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Mesenchymal stem cell-derived microvesicles protect against acute tubular injury.

ABSTRACT: Administration of mesenchymal stem cells (MSCs) improves the recovery from acute kidney injury (AKI). The mechanism may involve paracrine factors promoting proliferation of surviving intrinsic epithelial cells, but these factors remain unknown. In the current study, we found that microvesicles derived from human bone marrow MSCs stimulated proliferation in vitro and conferred resistance of tubular epithelial cells to apoptosis. The biologic action of microvesicles required their CD44- and beta1-integrin-dependent incorporation into tubular cells. In vivo, microvesicles accelerated the morphologic and functional recovery of glycerol-induced AKI in SCID mice by inducing proliferation of tubular cells. The effect of microvesicles on the recovery of AKI was similar to the effect of human MSCs. RNase abolished the aforementioned effects of microvesicles in vitro and in vivo, suggesting RNA-dependent biologic effects. Microarray analysis and quantitative real time PCR of microvesicle-RNA extracts indicate that microvesicles shuttle a specific subset of cellular mRNA, such as mRNAs associated with the mesenchymal phenotype and with control of transcription, proliferation, and immunoregulation. These results suggest that microvesicles derived from MSCs may activate a proliferative program in surviving tubular cells after injury via a horizontal transfer of mRNA.

SUBMITTER: Bruno S

PROVIDER: S-EPMC2676194 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Microvesicles derived from human mesenchymal stem cells protect against acute tubular injury

Project description:Administration of exogenous mesenchymal stem cells (MSCs) has been shown to improve the recovery from acute kidney injury (AKI). It has been suggested that the beneficial effect of MSCs is related to the paracrine release of factors favouring proliferation of intrinsic epithelial cells survived to injury rather than to their trans-differentiation. However the factors involved remain to be determined. In the present study we demonstrated that microvesicles (MVs) derived from human bone marrow MSCs are able to stimulate in vitro proliferation and apoptosis resistance of tubular epithelial cells (TEC). In addition, MVs were found to accelerate in vivo the morphological and functional recovery of glycerol induced AKI in SCID mice by inducing TEC proliferation. The effect of MVs on the recovery of AKI was comparable to that of human MSC treatment. In vitro we found that the CD44 and beta1-integrin-dependent incorporation of MVs in TEC was required for their biological action. However, despite their internalization, RNase-treated MVs failed to induce in vitro apoptosis resistance and TEC proliferation, and in vivo recovery from AKI, suggesting an RNA-dependent biological effect. Microarray analysis and quantitative RT-PCR of MV-RNA extract indicated that MVs were shuttling a specific subset of cellular mRNA, such as mRNA associated with the mesenchymal differentiative phenotype and with several cell functions involved in the control of transcription, proliferation, apoptosis and cell immune regulation. These results suggest that MVs derived from MSCs may activate a proliferative program in TEC survived to injury in AKI by an horizontal transfer of mRNA.

2009-01-20 | GSE12243 | GEO

Extracellular vesicles from bone marrow-derived mesenchymal stem cells protect against murine hepatic ischemia/reperfusion injury.

Project description:Hepatic ischemia/reperfusion injury (IRI) and associated inflammation contributes to liver dysfunction and complications after liver surgery and transplantation. Mesenchymal stem cells (MSCs) have been reported to reduce hepatic IRI because of their reparative immunomodulatory effects in injured tissues. Recent studies have highlighted beneficial effects of extracellular vesicles from mesenchymal stem cells (MSC-EV) on tissue injury. The effects of systemically administered mouse bone marrow-derived MSC-EV were evaluated in an experimental murine model of hepatic IRI induced by cross-clamping the hepatic artery and portal vein for 90 minutes followed by reperfusion for periods of up to 6 hours. Compared with controls, intravenous administration of MSC-EV 30 minutes prior to IRI dramatically reduced the extent of tissue necrosis, decreased caspase 3-positive and apoptotic cells, and reduced serum aminotransferase levels. MSC-EV increased hepatic messenger RNA (mRNA) expression of NACHT, LRR, and PYD domains-containing protein 12, and the chemokine (C-X-C motif) ligand 1, and reduced mRNA expression of several inflammatory cytokines such as interleukin 6 during IRI. MSC-EV increased cell viability and suppressed both oxidative injury and nuclear factor kappa B activity in murine hepatocytes in vitro. In conclusion, the administration of extracellular vesicles derived from bone marrow-derived MSCs may ameliorate hepatic IRI by reducing hepatic injury through modulation of the inflammatory response.Liver Transplantation 23 791-803 2017 AASLD.

| S-EPMC5495137 | biostudies-literature

Gene-modified mesenchymal stem cells protect against radiation-induced lung injury.

