Mesenchymal stem cell–derived extracellular vesicles attenuate kidney inflammation
TL;DR: Renal blood flow and glomerular filtration rate fell in metabolic syndrome and renal artery stenosis compared to metabolic syndrome, but was restored in pigs treated with extracellular vesicle-based regenerative strategies, and renoprotective effects were blunted in pigs treating with IL10-depleted extrace cellular vesicles.
About: This article is published in Kidney International.The article was published on 2017-07-01 and is currently open access. It has received 222 citations till now. The article focuses on the topics: Extracellular vesicle & Kidney.
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TL;DR: Current understanding of the immunomodulatory mechanisms of MSCs and issues related to their therapeutic application are discussed, which suggest the plasticity of immunoregulation by M SCs is controlled by the intensity and complexity of inflammatory stimuli.
Abstract: Mesenchymal stem cells (MSCs; also referred to as mesenchymal stromal cells) have attracted much attention for their ability to regulate inflammatory processes. Their therapeutic potential is currently being investigated in various degenerative and inflammatory disorders such as Crohn’s disease, graft-versus-host disease, diabetic nephropathy and organ fibrosis. The mechanisms by which MSCs exert their therapeutic effects are multifaceted, but in general, these cells are thought to enable damaged tissues to form a balanced inflammatory and regenerative microenvironment in the presence of vigorous inflammation. Studies over the past few years have demonstrated that when exposed to an inflammatory environment, MSCs can orchestrate local and systemic innate and adaptive immune responses through the release of various mediators, including immunosuppressive molecules, growth factors, exosomes, chemokines, complement components and various metabolites. Interestingly, even nonviable MSCs can exert beneficial effects, with apoptotic MSCs showing immunosuppressive functions in vivo. Because the immunomodulatory capabilities of MSCs are not constitutive but rather are licensed by inflammatory cytokines, the net outcomes of MSC activation might vary depending on the levels and the types of inflammation within the residing tissues. Here, we review current understanding of the immunomodulatory mechanisms of MSCs and the issues related to their therapeutic applications.
628 citations
TL;DR: Recent approaches and advances of EV-based therapies are covered, showing how EVs can potentiate tissue regeneration, participate in immune modulation, and function as potential alternatives to stem cell therapy and bioengineered EVs can act as delivery vehicles for therapeutic agents.
Abstract: Extracellular vesicles (EVs) are nanometer-sized, lipid membrane-enclosed vesicles secreted by most, if not all, cells and contain lipids, proteins, and various nucleic acid species of the source cell. EVs act as important mediators of intercellular communication that influence both physiological and pathological conditions. Given their ability to transfer bioactive components and surmount biological barriers, EVs are increasingly being explored as potential therapeutic agents. EVs can potentiate tissue regeneration, participate in immune modulation, and function as potential alternatives to stem cell therapy, and bioengineered EVs can act as delivery vehicles for therapeutic agents. Here, we cover recent approaches and advances of EV-based therapies.
512 citations
Cites background from "Mesenchymal stem cell–derived extra..."
...The reno-protective effects of MSC-EVs were attributed to vesicular IL-10 (33)....
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...M. A. Ruffner, S. H. Kim, N. R. Bianco, L. M. Francisco, A. H. Sharpe, P. D. Robbins, B7-1/2, but not PD-L1/2 molecules, are required on IL-10-treated tolerogenic DC and DC-derived exosomes for in vivo function....
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TL;DR: Unique EV features that are relevant for drug delivery are reviewed and emerging strategies to make use of those features for drug loading and targeted delivery are highlighted.
471 citations
TL;DR: ExoFlo is a promising therapeutic candidate for severe COVID-19 due to its safety profile, capacity to restore oxygenation, downregulate cytokine storm, and reconstitute immunity, and future RCTs are needed to determine ExoFlo therapeutic potential.
Abstract: This prospective nonrandomized open-label cohort study addresses the safety and efficacy of exosomes (ExoFlo™) derived from allogeneic bone marrow mesenchymal stem cells as treatment for severe COVID-19. During April 2020, ExoFlo was provided to 24 SARS-CoV-2 polymerase chain reaction-positive patients at a single hospital center, all of whom met criteria for severe COVID-19 as well as moderate-to-severe acute respiratory distress syndrome. Patients received a single 15 mL intravenous dose of ExoFlo and were evaluated for both safety and efficacy from days 1 to 14 post-treatment. All safety endpoints were met with no adverse events observed within 72 h of ExoFlo administration. A survival rate of 83% was observed. In total, 17 of 24 (71%) patients recovered, 3 of 24 (13%) patients remained critically ill though stable, and 4 of 24 (16%) patients expired for reasons unrelated to the treatment. Overall, after one treatment, patients' clinical status and oxygenation improved with an average pressure of arterial oxygen to fraction of inspired oxygen ratio (PaO2/FiO2) increase of 192% (P < 0.001). Laboratory values revealed significant improvements in absolute neutrophil count [mean reduction 32% (P value <0.001)] and lymphopenia with average CD3+, CD4+, and CD8+ lymphocyte counts increasing by 46% (P < 0.05), 45% (P < 0.05), and 46% (P < 0.001), respectively. Likewise, acute phase reactants declined, with mean C-reactive protein, ferritin, and D-dimer reduction of 77% (P < 0.001), 43% (P < 0.001), and 42% (P < 0.05), respectively. In conclusion, owing to its safety profile, capacity to restore oxygenation, downregulate cytokine storm, and reconstitute immunity, ExoFlo is a promising therapeutic candidate for severe COVID-19. Future randomized controlled trials (RCTs) are needed to determine ExoFlo therapeutic potential.
