scholarly journals Enhanced anti-inflammatory effects of mesenchymal stromal cells mediated by the transient ectopic expression of CXCR4 and IL10

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Rosario Hervás-Salcedo ◽  
María Fernández-García ◽  
Miriam Hernando-Rodríguez ◽  
Oscar Quintana-Bustamante ◽  
Jose-Carlos Segovia ◽  
...  
Keyword(s):  
Transient Expression ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Therapeutic Potential ◽  
Ectopic Expression ◽  
In Vivo Studies ◽  
Anti Inflammatory ◽  
The Impact

Abstract Background Mesenchymal stromal cells (MSCs) constitute one of the cell types most frequently used in cell therapy. Although several studies have shown the efficacy of these cells to modulate inflammation in different animal models, the results obtained in human clinical trials have been more modest. Here, we aimed at improving the therapeutic properties of MSCs by inducing a transient expression of two molecules that could enhance two different properties of these cells. With the purpose of improving MSC migration towards inflamed sites, we induced a transient expression of the C-X-C chemokine receptor type 4 (CXCR4). Additionally, to augment the anti-inflammatory properties of MSCs, a transient expression of the anti-inflammatory cytokine, interleukin 10 (IL10), was also induced. Methods Human adipose tissue-derived MSCs were transfected with messenger RNAs carrying the codon-optimized versions of CXCR4 and/or IL10. mRNA-transfected MSCs were then studied, first to evaluate whether the characteristic phenotype of MSCs was modified. Additionally, in vitro and also in vivo studies in an LPS-induced inflamed pad model were conducted to evaluate the impact associated to the transient expression of CXCR4 and/or IL10 in MSCs. Results Transfection of MSCs with CXCR4 and/or IL10 mRNAs induced a transient expression of these molecules without modifying the characteristic phenotype of MSCs. In vitro studies then revealed that the ectopic expression of CXCR4 significantly enhanced the migration of MSCs towards SDF-1, while an increased immunosuppression was associated with the ectopic expression of IL10. Finally, in vivo experiments showed that the co-expression of CXCR4 and IL10 increased the homing of MSCs into inflamed pads and induced an enhanced anti-inflammatory effect, compared to wild-type MSCs. Conclusions Our results demonstrate that the transient co-expression of CXCR4 and IL10 enhances the therapeutic potential of MSCs in a local inflammation mouse model, suggesting that these mRNA-modified cells may constitute a new step in the development of more efficient cell therapies for the treatment of inflammatory diseases.

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 Exofucosylation of Adipose Mesenchymal Stromal Cells Alters Their Secretome Profile

2020 ◽  
Vol 8 ◽  
Author(s):  
David García-Bernal ◽  
Mariano García-Arranz ◽  
Ana I. García-Guillén ◽  
Ana M. García-Hernández ◽  
Miguel Blanquer ◽  
...  
Keyword(s):  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Culture Conditions ◽  
Peripheral Tissues ◽  
Standard Culture ◽  
Anti Inflammatory ◽  
Selectin Binding ◽  
The Impact

Mesenchymal stromal cells (MSCs) constitute the cell type more frequently used in many regenerative medicine approaches due to their exclusive immunomodulatory properties, and they have been reported to mediate profound immunomodulatory effects in vivo. Nevertheless, MSCs do not express essential adhesion molecules actively involved in cell migration, a phenotypic feature that hampers their ability to home inflamed tissues following intravenous administration. In this study, we investigated whether modification by fucosylation of murine AdMSCs (mAdMSCs) creates Hematopoietic Cell E-/L-selectin Ligand, the E-selectin-binding CD44 glycoform. This cell surface glycan modification of CD44 has previously shown in preclinical studies to favor trafficking of mAdMSCs to inflamed or injured peripheral tissues. We analyzed the impact that exofucosylation could have in other innate phenotypic and functional properties of MSCs. Compared to unmodified counterparts, fucosylated mAdMSCs demonstrated higher in vitro migration, an altered secretome pattern, including increased expression and secretion of anti-inflammatory molecules, and a higher capacity to inhibit mitogen-stimulated splenocyte proliferation under standard culture conditions. Together, these findings indicate that exofucosylation could represent a suitable cell engineering strategy, not only to facilitate the in vivo MSC colonization of damaged tissues after systemic administration, but also to convert MSCs in a more potent immunomodulatory/anti-inflammatory cell therapy-based product for the treatment of a variety of autoimmune, inflammatory, and degenerative diseases.

scholarly journals Anti-Inflammatory Potential of Daturaolone from Datura innoxia Mill.: In Silico, In Vitro and In Vivo Studies

2021 ◽  
Vol 14 (12) ◽  
pp. 1248
Author(s):  
Muhammad Waleed Baig ◽  
Humaira Fatima ◽  
Nosheen Akhtar ◽  
Hidayat Hussain ◽  
Mohammad K. Okla ◽  
...  
Keyword(s):  
In Silico ◽  
Therapeutic Potential ◽  
In Vivo Studies ◽  
Metabolic Reaction ◽  
Datura Innoxia ◽  
In Vivo Models ◽  
Immobility Time ◽  
Anti Inflammatory