Project description:Radiation-induced lung injury (RILI) presents a common and major obstacle in the radiotherapy of thoracic cancers. The aim of this study was to examine whether RILI could be alleviated by mesenchymal stem cells (MSCs) expressing soluble transforming growth factor-? (TGF-?) type II receptor via an adenovirus (Ad-sT?R). Here, we systemically administered male MSCs into female mice challenged with thoracic irradiation. The data showed that either MSCs or Ad-sT?R transduced MSCs (Ad-sT?R-MSCs) specifically migrated into radiation-injured lung. Ad-sT?R-MSCs obviously alleviated lung injury, as reflected by survival and histopathology data, as well as the assays of malondialdehyde (MDA), hydroxyproline, plasma cytokines, and the expression of connective tissue growth factor (CTGF) and ?-smooth muscle actin (?-SMA). Furthermore, MSCs and Ad-sT?R-MSCs could adopt the characteristics of alveolar type II (ATII) cells. However, the MSCs levels in the lungs were relatively low to account for the noted therapeutic effects, suggesting the presence of other mechanisms. In vivo, MSCs-conditioned medium (MSCs CM) significantly attenuated RILI. In vitro, MSCs CM protected ATII cells against radiation-induced apoptosis and DNA damage, and modulated the inflammatory response, indicating the beneficial effects of MSCs are largely due to its paracrine activity. Our results provide a novel insight for RILI therapy that currently lack efficient treatments.

| S-EPMC3594026 | biostudies-literature

Human mesenchymal stem cell microvesicles for treatment of Escherichia coli endotoxin-induced acute lung injury in mice.

Project description:We previously found that human mesenchymal stem cells (MSC) or its conditioned medium restored lung protein permeability and reduced alveolar inflammation following Escherichia coli endotoxin-induced acute lung injury (ALI) in an ex vivo perfused human lung in part through the secretion of soluble factors such as keratinocyte growth factor (KGF). Recently, MSC were found to release microvesicles (MVs) that were biologically active because of the presence of mRNA or miRNA with reparative properties. MVs are circular fragments of membrane released from the endosomal compartment as exosomes or shed from the surface membranes. These studies were designed to determine if MVs released by human bone marrow derived MSCs would be effective in restoring lung protein permeability and reducing inflammation in E. coli endotoxin-induced ALI in C57BL/6 mice. The intratracheal instillation of MVs improved several indices of ALI at 48 hours. Compared to endotoxin-injured mice, MVs reduced extravascular lung water by 43% and reduced total protein levels in the bronchoalveolar lavage (BAL) fluid by 35%, demonstrating a reduction in pulmonary edema and lung protein permeability. MVs also reduced the influx of neutrophils and macrophage inflammatory protein-2 levels in the BAL fluid by 73% and 49%, respectively, demonstrating a reduction in inflammation. KGF siRNA-pretreatment of MSC partially eliminated the therapeutic effects of MVs released by MSCs, suggesting that KGF protein expression was important for the underlying mechanism. In summary, human MSC-derived MVs were therapeutically effective following E. coli endotoxin-induced ALI in mice in part through the expression of KGF mRNA in the injured alveolus.

| S-EPMC3947321 | biostudies-literature

Mesenchymal Stem Cell Induced Foxp3(+) Tregs Suppress Effector T Cells and Protect against Retinal Ischemic Injury.