427 citations
TL;DR: Overall, this paper provides a general overview of MSC-exosomes as a new cell-free therapeutic paradigm and highlights the therapeutic potential of M SC-derived exosomes in liver, kidney, cardiovascular and neurological disease.
Abstract: Mesenchymal stem/stromal cells (MSCs) have been demonstrated to hold great potential for the treatment of several diseases. Their therapeutic effects are largely mediated by paracrine factors including exosomes, which are nanometer-sized membrane-bound vesicles with functions as mediators of cell-cell communication. MSC-derived exosomes contain cytokines and growth factors, signaling lipids, mRNAs, and regulatory miRNAs. Increasing evidence suggests that MSC-derived exosomes might represent a novel cell-free therapy with compelling advantages over parent MSCs such as no risk of tumor formation and lower immunogenicity. This paper reviews the characteristics of MSC exosomes and their fate after in vivo administration, and highlights the therapeutic potential of MSC-derived exosomes in liver, kidney, cardiovascular and neurological disease. Particularly, we summarize the recent clinical trials performed to evaluate the safety and efficacy of MSC exosomes. Overall, this paper provides a general overview of MSC-exosomes as a new cell-free therapeutic paradigm.
211 citations
Cites background from "Mesenchymal stem cell–derived extra..."
...adipose tissue-derived autologous MSCs renal artery stenosis TNF-α, IL-6, IL10 and IL-1-β [35]...
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...A single intrarenal administration of adipose tissue-derived autologous MSCs-derived EVs in pigs with renal artery stenosis attenuated renal inflammation, disclosed by decreased renal vein levels of several pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1-β....
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...Contrarily, renal vein levels of IL-10 increased in EV-treated pigs, associated with a shift from pro-inflammatory to reparative macrophages populating the stenotic kidney, underscoring the immunomodulatory potential of EVs [35]....
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References
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TL;DR: This comprehensive review summarizes current knowledge of EV uptake mechanisms and seems likely that a heterogeneous population of EVs may gain entry into a cell via more than one route.
Abstract: Extracellular vesicles (EVs) are small vesicles released by donor cells that can be taken up by recipient cells. Despite their discovery decades ago, it has only recently become apparent that EVs play an important role in cell-to-cell communication. EVs can carry a range of nucleic acids and proteins which can have a significant impact on the phenotype of the recipient. For this phenotypic effect to occur, EVs need to fuse with target cell membranes, either directly with the plasma membrane or with the endosomal membrane after endocytic uptake. EVs are of therapeutic interest because they are deregulated in diseases such as cancer and they could be harnessed to deliver drugs to target cells. It is therefore important to understand the molecular mechanisms by which EVs are taken up into cells. This comprehensive review summarizes current knowledge of EV uptake mechanisms. Cells appear to take up EVs by a variety of endocytic pathways, including clathrin-dependent endocytosis, and clathrin-independent pathways such as caveolin-mediated uptake, macropinocytosis, phagocytosis, and lipid raft–mediated internalization. Indeed, it seems likely that a heterogeneous population of EVs may gain entry into a cell via more than one route. The uptake mechanism used by a given EV may depend on proteins and glycoproteins found on the surface of both the vesicle and the target cell. Further research is needed to understand the precise rules that underpin EV entry into cells. Keywords: extracellular vesicles; EV uptake; EV internalization; cell–EV interaction; endocytosis; cell communication; exosomes (Published: 4 August 2014) Citation: Journal of Extracellular Vesicles 2014, 3 : 24641 - http://dx.doi.org/10.3402/jev.v3.24641
1,809 citations
TL;DR: This review deals with emerging evidence of an association between systemic or local hypoxia and inflammation in a variety of diseases and points to new ways of treating inflammatory disorders or conditions such as certain cancers with intralesional Hypoxia.
Abstract: This review deals with emerging evidence of an association between systemic or local hypoxia and inflammation in a variety of diseases. The evidence points to new ways of treating inflammatory disorders or conditions such as certain cancers with intralesional hypoxia.
1,603 citations
TL;DR: It is found that microvesicles derived from human bone marrow MSCs stimulated proliferation in vitro and conferred resistance of tubular epithelial cells to apoptosis, suggesting RNA-dependent biologic effects.
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.
1,135 citations
TL;DR: This review summarizes macrophage phenotype and function in the orchestration of kidney repair and replacement of specialized renal cells following injury and suggests new and exciting therapeutic possibilities to attenuate or conceivably reverse progressive renal disease in the context of fibrosis.
Abstract: Monocyte-derived macrophages can determine the outcome of the immune response and whether this response contributes to tissue repair or mediates tissue destruction. In addition to their important role in immune-mediated renal disease and host defense, macrophages play a fundamental role in tissue remodeling during embryonic development, acquired kidney disease, and renal allograft responses. This review summarizes macrophage phenotype and function in the orchestration of kidney repair and replacement of specialized renal cells following injury. Recent advances in our understanding of macrophage heterogeneity in response to their microenvironment raise new and exciting therapeutic possibilities to attenuate or conceivably reverse progressive renal disease in the context of fibrosis. Furthermore, parallels with pathological processes in many other organs also exist.
678 citations
TL;DR: Of the cell types known to produce exosomes, the readily available proliferative, immunosuppressive and clinically tested human mesenchymal stem cell (MSC) is the most prolific producer.
620 citations