scholarly journals Very Long-Chain C24:1 Ceramide Is Increased in Serum Extracellular Vesicles with Aging and Can Induce Senescence in Bone-Derived Mesenchymal Stem Cells

Cells ◽  
2019 ◽  
Vol 8 (1) ◽  
pp. 37 ◽  
Author(s):  
Andrew Khayrullin ◽  
Priyanka Krishnan ◽  
Luis Martinez-Nater ◽  
Bharati Mendhe ◽  
Sadanand Fulzele ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Extracellular Vesicles ◽  
Cardiovascular Health ◽  
Rhesus Macaques ◽  
Cell Communication ◽  
Size Exclusion ◽  
Target Cells ◽  
Serum Samples

Extracellular vesicles (EVs), including exosomes and microvesicles, function in cell-to-cell communication through delivery of proteins, lipids and microRNAs to target cells via endocytosis and membrane fusion. These vesicles are enriched in ceramide, a sphingolipid associated with the promotion of cell senescence and apoptosis. We investigated the ceramide profile of serum exosomes from young (24–40 yrs.) and older (75–90 yrs.) women and young (6–10 yrs.) and older (25–30 yrs.) rhesus macaques to define the role of circulating ceramides in the aging process. EVs were isolated using size-exclusion chromatography. Proteomic analysis was used to validate known exosome markers from Exocarta and nanoparticle tracking analysis used to characterize particle size and concentration. Specific ceramide species were identified with lipidomic analysis. Results show a significant increase in the average amount of C24:1 ceramide in EVs from older women (15.4 pmol/sample) compared to those from younger women (3.8 pmol/sample). Results were similar in non-human primate serum samples with increased amounts of C24:1 ceramide (9.3 pmol/sample) in older monkeys compared to the younger monkeys (1.8 pmol/sample). In vitro studies showed that primary bone-derived mesenchymal stem cells (BMSCs) readily endocytose serum EVs, and serum EVs loaded with C24:1 ceramide can induce BMSC senescence. Elevated ceramide levels have been associated with poor cardiovascular health and memory impairment in older adults. Our data suggest that circulating EVs carrying C24:1 ceramide may contribute directly to cell non-autonomous aging.

scholarly journals miR-330–5p in Small Extracellular Vesicles Derived From Plastrum testudinis-Preconditioned Bone Mesenchymal Stem Cells Attenuates Osteogenesis by Modulating Wnt/β-Catenin Signaling

2021 ◽  
Vol 8 ◽  
Author(s):  
Xiaoyun Li ◽  
Yan Cui ◽  
Qing Lin ◽  
Panpan Wang ◽  
Rumeng Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Extracellular Vesicles ◽  
High Throughput Sequencing ◽  
Animal Experiments ◽  
Ovariectomized Rats ◽  
Luciferase Reporter ◽  
Target Cells ◽  
Bone Mesenchymal Stem Cells

The bone microenvironment is crucial for the growth and development of different types of osteocytes. Small extracellular vesicles (sEVs) secreted by bone mesenchymal stem cells are delivered to target cells where their contents regulate biological functions. Here, we evaluated the osteogenic effects and mechanism of sEVs derived from Plastrum testudinis-preconditioned bone mesenchymal stem cells (PT-sEV). The osteogenic effects of PT-sEV were evaluated by the differentiation of osteoblasts and the alternation of bone quality and quantity in ovariectomized rats. The specific mechanism was explored by high-throughput sequencing and verified by transfection with the corresponding miRNA mimic and inhibitor. RNA-sequence identified a unique enrichment of a set of miRNAs in PT-sEV compared with sEVs derived from untreated BMSCs. Overexpression or inhibition in vitro indicated that the osteogenic inducing potential of sEVs was mainly attributable to miR-330-5p, one of the most dramatically downregulated miRNAs in the PT-sEV fraction. Dual luciferase reporter assays showed that miR-330-5p negatively regulated osteogenesis by directly binding to the 3′ untranslated region of Tnc. Additional experiments showed that Tnc regulated Wnt/β-catenin signaling, and rescue experiment showed that miR-330-5p could restore β-catenin expression; additionally, animal experiments indicated that Wnt signaling was inactivated in the ovariectomized rats. These data demonstrated the regenerative potential of PT-sEV, which induced osteogenic differentiation of pre-osteoblasts, leading to bone formation. This process was achieved by delivering miR-330-5p, which regulated Tnc to control Wnt/β-catenin signaling.

scholarly journals Extracellular vesicles from human mesenchymal stem cells expedite chondrogenesis in 3D human degenerative disc cell cultures

