Mesenchymal Stem Cell-derived Extracellular Vesicles for Renal Repair

Nargesi, Arash Aghajani; Lerman, Lilach O.; Eirin, Alfonso

doi:10.2174/1566523217666170412110724

Cited by 86 publications

(71 citation statements)

References 99 publications

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“…Collectively, these observations suggest that EVs produced by Lean-MSCs might mitigate cellular injury by modulating multiple reparative pathways. Current evidence suggests that MSC possess potent immunomodulatory properties that are primarily mediated by the release of EVs [36], which carry anti-inflammatory elements in the form of genes, proteins, and microRNAs [8,37]. Furthermore, we have recently shown that knocking down the anti-inflammatory gene IL-10 in MSC-derived EVs blunts their capacity to repair the poststenotic kidney, implying that the salutary effects of EVs are mediated by their anti-inflammatory cargo [9].…”

Section: Discussionmentioning

confidence: 99%

Metabolic Syndrome Interferes with Packaging of Proteins within Porcine Mesenchymal Stem Cell-Derived Extracellular Vesicles

Eirin

Zhu

Woollard

et al. 2019

Stem Cells Translational Medicine

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Mesenchymal stem/stromal cells (MSCs) release extracellular vesicles (EVs), which shuttle proteins to recipient cells, promoting cellular repair. We hypothesized that cardiovascular risk factors may alter the pattern of proteins packed within MSC‐derived EVs. To test this, we compared the protein cargo of EVs to their parent MSCs in pigs with metabolic syndrome (MetS) and Lean controls. Porcine MSCs were harvested from abdominal fat after 16 weeks of Lean‐ or MetS‐diet ( n = 5 each), and their EVs isolated. Following liquid chromatography mass spectrometry proteomic analysis, proteins were classified based on cellular component, molecular function, and protein class. Five candidate proteins were validated by Western blot. Clustering analysis was performed to identify primary functional categories of proteins enriched in or excluded from EVs. Proteomics analysis identified 6,690 and 6,790 distinct proteins in Lean‐ and MetS‐EVs, respectively. Differential expression analysis revealed that 146 proteins were upregulated and 273 downregulated in Lean‐EVs versus Lean‐MSCs, whereas 787 proteins were upregulated and 185 downregulated in MetS‐EVs versus MetS‐MSCs. Proteins enriched in both Lean‐ and MetS‐EVs participate in vesicle‐mediated transport and cell‐to‐cell communication. Proteins enriched exclusively in Lean‐EVs modulate pathways related to the MSC reparative capacity, including cell proliferation, differentiation, and activation, as well as transforming growth factor‐β signaling. Contrarily, proteins enriched only in MetS‐EVs are linked to proinflammatory pathways, including acute inflammatory response, leukocyte transendothelial migration, and cytokine production. Coculture with MetS‐EVs increased renal tubular cell inflammation. MetS alters the protein cargo of porcine MSC‐derived EVs, selectively packaging specific proinflammatory signatures that may impair their ability to repair damaged tissues. stem cells translational medicine 2019;8:430–440

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Section: Discussionmentioning

confidence: 99%

Metabolic Syndrome Interferes with Packaging of Proteins within Porcine Mesenchymal Stem Cell-Derived Extracellular Vesicles

Eirin

Zhu

Woollard

et al. 2019

Stem Cells Translational Medicine

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“…EVs are secreted by MSCs and are present in the original cell. A large amount of evidence has indicated that MSC-derived EVs can alleviate both acute and chronic kidney injury and preserve renal function, which has led to cell-free treatment in renal injury repair [5]. RNAs expressed in EVs are regarded as the most functional elements of renal injury repair, and the main RNAs in huMSC-derived EVs are miRNAs [7].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, huMSC-derived EVs also exhibit therapeutic effects in the repair of kidney injury. Furthermore, Nargesi et al have confirmed the therapeutic effects of MSC-derived EVs in a kidney injury model as well as the underlying mechanisms [5]. It has also been shown that RNAs, especially microRNAs (miRNAs), play key roles in kidney injury repair, and the main RNAs in EVs are miRNAs [6-8].…”

Section: Introductionmentioning

confidence: 99%

Comprehensive miRNA Analysis of Human Umbilical Cord-Derived Mesenchymal Stromal Cells and Extracellular Vesicles

