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Mesenchymal stromal cell-derived extracellular vesicles reduce lung inflammation and damage in nonclinical acute lung injury: Implications for COVID-19

ABSTRACT: Mesenchymal stem cell derived extracellular vesicles (MSC-EVs) are bioactive particles that evoke beneficial responses in recipient cells. We identified a role for MSC-EV in immune modulation and cellular salvage in a model of SARS-CoV-2 induced acute lung injury (ALI) using pulmonary epithelial cells and exposure to cytokines or the SARS-CoV-2 receptor binding domain (RBD). Whereas RBD or cytokine exposure caused a pro-inflammatory cellular environment and injurious signaling, impairing alveolar-capillary barrier function, and inducing cell death, MSC-EVs reduced inflammation and reestablished target cell health. Importantly, MSC-EV treatment increased active ACE2 surface protein compared to RBD injury, identifying a previously unknown role for MSC-EV treatment in COVID-19 signaling and pathogenesis. The beneficial effect of MSC-EV treatment was confirmed in an LPS-induced rat model of ALI wherein MSC-EVs reduced pro-inflammatory cytokine secretion and respiratory dysfunction associated with disease. MSC-EV administration was dose-responsive, demonstrating a large effective dose range for clinical translation. These data provide direct evidence of an MSC-EV-mediated improvement in ALI and contribute new insights into the therapeutic potential of MSC-EVs in COVID-19 or similar pathologies of respiratory distress.

SUBMITTER: Cloer C

PROVIDER: S-EPMC8592477 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Mesenchymal Stromal Cell Derived Extracellular Vesicles Reduce Hypoxia-Ischaemia Induced Perinatal Brain Injury.

Project description:BackgroundNeonatal hypoxic-ischemic (HI) insult is a leading cause of disability and death in newborns, with therapeutic hypothermia being the only currently available clinical intervention. Thus there is a great need for adjunct and novel treatments for enhanced or alternative post-HI neuroprotection. Extracellular vesicles (EVs) derived from mesenchymal stromal/stem cells (MSCs) have recently been shown to exhibit regenerative effects in various injury models. Here we present findings showing neuroprotective effects of MSC-derived EVs in the Rice-Vannucci model of severe HI-induced neonatal brain insult.MethodsMesenchymal stromal/stem cell-derived EVs were applied intranasally immediately post HI-insult and behavioral outcomes were observed 48 h following MSC-EV treatment, as assessed by negative geotaxis. Brains were thereafter excised and assessed for changes in glial responses, cell death, and neuronal loss as markers of damage at 48 h post HI-insult.ResultsBrains of the MSC-EV treated group showed a significant decrease in microglial activation, cell death, and percentage tissue volume loss in multiple brain regions, compared to the control-treated groups. Furthermore, negative geotaxis test showed improved behavioral outcomes at 48 h following MSC-EV treatment.ConclusionOur findings highlight the clinical potential of using MSC-derived EVs following neonatal hypoxia-ischaemia.

| S-EPMC6433879 | biostudies-literature

Mesenchymal stromal cell-derived extracellular vesicles rescue radiation damage to murine marrow hematopoietic cells.

Project description:Mesenchymal stromal cells (MSCs) have been shown to reverse radiation damage to marrow stem cells. We have evaluated the capacity of MSC-derived extracellular vesicles (MSC-EVs) to mitigate radiation injury to marrow stem cells at 4?h to 7 days after irradiation. Significant restoration of marrow stem cell engraftment at 4, 24 and 168?h post irradiation by exposure to MSC-EVs was observed at 3 weeks to 9 months after transplant and further confirmed by secondary engraftment. Intravenous injection of MSC-EVs to 500cGy exposed mice led to partial recovery of peripheral blood counts and restoration of the engraftment of marrow. The murine hematopoietic cell line, FDC-P1 exposed to 500cGy, showed reversal of growth inhibition, DNA damage and apoptosis on exposure to murine or human MSC-EVs. Both murine and human MSC-EVs reverse radiation damage to murine marrow cells and stimulate normal murine marrow stem cell/progenitors to proliferate. A preparation with both exosomes and microvesicles was found to be superior to either microvesicles or exosomes alone. Biologic activity was seen in freshly isolated vesicles and in vesicles stored for up to 6 months in 10% dimethyl sulfoxide at -80?°C. These studies indicate that MSC-EVs can reverse radiation damage to bone marrow stem cells.

| S-EPMC5093052 | biostudies-literature

Mesenchymal Stromal Cell-Derived Extracellular Vesicles in Lung Diseases: Current Status and Perspectives.

