scholarly journals Sustained Released of Bioactive Mesenchymal Stromal Cell-Derived Extracellular Vesicles from 3D-Printed Gelatin Methacrylate Hydrogels

2021 ◽  
Author(s):  
Louis J Born ◽  
Shannon T McLoughlin ◽  
Dipankar Dutta ◽  
Bhushan Mahadik ◽  
Xiaofeng Jia ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Stromal Cells ◽  
Mesenchymal Stromal Cell ◽  
Stromal Cell ◽  
Therapeutic Potential ◽  
Burst Release ◽  
Gap Closure ◽  
3D Printed ◽  
Rapid Clearance

Extracellular vesicles (EVs) represent an emerging class of therapeutics with significant potential and broad applicability. However, a general limitation is their rapid clearance after administration. Thus, methods to enable sustained EV release are of great potential value. Here, we demonstrate that EVs from mesenchymal stem/stromal cells (MSCs) can be incorporated into 3D-printed gelatin methacrylate (GelMA) hydrogel bioink, and that the initial burst release of EVs can be reduced by increasing the concentration of crosslinker during gelation. Further, the data show that MSC EV bioactivity in an endothelial gap closure assay is retained after the 3D printing and photocrosslinking processes. Our group previously showed that MSC EV bioactivity in this assay correlates with pro-angiogenic bioactivity in vivo, thus these results indicate therapeutic potential of MSC EV-laden GelMA bioinks.

scholarly journals Methods and efficacy of extracellular vesicles derived from mesenchymal stromal cells in animal models of disease: a preclinical systematic review protocol

2019 ◽  
Vol 8 (1) ◽  
Author(s):  
Alvin Tieu ◽  
Mitchell Slobodian ◽  
Dean A. Fergusson ◽  
Joshua Montroy ◽  
Dylan Burger ◽  
...  
Keyword(s):  
Systematic Review ◽  
Extracellular Vesicles ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Mesenchymal Stromal Cell ◽  
Stromal Cell ◽  
Extracellular Vesicle ◽  
Preclinical Studies ◽  
Tissue Source ◽  
Models Of Disease

Abstract Background Over the past decade, mesenchymal stromal cells have been increasingly investigated for their therapeutic potential in several different illnesses. However, cell therapy can be limited by potentially serious adverse events including cell embolus formation and tumorigenesis. Importantly, the protective effects of mesenchymal stromal cells are largely mediated by paracrine mechanisms including release of extracellular vesicles. This systematic review intends to synthesize the current knowledge of mesenchymal stromal cell-derived extracellular vesicles as a therapeutic option for preclinical models of disease, inflammation, or injury. Methods A systematic literature search of MEDLINE, Embase, and BIOSIS databases will be conducted. Interventional preclinical in vivo studies using extracellular vesicles derived from any tissue source of mesenchymal stromal cells will be included. Studies will be screened by abstract, and full-text by two independent reviewers. Eligible studies will undergo data extraction with subcategorization into domains based on disease. Methods utilized for extracellular vesicle characterization and isolation will be collected, as well as information on interventional traits, such as tissue source of mesenchymal stromal cells, dosage regimen, and vesicle modifications. Reported outcomes will be collected to determine which diseases studied may be impacted most from treatment with mesenchymal stromal cell-derived extracellular vesicles. Discussion This systematic review will summarize preclinical studies investigating the therapeutic efficacy of both small and large extracellular vesicles derived by mesenchymal stromal cells. Extracellular vesicles represent a possibility to harness the benefits of mesenchymal stromal cells with added benefits of reduced manufacturing costs and an improved safety profile. Hence, there has been an exponential increase in interest for developing this cell-free therapy with hundreds of preclinical studies published to date. However, a vast amount of heterogeneity between groups relates to methods of extracellular vesicle isolation, characterization, and study design. This review will capture this heterogeneity and identify the most commonly used and optimal approaches to evaluate mesenchymal stromal cell-derived extracellular vesicle treatment. A meta-analysis of outcomes within each disease domain will help elucidate which fields of research demonstrate promise for developing extracellular vesicles as a novel cell-free therapy. Summarizing this robust information on extracellular vesicles as an intervention can provide guidance for designing preclinical studies with hopes of future clinical translation.