Zou

Yan

Lin

et al. 2018

Kidney Blood Press Res

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Background/Aims: Mesenchymal stromal cells (MSCs) participate in the tissue-specific repair of many different organs, especially the kidney. Their effects are primarily mediated by the paracrine release of factors including extracellular vesicles (EVs), which are composed of micro-vesicles and exosomes. The corresponding microRNAs (miRNAs) of EVs are considered important for their biological functions. Methods: MSCs were cultured from the human umbilical cord, and EVs were isolated from the medium. The expression levels of miRNAs in MSCs and EVs were determined by microarray analysis, and gene ontology (GO) was used to analyze the functions of their target genes. Results: MSCs and EVs had similar miRNA expression profiles, with the exception of a small number of selectively enriched miRNAs. GO analysis indicated that, unlike MSCs, the target genes of EV-enriched miRNAs were associated with calcium channel regulation and cell junction activities, which may indicate that MSC and EVs have different regulatory properties. Angiogenesis, oxidative stress, and inflammatory signaling pathways related to the repair of renal injury were also analyzed, and EV-enriched miRNAs targeted genes associated with oxidative stress, T cell activation, and Toll-like receptor signaling. The miRNAs enriched in both MSCs and EVs targeted different genes in signaling pathways regulating angiogenesis and chemokine release. Conclusion: MSCs and their EVs shared similar miRNA component, and some selectively enriched miRNAs observed in MSCs and EVs may affect different target genes through some specific signaling pathways.

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“…Injected MSCs can inhibit tubular cell apoptosis and interstitial fibrosis while stimulating proliferation of tissuespecific progenitor cells. Although MSCs can engraft in renal tubular and endothelial cells, regenerative actions are primarily mediated by EVs (157,158).…”

Section: Extracellular Vesicles As a Therapeutic Tool In Renal Transpmentioning

confidence: 99%

Extracellular Vesicles as Mediators of Cellular Crosstalk Between Immune System and Kidney Graft

et al. 2020

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Extracellular vesicles (EVs) are known immune-modulators exerting a critical role in kidney transplantation (KT). EV bioactive cargo includes graft antigens, costimulatory/inhibitory molecules, cytokines, growth factors, and functional microRNAs (miRNAs) that may modulate expression of recipient cell genes. As paracrine factors, neutrophil-and macrophage-derived EVs exert immunosuppressive and immune-stimulating effects on dendritic cells, respectively. Dendritic cell-derived EVs mediate alloantigen spreading and modulate antigen presentation to T lymphocytes. At systemic level, EVs exert pleiotropic effects on complement and coagulation. Depending on their biogenesis, they can amplify complement activation or shed complement inhibitors and prevent cell lysis. Likewise, endothelial-and platelet-derived EVs can exert procoagulant/prothrombotic effects and also promote endothelial survival and angiogenesis after ischemic injury. Kidney endothelial-and tubular-derived EVs play a key role in ischemia-reperfusion injury (IRI) and during the healing process; additionally, they can trigger rejection by inducing both alloimmune and autoimmune responses. Endothelial EVs have procoagulant/pro-inflammatory effects and can release sequestered self-antigens, generating a tissue-specific autoimmunity. Renal tubule-derived EVs shuttle pro-fibrotic mediators (TGF-β and miR-21) to interstitial fibroblasts and modulate neutrophil and T-lymphocyte influx. These processes can lead to peritubular capillary rarefaction and interstitial fibrosis-tubular atrophy. Different EVs, including those from mesenchymal stromal cells (MSCs), have been employed as a therapeutic tool in experimental models of rejection and IRI. These particles protect tubular and endothelial cells (by inhibition of apoptosis and inflammation-fibrogenesis or by inducing autophagy) and stimulate tissue regeneration (by triggering angiogenesis, cell proliferation, and migration). Finally, urinary and serum EVs represent potential biomarkers for delayed graft function (DGF) and acute rejection. In conclusion, EVs sustain an intricate crosstalk between graft tissue and innate/adaptive immune systems. EVs play a major role in allorecognition, IRI, autoimmunity, and alloimmunity and are promising as biomarkers and therapeutic tools in KT.

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Mesenchymal Stem Cell-derived Extracellular Vesicles for Renal Repair

Cited by 86 publications

References 99 publications

Metabolic Syndrome Interferes with Packaging of Proteins within Porcine Mesenchymal Stem Cell-Derived Extracellular Vesicles

Metabolic Syndrome Interferes with Packaging of Proteins within Porcine Mesenchymal Stem Cell-Derived Extracellular Vesicles

Comprehensive miRNA Analysis of Human Umbilical Cord-Derived Mesenchymal Stromal Cells and Extracellular Vesicles

Extracellular Vesicles as Mediators of Cellular Crosstalk Between Immune System and Kidney Graft

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