Project description:Mesenchymal stem/stromal cells (MSC) are well known for immunomodulation; however, the mechanisms involved in their benefits in the ischemic retina are unknown. This study tested the hypothesis that MSC induces upregulation of transcription factor forkhead box protein P3 (Foxp3) in T cells to elicit immune modulation, and thus, protect against retinal damage. Induced MSCs (iMSCs) were generated by differentiating the induced pluripotent stem cells (iPSC) derived from urinary epithelial cells through a noninsertional reprogramming approach. In in-vitro cultures, iMSC transferred mitochondria to immune cells via F-actin nanotubes significantly increased oxygen consumption rate (OCR) for basal respiration and ATP production, suppressed effector T cells, and promoted differentiation of CD4+CD25+ T regulatory cells (Tregs) in coculture with mouse splenocytes. In in-vivo studies, iMSCs transplanted in ischemia-reperfusion (I/R) injured eye significantly increased Foxp3+ Tregs in the retina compared to that of saline-injected I/R eyes. Furthermore, iMSC injected I/R eyes significantly decreased retinal inflammation as evidenced by reduced gene expression of IL1β, VCAM1, LAMA5, and CCL2 and improved b-wave amplitudes compared to that of saline-injected I/R eyes. Our study demonstrates that iMSCs can transfer mitochondria to immune cells to suppress the effector T cell population. Additionally, our current data indicate that iMSC can enhance differentiation of T cells into Foxp3 Tregs in vitro and therapeutically improve the retina's immune function by upregulation of Tregs to decrease inflammation and reduce I/R injury-induced retinal degeneration in vivo.

| S-EPMC8616393 | biostudies-literature

Proteomics Profiling of mesenchymal stem cell-derived microvesicles

Project description:Recently, mesenchymal stem cells-derived microvesicles (MMVs) attract much attention as a strategy of cell-free treatment. In our study, we found that MMVs could improve the organ dysfunction during sepsis. To investigate the mechanism, we harvested MMVs from mesenchymal stem cells to perform proteomic analysis, and chondrocyte-derived microvesicles (CMVs) were used as a negative control, and PGC-1α overexpressed-MMVs were used as a positive control. A total of 5411 proteins were identified in this study, and differentially expressed (DE) proteins were further identified with a cut-off of absolute fold change >1.5 and a significance p-value <0.05. Compared with CMV group, 321 proteins were upregulated and 209 proteins were downregulated in MMVs. This study illustrated the differences between MMVs and CMVs, and provided a sight for investigating the protective effect of MMVs.

2021-06-08 | PXD026344 | Pride

Mesenchymal Stem Cell-Derived Microvesicles Support Ex Vivo Expansion of Cord Blood-Derived CD34(+) Cells.

Project description:Mesenchymal stem cells (MSCs) are known to support the characteristic properties of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow hematopoietic microenvironment. MSCs are used in coculture systems as a feeder layer for the ex vivo expansion of umbilical cord blood (CB) to increase the relatively low number of HSPCs in CB. Findings increasingly suggest that MSC-derived microvesicles (MSC-MVs) play an important role in the biological functions of their parent cells. We speculate that MSC-MVs may recapitulate the hematopoiesis-supporting effects of their parent cells. In the current study, we found MSC-MVs containing microRNAs that are involved in the regulation of hematopoiesis. We also demonstrated that MSC-MVs could improve the expansion of CB-derived mononuclear cells and CD34(+) cells and generate a greater number of primitive progenitor cells in vitro. Additionally, when MSC-MVs were added to the CB-MSC coculture system, they could improve the hematopoiesis-supporting effects of MSCs. These findings highlight the role of MSC-MVs in the ex vivo expansion of CB, which may offer a promising therapeutic approach in CB transplantation.

| S-EPMC4799819 | biostudies-literature

Effect of Mesenchymal Stem Cell-derived Microvesicles on Megakaryocytic Differentiation of CD34+ Hematopoietic Stem Cells.