Exploration of leads with therapeutic potential in inflammatory disorders is worth pursuing. In line with this, the isolated natural compound daturaolone from Datura innoxia Mill. was evaluated for its anti-inflammatory potential using in silico, in vitro and in vivo models. Daturaolone follows Lipinski’s drug-likeliness rule with a score of 0.33. Absorption, distribution, metabolism, excretion and toxicity prediction show strong plasma protein binding; gastrointestinal absorption (Caco-2 cells permeability = 34.6 nm/s); no blood–brain barrier penetration; CYP1A2, CYP2C19 and CYP3A4 metabolism; a major metabolic reaction, being aliphatic hydroxylation; no hERG inhibition; and non-carcinogenicity. Predicted molecular targets were mainly inflammatory mediators. Molecular docking depicted H-bonding interaction with nuclear factor kappa beta subunit (NF-κB), cyclooxygenase-2, 5-lipoxygenase, phospholipase A2, serotonin transporter, dopamine receptor D1 and 5-hydroxy tryptamine. Its cytotoxicity (IC50) value in normal lymphocytes was >20 µg/mL as compared to cancer cells (Huh7.5; 17.32 ± 1.43 µg/mL). Daturaolone significantly inhibited NF-κB and nitric oxide production with IC50 values of 1.2 ± 0.8 and 4.51 ± 0.92 µg/mL, respectively. It significantly reduced inflammatory paw edema (81.73 ± 3.16%), heat-induced pain (89.47 ± 9.01% antinociception) and stress-induced depression (68 ± 9.22 s immobility time in tail suspension test). This work suggests a possible anti-inflammatory role of daturaolone; however, detailed mechanistic studies are still necessary to corroborate and extrapolate the findings.

Transient ectopic expression of CXCR4 and IL10 enhances in vivo anti-inflammatory potential of human mesenchymal stromal cells

Cytotherapy ◽  
2020 ◽  
Vol 22 (5) ◽  
pp. S60
Author(s):  
M. Hervas-Salcedo ◽  
M. Fernandez-Garcia ◽  
M. Hernando-Rodriguez ◽  
Ó. Quintana ◽  
J. Segovia ◽  
...  
Keyword(s):  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Ectopic Expression ◽  
Human Mesenchymal Stromal Cells ◽  
Anti Inflammatory

scholarly journals The Impact of Various Culture Conditions on Human Mesenchymal Stromal Cells Metabolism

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Pavla Tonarova ◽  
Katerina Lochovska ◽  
Robert Pytlik ◽  
Marie Hubalek Kalbacova
Keyword(s):  
Human Serum ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Reciprocal Relationship ◽  
Heat Inactivation ◽  
High Quality ◽  
Native Form ◽  
The Impact

In vitro and in vivo analyses are closely connected, and the reciprocal relationship between the two comprises a key assumption with concern to the conducting of meaningful research. The primary purpose of in vitro analysis is to provide a solid background for in vivo and clinical study purposes. The fields of cell therapy, tissue engineering, and regenerative medicine depend upon the high quality and appropriate degree of the expansion of mesenchymal stromal cells (MSCs) under low-risk and well-defined conditions. Hence, it is necessary to determine suitable alternatives to fetal bovine serum (FBS—the laboratory gold standard) that comply with all the relevant clinical requirements and that provide the appropriate quantity of high-quality cells while preserving the required properties. Human serum (autologous and allogeneic) and blood platelet lysates and releasates are currently considered to offer promising and relatively well-accessible MSC cultivation alternatives. Our study compared the effect of heat-inactivated FBS on MSC metabolism as compared to its native form (both are used as the standard in laboratory practice) and to potential alternatives with concern to clinical application—human serum (allogeneic and autologous) or platelet releasate (PR-SRGF). The influence of the origin of the serum (fetal versus adult) was also determined. The results revealed the key impact of the heat inactivation of FBS on MSCs and the effectiveness of human sera and platelet releasates with respect to MSC behaviour (metabolic activity, proliferation, morphology, and cytokine production).

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 New Class of Anti-Inflammatory Therapeutics Based on Gold (III) Complexes in Intestinal Inflammation–Proof of Concept Based on In Vitro and In Vivo Studies

2021 ◽  
Vol 22 (6) ◽  
pp. 3121
Author(s):  
Julia B. Krajewska ◽  
Jakub Włodarczyk ◽  
Damian Jacenik ◽  
Radzisław Kordek ◽  
Przemysław Taciak ◽  
...  
Keyword(s):  
Mouse Model ◽  
Intestinal Inflammation ◽  
Therapeutic Potential ◽  
Gastrointestinal Diseases ◽  
Neutral Red ◽  
Water Soluble ◽  
In Vivo Studies ◽  
Anti Inflammatory