scholarly journals Mesenchymal Stromal Cells From Emphysematous Donors and Their Extracellular Vesicles Are Unable to Reverse Cardiorespiratory Dysfunction in Experimental Severe Emphysema

2021 ◽  
Vol 9 ◽  
Author(s):  
Mariana A. Antunes ◽  
Cassia L. Braga ◽  
Tainá B. Oliveira ◽  
Jamil Z. Kitoko ◽  
Ligia L. Castro ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Therapeutic Potential ◽  
Chronic Obstructive ◽  
Severe Emphysema ◽  
Arginase 1 ◽  
The Impact

Although bone marrow-derived mesenchymal stromal cells (BM-MSCs) from patients with chronic obstructive pulmonary disease (COPD) appear to be phenotypically and functionally similar to BM-MSCs from healthy sources in vitro, the impact of COPD on MSC metabolism and mitochondrial function has not been evaluated. In this study, we aimed to comparatively characterize MSCs from healthy and emphysematous donors (H-MSCs and E-MSCs) in vitro and to assess the therapeutic potential of these MSCs and their extracellular vesicles (H-EVs and E-EVs) in an in vivo model of severe emphysema. For this purpose, C57BL/6 mice received intratracheal porcine pancreatic elastase once weekly for 4 weeks to induce emphysema; control animals received saline under the same protocol. Twenty-four hours after the last instillation, animals received saline, H-MSCs, E-MSCs, H-EVs, or E-EVs intravenously. In vitro characterization demonstrated that E-MSCs present downregulation of anti-inflammatory (TSG-6, VEGF, TGF-β, and HGF) and anti-oxidant (CAT, SOD, Nrf2, and GSH) genes, and their EVs had larger median diameter and lower average concentration. Compared with H-MSC, E-MSC mitochondria also exhibited a higher respiration rate, were morphologically elongated, expressed less dynamin-related protein-1, and produced more superoxide. When co-cultured with alveolar macrophages, both H-MSCs and E-MSCs induced an increase in iNOS and arginase-1 levels, but only H-MSCs and their EVs were able to enhance IL-10 levels. In vivo, emphysematous mice treated with E-MSCs or E-EVs demonstrated no amelioration in cardiorespiratory dysfunction. On the other hand, H-EVs, but not H-MSCs, were able to reduce the neutrophil count, the mean linear intercept, and IL-1β and TGF-β levels in lung tissue, as well as reduce pulmonary arterial hypertension and increase the right ventricular area in a murine model of elastase-induced severe emphysema. In conclusion, E-MSCs and E-EVs were unable to reverse cardiorespiratory dysfunction, whereas H-EVs administration was associated with a reduction in cardiovascular and respiratory damage in experimental severe emphysema.

scholarly journals Extracellular Vesicles from Interferon-γ–primed Human Umbilical Cord Mesenchymal Stromal Cells Reduce Escherichia coli–induced Acute Lung Injury in Rats

2019 ◽  
Vol 130 (5) ◽  
pp. 778-790 ◽  
Author(s):  
Amir K. Varkouhi ◽  
Mirjana Jerkic ◽  
Lindsay Ormesher ◽  
Stéphane Gagnon ◽  
Sakshi Goyal ◽  
...  
Keyword(s):  
Umbilical Cord ◽  
Extracellular Vesicles ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Mesenchymal Stromal Cell ◽  
Stromal Cell ◽  
Interferon Γ ◽  
Human Umbilical Cord ◽  
E Coli

Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Human umbilical cord mesenchymal stromal cells possess considerable therapeutic promise for acute respiratory distress syndrome. Umbilical cord mesenchymal stromal cells may exert therapeutic effects via extracellular vesicles, while priming umbilical cord mesenchymal stromal cells may further enhance their effect. The authors investigated whether interferon-γ–primed umbilical cord mesenchymal stromal cells would generate mesenchymal stromal cell–derived extracellular vesicles with enhanced effects in Escherichia coli (E. coli) pneumonia. Methods In a university laboratory, anesthetized adult male Sprague–Dawley rats (n = 8 to 18 per group) underwent intrapulmonary E. coli instillation (5 × 109 colony forming units per kilogram), and were randomized to receive (a) primed mesenchymal stromal cell–derived extracellular vesicles, (b) naïve mesenchymal stromal cell–derived extracellular vesicles (both 100 million mesenchymal stromal cell–derived extracellular vesicles per kilogram), or (c) vehicle. Injury severity and bacterial load were assessed at 48 h. In vitro studies assessed the potential for primed and naïve mesenchymal stromal cell–derived extracellular vesicles to enhance macrophage bacterial phagocytosis and killing. Results Survival increased with primed (10 of 11 [91%]) and naïve (8 of 8 [100%]) mesenchymal stromal cell–derived extracellular vesicles compared with vehicle (12 of 18 [66.7%], P = 0.038). Primed—but not naïve—mesenchymal stromal cell–derived extracellular vesicles reduced alveolar–arterial oxygen gradient (422 ± 104, 536 ± 58, 523 ± 68 mm Hg, respectively; P = 0.008), reduced alveolar protein leak (0.7 ± 0.3, 1.4 ± 0.4, 1.5 ± 0.7 mg/ml, respectively; P = 0.003), increased lung mononuclear phagocytes (23.2 ± 6.3, 21.7 ± 5, 16.7 ± 5 respectively; P = 0.025), and reduced alveolar tumor necrosis factor alpha concentrations (29 ± 14.5, 35 ± 12.3, 47.2 ± 6.3 pg/ml, respectively; P = 0.026) compared with vehicle. Primed—but not naïve—mesenchymal stromal cell–derived extracellular vesicles enhanced endothelial nitric oxide synthase production in the injured lung (endothelial nitric oxide synthase/β-actin = 0.77 ± 0.34, 0.25 ± 0.29, 0.21 ± 0.33, respectively; P = 0.005). Both primed and naïve mesenchymal stromal cell–derived extracellular vesicles enhanced E. coli phagocytosis and bacterial killing in human acute monocytic leukemia cell line (THP-1) in vitro (36.9 ± 4, 13.3 ± 8, 0.1 ± 0.01%, respectively; P = 0.0004) compared with vehicle. Conclusions Extracellular vesicles from interferon-γ–primed human umbilical cord mesenchymal stromal cells more effectively attenuated E. coli–induced lung injury compared with extracellular vesicles from naïve mesenchymal stromal cells, potentially via enhanced macrophage phagocytosis and killing of E. coli.

scholarly journals Mesenchymal Stromal Cell-Derived Extracellular Vesicles Regulate the Mitochondrial Metabolism via Transfer of miRNAs

2021 ◽  
Vol 12 ◽  
Author(s):  
Claire Loussouarn ◽  
Yves-Marie Pers ◽  
Claire Bony ◽  
Christian Jorgensen ◽  
Danièle Noël
Keyword(s):  
Energy Metabolism ◽  
Extracellular Vesicles ◽  
Stromal Cells ◽  
Mesenchymal Stromal Cell ◽  
Tissue Repair ◽  
Stromal Cell ◽  
Target Cells ◽  
Different Types ◽  
And Oxidative Stress

Mesenchymal stromal cells (MSCs) are the most commonly tested adult progenitor cells in regenerative medicine. They stimulate tissue repair primarily through the secretion of immune-regulatory and pro-regenerative factors. There is increasing evidence that most of these factors are carried on extracellular vesicles (EVs) that are released by MSCs, either spontaneously or after activation. Exosomes and microvesicles are the most investigated types of EVs that act through uptake by target cells and cargo release inside the cytoplasm or through interactions with receptors expressed on target cells to stimulate downstream intracellular pathways. They convey different types of molecules, including proteins, lipids and acid nucleics among which, miRNAs are the most widely studied. The cargo of EVs can be impacted by the culture or environmental conditions that MSCs encounter and by changes in the energy metabolism that regulate the functional properties of MSCs. On the other hand, MSC-derived EVs are also reported to impact the metabolism of target cells. In the present review, we discuss the role of MSC-EVs in the regulation of the energy metabolism and oxidative stress of target cells and tissues with a focus on the role of miRNAs.