Project description:Purpose: Mesenchymal stem cells (MSCs) release hematopoietic cytokines, growth factors, and Microvesicles (MVs) supporting the hematopoietic stem cells (HSCs). MVs released from various cells, playing a crucial role in biological functions of their parental cells. MSC-derived MVs contain microRNAs and proteins with key roles in the regulation of hematopoiesis. Umbilical cord blood (UCB) is a source for transplantation but the long-term recovery of platelets is a main problem. Therefore, we intend to show that MSC-MVs are able to improve the differentiation of UCB-derived CD34+ cells to megakaryocyte lineage. Methods: In this descriptive study, MSCs were cultured in DMEM to collect the culture supernatant, which was ultracentrifuged for the isolation of MVs. HSCs were isolated from UCB using MACS method and cultured in IMDM supplemented with cytokines and MVs in three different conditions. Megakaryocyte differentiation was evaluated through the expression of specific markers and genes after 72 hours, and the data was analyzed by t test (P<0.05). Results: The expression of specific megakaryocyte markers (CD41 and CD61) in the presence of different concentrations of MSC-MVs did not show any significant difference. Also, the expression of specific genes of megakaryocyte lineage was compared with control group. The expression of GATA2 and c-Mpl was significantly increased, GATA1 was not significantly decreased, and FLI1 was significantly decreased. Conclusion: MSC-MVs could improve the expression of specific megakaryocyte genes; however, there was no significant expression of CD markers. Further studies, including the evaluation of late stages of megakaryocyte differentiation, are required to evaluate platelet production and shedding.

| S-EPMC7191234 | biostudies-literature

Therapeutic use of mesenchymal stem cell-derived extracellular vesicles in acute lung injury.

Project description:Acute respiratory distress syndrome is a major cause of respiratory failure in critically ill patients. Despite extensive research into its pathophysiology, mortality remains high. No effective pharmacotherapy exists. Based largely on numerous preclinical animal studies, administration of mesenchymal stem or stromal cell (MSC) as a therapeutic for acute lung injury (ALI) holds great promise, and Phase I and II clinical trials are currently under way internationally. However, concern for the use of stem cells, specifically the risk of iatrogenic tumor formation, as well as the prohibitive cost of production, storage, and distribution of cells in bone marrow transplant facilities, may limit access to this lifesaving therapy. Accumulating evidence now suggest that novel stem cell-derived therapies, including MSC-conditioned medium and extracellular vesicles (EVs) released from MSCs, might constitute compelling alternatives. The current review summarizes the preclinical studies testing MSC EVs as treatment for ALI and other inflammatory lung diseases. While certain logistic obstacles limit the clinical applications of MSC-conditioned medium such as the volume required for treatment and lack of standardization of what constitutes the components of conditioned medium, the therapeutic application of MSC EVs remains promising, primarily due to ability of EVs to maintain the functional phenotype of the parent cell. However, utilization of MSC EVs will require large-scale production and standardization concerning identification, characterization, and quantification.

| S-EPMC6368889 | biostudies-literature

Inducible pluripotent stem cell-derived mesenchymal stem cell therapy effectively protected kidney from acute ischemia-reperfusion injury.

Project description:This study tested whether inducible pluripotent stem cell (iPSC)-derived mesenchymal stem cell (MSC) therapy could effectively protect kidney from acute ischemia (1 h) - reperfusion (5 day) injury (IRI). Male-adult SD-rats (n = 24) were equally categorized into groups 1 (sham-control), 2 [sham-control + iPSC-MSC (1.2 × 106 cells/rat)], 3 (IR only) and 4 (IR + iPSC-MSC). Blood urine nitrogen/creatinine levels and ratio of urine protein to creatinine, kidney weight and expressions of inflammation (TNF-?/NF-?B), oxidative-stress (NOX-1/NOX-2/oxidized protein) and apoptosis (mitochondrial-Bax/cleaved caspase-3/PARP) were significantly higher in group 3 than in groups 1, 2 and 4 and significantly higher in group 4 than in groups 1 and 2 (all P<0.0001), but showed no differences between groups 1 and 2, whereas the protein expressions of anti-inflammation (IL-4/IL-10) and endothelial (CD31/vWF) markers exhibited an opposite pattern to inflammation among the four groups (all P<0.0001). Protein expressions of angiogenesis (VEGF/CXCR4/SDF-1?) markers progressively increased from groups 1 to 4 (all P<0.0001). Cellular expressions of kidney injury score/DNA-damage (?-H2AX)/apoptotic nuclei and glomerulus-tubular-damage (KIM/FSP-1) displayed an identical pattern to inflammation, whereas the cellular expressions of glomerulus-tubular-integrity (dystroglycan/podocin/p-cadherin/synaptopodin/ZO-1/fibronectin) revealed an opposite pattern to inflammation among the four groups (all P<0.0001). In conclusion, iPSC-derived MSC therapy effectively protected kidney against IRI.

| S-EPMC6220224 | biostudies-literature

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