Project description:Extracellular vesicles (EVs) have emerged as a potential therapy for several diseases. These plasma membrane-derived fragments are released constitutively by virtually all cell types-including mesenchymal stromal cells (MSCs)-under stimulation or following cell-to-cell interaction, which leads to activation or inhibition of distinct signaling pathways. Based on their size, intracellular origin, and secretion pathway, EVs have been grouped into three main populations: exosomes, microvesicles (or microparticles), and apoptotic bodies. Several molecules can be found inside MSC-derived EVs, including proteins, lipids, mRNA, microRNAs, DNAs, as well as organelles that can be transferred to damaged recipient cells, thus contributing to the reparative process and promoting relevant anti-inflammatory/resolutive actions. Indeed, the paracrine/endocrine actions induced by MSC-derived EVs have demonstrated therapeutic potential to mitigate or even reverse tissue damage, thus raising interest in the regenerative medicine field, particularly for lung diseases. In this review, we summarize the main features of EVs and the current understanding of the mechanisms of action of MSC-derived EVs in several lung diseases, such as chronic obstructive pulmonary disease (COPD), pulmonary infections [including coronavirus disease 2019 (COVID-19)], asthma, acute respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis (IPF), and cystic fibrosis (CF), among others. Finally, we list a number of limitations associated with this therapeutic strategy that must be overcome in order to translate effective EV-based therapies into clinical practice.

| S-EPMC7917181 | biostudies-literature

Effects of Mesenchymal Stromal Cell-Derived Extracellular Vesicles in Lung Diseases: Current Status and Future Perspectives.

Project description:Mesenchymal stromal cells (MSCs) as a kind of pluripotent adult stem cell have shown great therapeutic potential in relation to many diseases in anti-inflammation and regeneration. The results of preclinical experiments and clinical trials have demonstrated that MSC-derived secretome possesses immunoregulatory and reparative abilities and that this secretome is capable of modulating innate and adaptive immunity and reprograming the metabolism of recipient cells via paracrine mechanisms. It has been recognized that MSC-derived secretome, including soluble proteins (cytokines, chemokines, growth factors, proteases), extracellular vesicles (EVs) and organelles, plays a key role in tissue repair and regeneration in bronchopulmonary dysplasia, acute respiratory distress syndrome (ARDS), bronchial asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), pulmonary arterial hypertension, and silicosis. This review summarizes the known functions of MSC-EV modulation in lung diseases, coupled with the future challenges of MSC-EVs as a new pharmaceutical agent. The identification of underlying mechanisms for MSC-EV might provide a new direction for MSC-centered treatment in lung diseases.Graphical abstract.

| S-EPMC7675022 | biostudies-literature

Clinical potential of mesenchymal stem/stromal cell-derived extracellular vesicles.

Project description:Within the last two decades mesenchymal stem/stromal cells (MSCs) emerged after hematopoietic stem cells as the second most investigated and applied somatic stem cell entity so far. MSCs mediate immunosuppressive as well as pro-regenerative activities. Against the initial assumption, MSCs may not primarily exert their therapeutic functions in a cellular but rather in a paracrine manner. Here, extracellular vesicles (EVs), such as exosomes and microvesicles, have been identified as major mediators of these paracrine effects. Meanwhile, MSC-EVs have been applied to an increasing amount of different animal models and were tested in a patient suffering from steroid-refractory acute graft-versus-host disease (acute GvHD) as well as in a patient cohort with chronic kidney disease. So far, the MSC-EV administration appears to be safe in humans and all tested animal models. Improvements were reported in all settings. Thus, MSC-EVs appear as promising novel therapeutic agents which might help to improve disease associated symptoms in millions of patients. Here, we review some of the milestones in the field, briefly discuss challenges and highlight clinical aspects of acute GvHD and its treatment with MSCs and MSC-EVs.

| S-EPMC5676188 | biostudies-literature

Efficient Route to Label Mesenchymal Stromal Cell-Derived Extracellular Vesicles.

Project description:Recent research results report that extracellular vesicles (EVs) have a central role in both physiological and pathological processes involving intercellular communication. Herein, a simple EVs labeling procedure based on the metabolic labeling of secreting cells (mesenchymal stroma cells, MSCs) with a fluorescein-containing bio-orthogonal dye is described. This procedure was carried out by incubating cells for 72 h with tetraacetylated N-azidoacetyl-d-mannosamine (Ac4ManNAz), a modified sugar containing an azido group that, upon incorporation on the external surface of the cytoplasmatic cell membrane, is specifically conjugated with cyclooctyne-modified fluorescein isothiocyanate (ADIBO-FITC). MSCs released fluorescent EVs did not need any further purification. Finally, cellular uptake and tracking of the fluorescein-labeled EVs were successfully assessed by targeting experiments with MSCs. The method appears of general applicability and it may be very useful opening new horizon on diagnostic and therapeutic protocols exploiting EVs.

| S-EPMC6072237 | biostudies-literature

Platelet-derived extracellular vesicles promote osteoinduction of mesenchymal stromal cells.