Inflammatory bowel diseases (IBD) are at the top of the worldwide rankings for gastrointestinal diseases as regards occurrence, yet efficient and side-effect-free treatments are currently unavailable. In the current study, we proposed a new concept for anti-inflammatory treatment based on gold (III) complexes. A new gold (III) complex TGS 121 was designed and screened in the in vitro studies using a mouse macrophage cell line, RAW264.7, and in vivo, in the dextran sulphate sodium (DSS)-induced mouse model of colitis. Physicochemical studies showed that TGS 121 was highly water-soluble; it was stable in water, blood, and lymph, and impervious to sunlight. In lipopolysaccharide (LPS)-stimulated RAW264.7 cells, the complex showed a potent anti-inflammatory profile, as evidenced in neutral red uptake and Griess tests. In the DSS-induced mouse model of colitis, the complex administered in two doses (1.68 μg/kg, intragastrically, and 16.8 μg/kg, intragastrically, once daily) produced a significant (* p < 0.05) anti-inflammatory effect, as shown by macroscopic score. The mechanism of action of TGS 121 was related to the enzymatic and non-enzymatic antioxidant system; moreover, TGS 121 induced changes in the tight junction complexes expression in the intestinal wall. This is the first study proving that gold (III) complexes may have therapeutic potential in the treatment of IBD.

scholarly journals Inflammation and Hypoxia Negatively Impact the Survival and Immunosuppressive Properties of Mesenchymal Stromal Cells In Vitro

2021 ◽  
Vol 31 (3) ◽  
pp. 547-554
Author(s):  
Carmen Alexandra NECULACHI ◽  
◽  
Livia Ioana LETI ◽  
Alexandrina BURLACU ◽  
Mihai Bogdan PREDA ◽  
...  
Keyword(s):  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Therapeutic Potential ◽  
No Production ◽  
Low Oxygen ◽  
Post Transplantation ◽  
Murine Bone Marrow ◽  
Cell Mortality

Mesenchymal stromal cells (MSC) are nonhematopoietic cells with fi broblast-like morphology and multipotent capacity that are widely used in pre-clinical and clinical investigations. Unfortunately, the efficiency of MSC treatment is hindered by the poor survival rate after transplantation at the damaged tissue. The goal of this study was to investigate the fate of MSC exposed to various stimuli mimicking the in vivo microenvironment post transplantation. To this aim, murine bone marrow–derived MSC were stimulated with IFNgama and TNFalfa under low oxygen (hypoxia) or atmospheric (normoxia) conditions for 24 to 72 hours, in order to better mimic an ischemic injury. The results showed that MSC pre-stimulation with TNFalfa and IFNgama enhanced immunosuppressive pathways by over-expression of NOS2, IDO, COX2 and production of NO. However, MSC viability was affected by these two cytokines in dose-dependent and time-dependent manners. Besides, priming with TNFalfa and/or IFNgama under low oxygen concentrations revealed that significantly increased cell mortality rate and decreased NO production. Our data suggest that both hypoxia and infl ammation could impact the cell survival after transplantation and reinforces the necessity of further investigations to better understand MSC behavior after transplantation in order to identify the MSC-based strategies with the highest therapeutic potential.

Human marrow-derived mesenchymal stromal cells decrease cisplatin renotoxicity in vitro and in vivo and enhance survival of mice post-intraperitoneal injection

2010 ◽  
Vol 299 (6) ◽  
pp. F1288-F1298 ◽  
Author(s):  
Nicoletta Eliopoulos ◽  
Jing Zhao ◽  
Manaf Bouchentouf ◽  
Kathy Forner ◽  
Elena Birman ◽  
...  
Keyword(s):  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Therapeutic Potential ◽  
Human Kidney ◽  
Chemotherapeutic Agents ◽  
Human Mscs ◽  
Proliferating Cells ◽  
Phosphorylated Akt

Acute kidney injury (AKI) can occur from the toxic side-effects of chemotherapeutic agents such as cisplatin. Bone marrow-derived mesenchymal stromal cells (MSCs) have demonstrated wide therapeutic potential often due to beneficial factors they secrete. The goal of this investigation was to evaluate in vitro the effect of human MSCs (hMSCs) secretome on cisplatin-treated human kidney cells, and in vivo the consequence of hMSCs intraperitoneal (ip) implantation in mice with AKI. Our results revealed that hMSCs-conditioned media improved survival of HK-2 human proximal tubular cells exposed to cisplatin in vitro. This enhanced survival was linked to increased expression of phosphorylated Akt (Ser473) and was reduced by a VEGF-neutralizing antibody. In vivo testing of these hMSCs established that ip administration in NOD-SCID mice decreased cisplatin-induced kidney function impairment, as demonstrated by lower blood urea nitrogen levels and higher survival. In addition, blood phosphorous and amylase levels were also significantly decreased. Moreover, hMSCs reduced the plasma levels of several inflammatory cytokines/chemokines. Immunohistochemical examination of kidneys showed less apoptotic and more proliferating cells. Furthermore, PCR indicated the presence of hMSCs in mouse kidneys, which also showed enhanced expression of phosphorylated Akt. In conclusion, our study reveals that hMSCs can exert prosurvival effects on renal cells in vitro and in vivo, suggests a paracrine contribution for kidney protective abilities of hMSCs delivered ip, and supports their clinical potential in AKI.

Sign in / Sign up

Export Citation Format

Share Document