scholarly journals Extracellular Vehicles of Oxygen-Depleted Mesenchymal Stromal Cells: Route to Off-Shelf Cellular Therapeutics?

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2199
Author(s):  
Dhir Gala ◽  
Sidhesh Mohak ◽  
Zsolt Fábián
Keyword(s):  
Extracellular Vesicles ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Cellular Therapy ◽  
Therapeutic Effects ◽  
Low Oxygen ◽  
Inflammatory Conditions ◽  
Promising Tool ◽  
Oxygen Conditions ◽  
Key Aspects

Cellular therapy is a promising tool of human medicine to successfully treat complex and challenging pathologies such as cardiovascular diseases or chronic inflammatory conditions. Bone marrow-derived mesenchymal stromal cells (BMSCs) are in the limelight of these efforts, initially, trying to exploit their natural properties by direct transplantation. Extensive research on the therapeutic use of BMSCs shed light on a number of key aspects of BMSC physiology including the importance of oxygen in the control of BMSC phenotype. These efforts also led to a growing number of evidence indicating that the beneficial therapeutic effects of BMSCs can be mediated by BMSC-secreted agents. Further investigations revealed that BMSC-excreted extracellular vesicles could mediate the potentially therapeutic effects of BMSCs. Here, we review our current understanding of the relationship between low oxygen conditions and the effects of BMSC-secreted extracellular vesicles focusing on the possible medical relevance of this interplay.

scholarly journals Stem cells out of the bag: characterization of ex vivo expanded mesenchymal stromal cells for possible clinical use

2020 ◽  
Vol 6 (3) ◽  
pp. FSO449
Author(s):  
Sérgio M Lopes ◽  
Susana Roncon ◽  
Filipa Bordalo ◽  
Fátima Amado ◽  
Sara Ferreira ◽  
...  
Keyword(s):  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Mononuclear Cells ◽  
Cellular Therapy ◽  
Ex Vivo ◽  
Clinical Settings ◽  
Proliferating Cells ◽  
Promising Tool ◽  
Expansion Protocol ◽  
And Function

Aim: Mesenchymal stromal cells (MSC) are a promising tool for cellular therapy and regenerative medicine. One major difficulty in establishing a MSC expansion protocol is the large volume of bone marrow (BM) required. We studied whether cells trapped within a collection bag and filter system could be considered as a source of MSC. Results: From the 20 BM collection bag and filter systems, we recovered an average of 1.68 × 108 mononuclear cells, which is the equivalent to 60 ml of filtered BM. Mononuclear cells were expanded ex vivo to 17 × 106 MSC, with purity shown by a CD44+, CD105+, CD90+ and CD73+ immunophenotype, a reduction of 20% proliferating cells in a mixed lymphocyte reaction and also the ability of adipocyte differentiation. Conclusion: Long-term MSC cultures were established from the usually discarded BM collection bag and filter, maintaining an appropriate phenotype and function, being suitable for both investigation and clinical settings.

scholarly journals Therapeutic effects of adipose-tissue-derived mesenchymal stromal cells and their extracellular vesicles in experimental silicosis

2018 ◽  
Vol 19 (1) ◽  
Author(s):  
Elga Bandeira ◽  
Helena Oliveira ◽  
Johnatas D. Silva ◽  
Rubem F. S. Menna-Barreto ◽  
Christina M. Takyia ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Extracellular Vesicles ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Therapeutic Effects ◽  
Experimental Silicosis

scholarly journals From Mesenchymal Stromal Cells to Engineered Extracellular Vesicles: A New Therapeutic Paradigm

2021 ◽  
Vol 9 ◽  
Author(s):  
Jancy Johnson ◽  
Mozhgan Shojaee ◽  
James Mitchell Crow ◽  
Ramin Khanabdali
Keyword(s):  
Stem Cell ◽  
Cell Therapy ◽  
Extracellular Vesicles ◽  
Mesenchymal Stromal Cells ◽  
Stem Cell Therapy ◽  
Stromal Cells ◽  
Therapeutic Effects ◽  
Paracrine Factor ◽  
Cell Source ◽  
Therapeutic Development