Effects of Extracellular Vesicles Derived from Mesenchymal Stem/Stromal Cells on Liver Diseases

2019 ◽  
Vol 14 (5) ◽  
pp. 442-452 ◽  
Author(s):  
Wenjie Zheng ◽  
Yumin Yang ◽  
Russel Clive Sequeira ◽  
Colin E. Bishop ◽  
Anthony Atala ◽  
...  
Keyword(s):  
Regenerative Medicine ◽  
Extracellular Vesicles ◽  
Stromal Cells ◽  
Liver Diseases ◽  
Therapeutic Potential ◽  
Mechanisms Of Action ◽  
Therapeutic Effects ◽  
Chronic Liver Injury ◽  
Mediated Effects ◽  
Therapeutic Benefits

Therapeutic effects of Mesenchymal Stem/Stromal Cells (MSCs) transplantation have been observed in various disease models. However, it is thought that MSCs-mediated effects largely depend on the paracrine manner of secreting cytokines, growth factors, and Extracellular Vesicles (EVs). Similarly, MSCs-derived EVs also showed therapeutic benefits in various liver diseases through alleviating fibrosis, improving regeneration of hepatocytes, and regulating immune activity. This review provides an overview of the MSCs, their EVs, and their therapeutic potential in treating various liver diseases including liver fibrosis, acute and chronic liver injury, and Hepatocellular Carcinoma (HCC). More specifically, the mechanisms by which MSC-EVs induce therapeutic benefits in liver diseases will be covered. In addition, comparisons between MSCs and their EVs were also evaluated as regenerative medicine against liver diseases. While the mechanisms of action and clinical efficacy must continue to be evaluated and verified, MSCs-derived EVs currently show tremendous potential and promise as a regenerative medicine treatment for liver disease in the future.

scholarly journals Transformation-associated alterations in interactions between pre-B cells and fibronectin

Blood ◽  
1990 ◽  
Vol 76 (11) ◽  
pp. 2311-2320 ◽  
Author(s):  
FM Lemoine ◽  
S Dedhar ◽  
GM Lima ◽  
CJ Eaves
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Line ◽  
Cell Lines ◽  
Stromal Cells ◽  
Stromal Cell ◽  
Cell Attachment ◽  
Attachment Site ◽  
Receptor Antibodies

Abstract Marrow stromal elements produce as yet uncharacterized soluble growth factors that can stimulate the proliferation of murine pre-B cells, although close contact between these two cell types appears to ensure a better pre-B cell response. We have now shown that freshly isolated normal pre-B cells (ie, the B220+, surface mu- fraction of adult mouse bone marrow) adhere to fibronectin (FN) via an RGD cell-attachment site, as shown in a serum-free adherence assay, and they lose this functional ability on differentiation in vivo into B cells (ie, the B220+, surface mu+ fraction). Similarly, cells from an immortalized but stromal cell-dependent and nontumorigenic murine pre-B cell line originally derived from a Whitlock-Witte culture were also found to adhere to fibronectin (FN) via an RGD cell-attachment site. Moreover, in the presence of anti-FN receptor antibodies, the ability of this immortalized pre-B cell line to proliferate when co-cultured with a supportive stromal cell line (M2–10B4 cells) was markedly reduced (down to 30% of control). This suggests that pre-B cell attachment to FN on stromal cells may be an important component of the mechanism by which stromal cells stimulate normal pre-B cell proliferation and one that is no longer operative to control their more differentiated progeny. Two differently transformed pre-B cell lines, both of which are autocrine, stromal-independent, tumorigenic in vivo, and partially or completely differentiation-arrested at a very early stage of pre-B cell development, did not bind to FN. In addition, anti-FN receptor antibodies were much less effective in diminishing the ability of these tumorigenic pre-B cells to respond to M2–10B4 cell stimulation, which could still be demonstrated when the tumorigenic pre-B cells were co- cultured with M2–10B4 cells at a sufficiently low cell density. Analysis of cell surface molecules immunoprecipitated from both the nontumorigenic and tumorigenic pre-B cell lines by an anti-FN receptor antibody showed an increase in very late antigen (VLA) alpha chain(s) in both tumorigenic pre-B cell lines and a decrease in the beta 1 chain in one. Interestingly, all of the pre-B cell lines expressed similar amounts of messenger RNA for the beta 1 chain of the FN receptor. These results suggest that alteration of FN receptor expression on pre-B cells may represent a mechanism contributing to the outgrowth of leukemic pre-B cells with an autocrine phenotype and capable of stromal cell-independent, autonomous growth.

Sign in / Sign up

Export Citation Format

Share Document