-Jun Wu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Luciferase Reporter ◽  
Dismal Prognosis ◽  
Huh7 Cells ◽  
Gene Assay ◽  
The Impact ◽  
Hcc Cells

AbstractHepatocellular carcinoma (HCC) is a heterogeneous tumor with an increased incidence worldwide accompanied by high mortality and dismal prognosis. Emerging evidence indicates that mesenchymal stem cells (MSCs)-derived exosomes possess protective effects against various human diseases by transporting microRNAs (miRNAs or miRs). We aimed to explore the role of exosomal miR-15a derived from MSCs and its related mechanisms in HCC. Exosomes were isolated from transduced MSCs and co-incubated with Hep3B and Huh7 cells. miR-15a expression was examined by RT-qPCR in HCC cells, MSCs, and secreted exosomes. CCK-8, transwell, and flow cytometry were used to detect the effects of miR-15a or spalt-like transcription factor 4 (SALL4) on cell proliferative, migrating, invasive, and apoptotic properties. A dual-luciferase reporter gene assay was performed to validate the predicted targeting relationship of miR-15a with SALL4. Finally, in vivo experiments in nude mice were implemented to assess the impact of exosome-delivered miR-15a on HCC. The exosomes from MSCs restrained HCC cell proliferative, migrating, and invasive potentials, and accelerated their apoptosis. miR-15a was expressed at low levels in HCC cells and could bind to SALL4, thus curtailing the proliferative, migrating, and invasive abilities of HCC cells. Exosomes successfully delivered miR-15a to HCC cells. Exosomal miR-15a depressed tumorigenicity and metastasis of HCC tumors in vivo. Overall, exosomal miR-15a from MSCs can downregulate SALL4 expression and thereby retard HCC development.

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