Mesenchymal stromal cells (MSCs) are multipotent cells obtained from many tissues including bone marrow, adipose tissue, umbilical cord, amniotic fluid, and placenta. MSCs are the leading cell source for stem cell therapy due to their regenerative and immunomodulatory properties, their low risk of tumorigenesis and lack of ethical constraints. However, clinical applications of MSCs remain limited. MSC therapeutic development continues to pose challenges in terms of preparation, purity, consistency, efficiency, reproducibility, processing time and scalability. Additionally, there are issues with their poor engraftment and survival in sites of disease or damage that limit their capacity to directly replace damaged cells. A key recent development in MSC research, however, is the now widely accepted view that MSCs primarily exert therapeutic effects via paracrine factor secretion. One of the major paracrine effectors are extracellular vesicles (EVs). EVs represent a potential cell-free alternative to stem cell therapy but are also rapidly emerging as a novel therapeutic platform in their own right, particularly in the form of engineered EVs (EEVs) tailored to target a broad range of clinical indications. However, the development of EVs and EEVs for therapeutic application still faces a number of hurdles, including the establishment of a consistent, scalable cell source, and the development of robust GMP-compliant upstream and downstream manufacturing processes. In this review we will highlight the clinical challenges of MSC therapeutic development and discuss how EVs and EEVs can overcome the challenges faced in the clinical application of MSCs.

scholarly journals Mesenchymal Stromal Cells Are More Effective Than Their Extracellular Vesicles at Reducing Lung Injury Regardless of Acute Respiratory Distress Syndrome Etiology

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Johnatas D. Silva ◽  
Ligia L. de Castro ◽  
Cassia L. Braga ◽  
Gisele P. Oliveira ◽  
Stefano A. Trivelin ◽  
...  
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Growth Factor ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Extracellular Vesicles ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Interleukin 6 ◽  
Distress Syndrome ◽  
Therapeutic Effects

Although mesenchymal stromal cells (MSCs) have demonstrated beneficial effects on experimental acute respiratory distress syndrome (ARDS), preconditioning may be required to potentiate their therapeutic effects. Additionally, administration of cell-free products, such as extracellular vesicles (EVs) obtained from MSC-conditioned media, might be as effective as MSCs. In this study, we comparatively evaluated the effects of MSCs, preconditioned or not with serum collected from mice with pulmonary or extrapulmonary ARDS (ARDSp and ARDSexp, respectively), and the EVs derived from these cells on lung inflammation and remodeling in ARDSp and ARDSexp mice. Administration of MSCs (preconditioned or not), but not their EVs, reduced static lung elastance, interstitial edema, and collagen fiber content in both ARDSp and ARDSexp. Although MSCs and EVs reduced alveolar collapse and neutrophil cell counts in lung tissue, therapeutic responses were superior in mice receiving MSCs, regardless of preconditioning. Despite higher total cell, macrophage, and neutrophil counts in bronchoalveolar lavage fluid in ARDSp than ARDSexp, MSCs and EVs (preconditioned or not) led to a similar decrease. In ARDSp, both MSCs and EVs, regardless of preconditioning, reduced levels of tumor necrosis factor- (TNF-) α, interleukin-6, keratinocyte chemoattractant (KC), vascular endothelial growth factor (VEGF), and transforming growth factor- (TGF-) β in lung homogenates. In ARDSexp, TNF-α, interleukin-6, and KC levels were reduced by MSCs and EVs, preconditioned or not; only MSCs reduced VEGF levels, while TGF-β levels were similarly increased in ARDSexp treated either with saline, MSCs, or EVs, regardless of preconditioning. In conclusion, MSCs yielded greater overall improvement in ARDS in comparison to EVs derived from the same number of cells and regardless of the preconditioning status. However, the effects of MSCs and EVs differed according to ARDS etiology.

scholarly journals Extracellular Vesicles from Mesenchymal Stromal Cells for the Treatment of Inflammation-Related Conditions

2021 ◽  
Vol 22 (6) ◽  
pp. 3023
Author(s):  
Sean T. Ryan ◽  
Elham Hosseini-Beheshti ◽  
Dinara Afrose ◽  
Xianting Ding ◽  
Binbin Xia ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Animal Studies ◽  
Therapeutic Potential ◽  
Early Stage ◽  
Small Animal ◽  
Therapeutic Effects ◽  
Anti Inflammatory