Project description:AimsPlatelet concentrates, like platelet-rich plasma (PRP) and platelet lysate (PL), are widely used in regenerative medicine, especially in bone regeneration. However, the lack of standard procedures and controls leads to high variability in the obtained results, limiting their regular clinical use. Here, we propose the use of platelet-derived extracellular vesicles (EVs) as an off-the-shelf alternative for PRP and PL for bone regeneration. In this article, we evaluate the effect of PL-derived EVs on the biocompatibility and differentiation of mesenchymal stromal cells (MSCs).MethodsEVs were obtained first by ultracentrifugation (UC) and then by size exclusion chromatography (SEC) from non-activated PL. EVs were characterized by transmission electron microscopy, nanoparticle tracking analysis, and the expression of CD9 and CD63 markers by western blot. The effect of the obtained EVs on osteoinduction was evaluated in vitro on human umbilical cord MSCs by messenger RNA (mRNA) expression analysis of bone markers, alkaline phosphatase activity (ALP), and calcium (Ca2+) content.ResultsOsteogenic differentiation of MSCs was confirmed when treated with UC-isolated EVs. In order to disprove that the effect was due to co-isolated proteins, EVs were isolated by SEC. Purer EVs were obtained and proved to maintain the differentiation effect on MSCs and showed a dose-dependent response.ConclusionPL-derived EVs present an osteogenic capability comparable to PL treatments, emerging as an alternative able to overcome PL and PRP limitations.Cite this article: Bone Joint Res 2020;9(10):667-674.

| S-EPMC7563034 | biostudies-literature

Mesenchymal stem cell-derived extracellular vesicles attenuate kidney inflammation.

Project description:Mesenchymal stem/stromal cells (MSCs) have distinct capability for renal repair, but may have safety concerns. MSC-derived extracellular vesicles emerged as a novel noncellular alternative. Using a porcine model of metabolic syndrome and renal artery stenosis we tested whether extracellular vesicles attenuate renal inflammation, and if this capacity is mediated by their cargo of the anti-inflammatory cytokine interleukin (IL) 10. Pigs with metabolic syndrome were studied after 16 weeks of renal artery stenosis untreated or treated four weeks earlier with a single intrarenal delivery of extracellular vesicles harvested from adipose tissue-derived autologous MSCs. Lean and sham metabolic syndrome animals served as controls (seven each). Five additional pigs with metabolic syndrome and renal artery stenosis received extracellular vesicles with pre-silenced IL10 (IL10 knock-down). Single-kidney renal blood flow, glomerular filtration rate, and oxygenation were studied in vivo and renal injury pathways ex vivo. Retention of extracellular vesicles in the stenotic kidney peaked two days after delivery and decreased thereafter. Four weeks after injection, extracellular vesicle fragments colocalized with stenotic-kidney tubular cells and macrophages, indicating internalization or fusion. Extracellular vesicle delivery attenuated renal inflammation, and improved medullary oxygenation and fibrosis. 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 vesicles. These renoprotective effects were blunted in pigs treated with IL10-depleted extracellular vesicles. Thus, extracellular vesicle-based regenerative strategies might be useful for patients with metabolic syndrome and renal artery stenosis.

| S-EPMC5483390 | biostudies-literature

The Unsettling Ambiguity of Therapeutic Extracellular Vesicles from Mesenchymal Stromal Cells.

Project description: Not available

| S-EPMC7193795 | biostudies-literature

Dendritic Cell-derived Extracellular Vesicles mediate Mesenchymal Stem/Stromal Cell recruitment.

Project description:Orchestration of bone repair processes requires crosstalk between different cell populations, including immune cells and mesenchymal stem/stromal cells (MSC). Extracellular vesicles (EV) as mediators of these interactions remain vastly unexplored. Here, we aimed to determine the mechanism of MSC recruitment by Dendritic Cells (DC), hypothesising that it would be mediated by EV. Primary human DC-secreted EV (DC-EV), isolated by ultracentrifugation, were characterized for their size, morphology and protein markers, indicating an enrichment in exosomes. DC-EV were readily internalized by human bone marrow-derived MSC, without impacting significantly their proliferation or influencing their osteogenic/chondrogenic differentiation. Importantly, DC-EV significantly and dose-dependently promoted MSC recruitment across a transwell system and enhanced MSC migration in a microfluidic chemotaxis assay. DC-EV content was analysed by chemokine array, indicating the presence of chemotactic mediators. Osteopontin and matrix metalloproteinase-9 were confirmed inside EV. In summary, DC-EV are naturally loaded with chemoattractants and can contribute to cell recruitment, thus inspiring the development of new tissue regeneration strategies.

| S-EPMC5431789 | biostudies-literature

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