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Daphne Hingert ◽  
Karin Ekström ◽  
Jonathan Aldridge ◽  
Rosella Crescitelli ◽  
Helena Brisby
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
Mesenchymal Stem Cells ◽  
Extracellular Vesicles ◽  
Treatment Strategies ◽  
Human Mesenchymal Stem Cells ◽  
Invasive Treatment ◽  
Disc Cells ◽  
Apoptotic Activity

Abstract Background Extracellular vesicles (EVs) from human mesenchymal stem cells (hMSCs) are known to be mediators of intercellular communication and have been suggested as possible therapeutic agents in many diseases. Their potential use in intervertebral disc (IVD) degeneration associated with low back pain (LBP) is yet to be explored. Since LBP affects more than 85% of the western population resulting in high socioeconomic consequences, there is a demand for exploring new and possibly mini-invasive treatment alternatives. In this study, the effect of hMSC-derived small EVs (sEVs) on degenerated disc cells (DCs) isolated from patients with degenerative discs and chronic LBP was investigated in a 3D in vitro model. Methods hMSCs were isolated from bone marrow aspirate, and EVs were isolated from conditioned media of the hMSCs by differential centrifugation and filtration. 3D pellet cultures of DCs were stimulated with the sEVs at 5 × 1010 vesicles/ml concentration for 28 days and compared to control. The pellets were harvested at days 7, 14, and 28 and evaluated for cell proliferation, viability, ECM production, apoptotic activity, chondrogenesis, and cytokine secretions. Results The findings demonstrated that treatment with sEVs from hMSCs resulted in more than 50% increase in cell proliferation and decrease in cellular apoptosis in degenerated DCs from this patient group. ECM production was also observed as early as in day 7 and was more than three times higher in the sEV-treated DC pellets compared to control cultures. Further, sEV treatment suppressed secretion of MMP-1 in the DCs. Conclusion hMSC-derived sEVs improved cell viability and expedited chondrogenesis in DCs from degenerated IVDs. These findings open up for new tissue regeneration treatment strategies to be developed for degenerative disorders of the spine.

scholarly journals Human mesenchymal stem cells derived from induced pluripotent stem cells down-regulate NK-cell cytolytic machinery

Blood ◽  
2011 ◽  
Vol 118 (12) ◽  
pp. 3254-3262 ◽  
Author(s):  
Massimo Giuliani ◽  
Noufissa Oudrhiri ◽  
Zaeem M. Noman ◽  
Amelia Vernochet ◽  
Salem Chouaib ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Nk Cell ◽  
Embryonic Stem ◽  
Attractive Alternative ◽  
Target Cells ◽  
Alternative Source ◽  
Activation Markers ◽  
Induced Pluripotent

Abstract A major issue in immunosuppressive biotherapy is the use of mesenchymal stem cells (MSCs) that harbor regulatory capacity. However, currently used bone marrow-derived MSCs (BM-MSCs) are short-lived and cannot assure long lasting immunoregulatory function both in vitro and in vivo. Consequently, we have generated MSCs from human induced pluripotent stem (IPS-MSCs) cells that share similar properties with embryonic stem cells (ES-MSCs). Herein, we compared the immunoregulatory properties of ES/IPS-MSCs with those of BM-MSCs and showed, for the first time, that IPS-derived MSCs display remarkable inhibition of NK-cell proliferation and cytolytic function in a similar way to ES-MSCs. Both MSCs disrupt NK-cell cytolytic machinery in the same fashion that BM-MSCs, by down-regulating the expression of different activation markers and ERK1/2 signaling, leading to an impairment to form immunologic synapses with target cells and, therefore, secretion of cytotoxic granules. In addition, they are more resistant than adult BM-MSCs to preactivated NK cells. IPS-MSCs could represent an attractive alternative source of immunoregulatory cells, and their capacity to impair NK-cell cytotoxicity constitutes a complex mechanism to prevent allograft rejection.

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 Higher Chondrogenic Potential of Extracellular Vesicles Derived from Mesenchymal Stem Cells Compared to Chondrocytes-EVs In Vitro

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Maryam Hosseinzadeh ◽  
Amir Kamali ◽  
Samaneh Hosseini ◽  
Mohamadreza Baghaban Eslaminejad
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Extracellular Vesicles ◽  
Surface Marker ◽  
Cellular Processes ◽  
Surface Marker Expression ◽  
Chondrogenic Potential ◽  
Cell Sources ◽  
Rabbit Bone