Over the past two decades, mesenchymal stromal cells (MSCs) have demonstrated great potential in the treatment of inflammation-related conditions. Numerous early stage clinical trials have suggested that this treatment strategy has potential to lead to significant improvements in clinical outcomes. While promising, there remain substantial regulatory hurdles, safety concerns, and logistical issues that need to be addressed before cell-based treatments can have widespread clinical impact. These drawbacks, along with research aimed at elucidating the mechanisms by which MSCs exert their therapeutic effects, have inspired the development of extracellular vesicles (EVs) as anti-inflammatory therapeutic agents. The use of MSC-derived EVs for treating inflammation-related conditions has shown therapeutic potential in both in vitro and small animal studies. This review will explore the current research landscape pertaining to the use of MSC-derived EVs as anti-inflammatory and pro-regenerative agents in a range of inflammation-related conditions: osteoarthritis, rheumatoid arthritis, Alzheimer’s disease, cardiovascular disease, and preeclampsia. Along with this, the mechanisms by which MSC-derived EVs exert their beneficial effects on the damaged or degenerative tissues will be reviewed, giving insight into their therapeutic potential. Challenges and future perspectives on the use of MSC-derived EVs for the treatment of inflammation-related conditions will be discussed.

scholarly journals Extracellular vesicles derived from umbilical cord mesenchymal stromal cells alleviate pulmonary fibrosis by means of transforming growth factor-β signaling inhibition

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Liyan Shi ◽  
Jing Ren ◽  
Jiping Li ◽  
Dongxu Wang ◽  
Yusu Wang ◽  
...  
Keyword(s):  
Growth Factor ◽  
Pulmonary Fibrosis ◽  
Umbilical Cord ◽  
Extracellular Vesicles ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
Therapeutic Effects

Abstract Background Pulmonary fibrosis (PF), the end point of interstitial lung diseases, is characterized by myofibroblast over differentiation and excessive extracellular matrix accumulation, leading to progressive organ dysfunction and usually a terminal outcome. Studies have shown that umbilical cord-derived mesenchymal stromal cells (uMSCs) could alleviate PF; however, the underlying mechanism remains to be elucidated. Methods The therapeutic effects of uMSC-derived extracellular vesicles (uMSC-EVs) on PF were evaluated using bleomycin (BLM)-induced mouse models. Then, the role and mechanism of uMSC-EVs in inhibiting myofibroblast differentiation were investigated in vivo and in vitro. Results Treatment with uMSC-EVs alleviated the PF and enhanced the proliferation of alveolar epithelial cells in BLM-induced mice, thus improved the life quality, including the survival rate, body weight, fibrosis degree, and myofibroblast over differentiation of lung tissue. Moreover, these effects of uMSC-EVs on PF are likely achieved by inhibiting the transforming growth factor-β (TGF-β) signaling pathway, evidenced by decreased expression levels of TGF-β2 and TGF-βR2. Using mimics of uMSC-EV-specific miRNAs, we found that miR-21 and miR-23, which are highly enriched in uMSC-EVs, played a critical role in inhibiting TGF-β2 and TGF-βR2, respectively. Conclusion The effects of uMSCs on PF alleviation are likely achieved via EVs, which reveals a new role of uMSC-EV-derived miRNAs, opening a novel strategy for PF treatment in the clinical setting.

scholarly journals Pro-Inflammatory Priming of Umbilical Cord Mesenchymal Stromal Cells Alters the Protein Cargo of Their Extracellular Vesicles

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 726
Author(s):  
Mairead Hyland ◽  
Claire Mennan ◽  
Emma Wilson ◽  
Aled Clayton ◽  
Oksana Kehoe
Keyword(s):  
Umbilical Cord ◽  
Extracellular Vesicles ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Protein Profile ◽  
Culture Conditions ◽  
Low Oxygen ◽  
Culture Environment ◽  
The Impact

Umbilical cord mesenchymal stromal cells (UCMSCs) have shown an ability to modulate the immune system through the secretion of paracrine mediators, such as extracellular vesicles (EVs). However, the culture conditions that UCMSCs are grown in can alter their secretome and thereby affect their immunomodulatory potential. UCMSCs are commonly cultured at 21% O2 in vitro, but recent research is exploring their growth at lower oxygen conditions to emulate circulating oxygen levels in vivo. Additionally, a pro-inflammatory culture environment is known to enhance UCMSC anti-inflammatory potential. Therefore, this paper examined EVs from UCMSCs grown in normal oxygen (21% O2), low oxygen (5% O2) and pro-inflammatory conditions to see the impact of culture conditions on the EV profile. EVs were isolated from UCMSC conditioned media and characterised based on size, morphology and surface marker expression. EV protein cargo was analysed using a proximity-based extension assay. Results showed that EVs had a similar size and morphology. Differences were found in EV protein cargo, with pro-inflammatory primed EVs showing an increase in proteins associated with chemotaxis and angiogenesis. This showed that the UCMSC culture environment could alter the EV protein profile and might have downstream implications for their functions in immunomodulation.

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.

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