The inability of cartilage to self-repair necessitates an effective therapeutic approach to restore damaged tissues. Extracellular vesicles (EVs) are attractive options because of their roles in cellular communication and tissue repair where they regulate the cellular processes of proliferation, differentiation, and recruitment. However, it is a challenge to determine the relevant cell sources for isolation of EVs with high chondrogenic potential. The current study aims to evaluate the chondrogenic potential of EVs derived from chondrocytes (Cho-EV) and mesenchymal stem cells (MSC-EV). The EVs were separately isolated from conditioned media of both rabbit bone marrow MSCs and chondrocyte cultures. The isolated vesicles were assessed in terms of size, morphology, and surface marker expression. The chondrogenic potential of MSCs in the presence of different concentrations of EVs (50, 100, and 150 μg/ml) was evaluated during 21 days, and chondrogenic surface marker expressions were checked by qRT-PCR and histologic assays. The extracted vesicles had a spherical morphology and a size of 44.25 ± 8.89  nm for Cho-EVs and 112.1 ± 10.10  nm for MSC-EVs. Both groups expressed the EV-specific surface markers CD9 and CD81. Higher expression of chondrogenic specified markers, especially collagen type II (COL II), and secretion of glycosaminoglycans (GAGs) and proteoglycans were observed in MSCs treated with 50 and 100 μg/ml MSC-EVs compared to the Cho-EVs. The results from the use of EVs, particularly MSC-EVs, with high chondrogenic ability will provide a basis for developing therapeutic agents for cartilage repair.

scholarly journals Extracellular vesicles from human mesenchymal stem cells expedite chondrogenesis in 3D human degenerative disc cell cultures

2020 ◽  
Author(s):  
Daphne Hingert ◽  
Karin Ekström ◽  
Jonathan Aldridge ◽  
Rosella Crescitelli ◽  
Helena Brisby
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
Mesenchymal Stem Cells ◽  
Extracellular Vesicles ◽  
Treatment Strategies ◽  
Human Mesenchymal Stem Cells ◽  
Invasive Treatment ◽  
Disc Cells ◽  
Apoptotic Activity

Abstract Background: Extracellular vesicles (EVs) from human mesenchymal stem cells (hMSCs) are known to be mediators of intercellular communication and has been suggested as possible therapeutic agents in many diseases. Their potential use in intervertebral disc (IVD) degeneration associated with low back pain (LBP) is yet to be explored. Since LBP affects more than 85% of the western population resulting in high socioeconomic consequences there is a demand for exploring new and possibly mini-invasive treatment alternatives. In this study, the effect of hMSCs derived small EVs (sEVs) on degenerated disc cells (DCs) isolated from patients with degenerative discs and chronic LBP was investigated in a 3D in vitro model. Methods: hMSCs were isolated from bone marrow aspirate and EVs were isolated from conditioned media of the hMSCs by differential centrifugation and filtration. 3D pellet cultures of DCs were stimulated with the EVs at 5x1010 vesicles/mL concentration for 28 days and compared to control. The pellets were harvested at day 7, 14, and 28 and evaluated for cell proliferation, viability, ECM production, apoptotic activity, chondrogenesis and cytokine secretions.Results: The findings demonstrated that treatment with sEVs from hMSCs resulted in more than 50% increase in cell proliferation and decrease in cellular apoptosis in degenerated DCs from this patient group. ECM production was also observed as early as in day 7 and was more than three times higher in the sEVs treated DC pellets compared to control cultures. Further, sEVs treatment suppressed secretion of MMP-1 in the DCs. Conclusion: hMSC derived sEVs improved cell viability and expedited chondrogenesis in DCs from degenerated IVDs. These findings open up for new tissue regeneration treatment strategies to be developed for degenerative disorders of the spine.

scholarly journals Differential Effects of Extracellular Vesicles of Lineage-Specific Human Pluripotent Stem Cells on the Cellular Behaviors of Isogenic Cortical Spheroids

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 993 ◽  
Author(s):  
Mark Marzano ◽  
Julie Bejoy ◽  
Mujeeb R. Cheerathodi ◽  
Li Sun ◽  
Sara B. York ◽  
...  
Keyword(s):  
Stem Cells ◽  
Extracellular Vesicles ◽  
Pluripotent Stem Cells ◽  
Physiological State ◽  
Cell Communication ◽  
Biological Properties ◽  
Cardiac Cells ◽  
Paracrine Signaling ◽  
Average Size

Extracellular vesicles (EVs) contribute to a variety of signaling processes and the overall physiological and pathological states of stem cells and tissues. Human induced pluripotent stem cells (hiPSCs) have unique characteristics that can mimic embryonic tissue development. There is growing interest in the use of EVs derived from hiPSCs as therapeutics, biomarkers, and drug delivery vehicles. However, little is known about the characteristics of EVs secreted by hiPSCs and paracrine signaling during tissue morphogenesis and lineage specification. Methods: In this study, the physical and biological properties of EVs isolated from hiPSC-derived neural progenitors (ectoderm), hiPSC-derived cardiac cells (mesoderm), and the undifferentiated hiPSCs (healthy iPSK3 and Alzheimer’s-associated SY-UBH lines) were analyzed. Results: Nanoparticle tracking analysis and electron microscopy results indicate that hiPSC-derived EVs have an average size of 100–250 nm. Immunoblot analyses confirmed the enrichment of exosomal markers Alix, CD63, TSG101, and Hsc70 in the purified EV preparations. MicroRNAs including miR-133, miR-155, miR-221, and miR-34a were differently expressed in the EVs isolated from distinct hiPSC lineages. Treatment of cortical spheroids with hiPSC-EVs in vitro resulted in enhanced cell proliferation (indicated by BrdU+ cells) and axonal growth (indicated by β-tubulin III staining). Furthermore, hiPSC-derived EVs exhibited neural protective abilities in Aβ42 oligomer-treated cultures, enhancing cell viability and reducing oxidative stress. Our results demonstrate that the paracrine signaling provided by tissue context-dependent EVs derived from hiPSCs elicit distinct responses to impact the physiological state of cortical spheroids. Overall, this study advances our understanding of cell‒cell communication in the stem cell microenvironment and provides possible therapeutic options for treating neural degeneration.

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 Mesenchymal Stem Cell-Derived Extracellular Vesicles: Roles in Tumor Growth, Progression, and Drug Resistance

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Xiaoyan Zhang ◽  
Huaijun Tu ◽  
Yazhi Yang ◽  
Lijun Fang ◽  
Qiong Wu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Tumor Growth ◽  
Extracellular Vesicles ◽  
Messenger Rna ◽  
Drug Response ◽  
Therapeutic Potential ◽  
Cell Communication ◽  
Malignant Diseases ◽  
Tumor Diseases

Mesenchymal stem cells (MSCs) are ubiquitously present in many tissues. Due to their unique advantages, MSCs have been widely employed in clinical studies. Emerging evidences indicate that MSCs can also migrate to the tumor surrounding stroma and exert complex effects on tumor growth and progression. However, the effect of MSCs on tumor growth is still a matter of debate. Several studies have shown that MSCs could favor tumor growth. On the contrary, other groups have demonstrated that MSCs suppressed tumor progression. Extracellular vesicles have emerged as a new mechanism of cell-to-cell communication in the development of tumor diseases. MSCs-derived extracellular vesicles (MSC-EVs) could mimic the effects of the mesenchymal stem cells from which they originate. Different studies have reported that MSC-EVs may exert various effects on the growth, metastasis, and drug response of different tumor cells by transferring proteins, messenger RNA, and microRNA to recipient cells. In the present review, we summarize the components of MSC-EVs and discuss the roles of MSC-EVs in different malignant diseases, including the related mechanisms that may account for their therapeutic potential. MSC-EVs open up a promising opportunity in the treatment of cancer with increased efficacy.

scholarly journals Extracellular Vesicles: A New Prospective in Crosstalk between Microenvironment and Stem Cells in Hematological Malignancies

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Ilaria Laurenzana ◽  
Daniela Lamorte ◽  
Stefania Trino ◽  
Luciana De Luca ◽  
Concetta Ambrosino ◽  
...  
Keyword(s):  
Stem Cells ◽  
Extracellular Vesicles ◽  
Hematological Malignancies ◽  
Cell Communication ◽  
Target Cells ◽  
Neoplastic Cells ◽  
Hematopoietic Stem ◽  
Bm Niche ◽  
Bidirectional Interactions

The bone marrow (BM) microenvironment in hematological malignancies (HMs) comprises heterogeneous populations of neoplastic and nonneoplastic cells. Cancer stem cells (CSCs), neoplastic cells, hematopoietic stem cells (HSCs), and mesenchymal stromal/stem cells (MSCs) are all components of this microenvironment. CSCs are the HM initiators and are associated with neoplastic growth and drug resistance, while HSCs are able to reconstitute the entire hematopoietic system; finally, MSCs actively support hematopoiesis. In some HMs, CSCs and neoplastic cells compromise the normal development of HSCs and perturb BM-MSCs. In response, “reprogrammed” MSCs generate a favorable environment to support neoplastic cells. Extracellular vesicles (EVs) are an important cell-to-cell communication type in physiological and pathological conditions. In particular, in HMs, EV secretion participates to unidirectional and bidirectional interactions between neoplastic cells and BM cells. The transfer of EV molecular cargo triggers different responses in target cells; in particular, malignant EVs modify the BM environment in favor of neoplastic cells at the expense of normal HSCs, by interfering with antineoplastic immunity and participating in resistance to treatment. Here, we review the role of EVs in BM cell communication in physiological conditions and in HMs, focusing on the effects of BM niche EVs on HSCs and MSCs.

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