scholarly journals Evaluation of the Effect of Mesenchymal Stem Cells on Cisplatin Induced Toxicity in Neuroblastoma Tumor Model

2021 ◽  
Vol 8 (12) ◽  
pp. 5836-5748
Author(s):  
Safiye Aktas ◽  
Yüksel Olgun ◽  
Hande Evin ◽  
Ayşe Pınar Erçetin ◽  
Tekincan Çağrı Aktaş ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Side Effects ◽  
Tumor Model ◽  
Research Area ◽  
High Dose ◽  
Treatment Groups ◽  
Neuroblastoma Tumor ◽  
Tumor Tissues ◽  
A Current

Objective: High-dose cisplatin (CDDP) causes dose-limiting side effects in neuroblastoma (NB) treatment. Mesenchymal stem cells (MSC) are a current research area. The aim of this study is to assess the interaction of MSC with CDDP in nude mouse NB model. Methods: Athymic male nude mice (n=28) thatbhad basal auditory tests, with subcutaneous NB were randomized to control, CDDP, MSC and CDDP+MSC treatment groups. Seven days later, hearing tests were repeatedand the animals were sacrificed. Necrosis, apoptosis and viabilitywere assessed in tumors. MSC rate within the tumor was assessed with flow cytometry for triple CD34+ CD44+ and CD117- expression. Expression of the cochlear cell proteins of calretinin, math-1 and myosin2A were immunohistochemically assessed. Results: Tumor tissues were found to have statistically significantly higher levels of necrosis in CDDP and CDDP+MSC groups. MSC did not change the tumor dimensions in the CDDP group. MSC group had higher triple CD34+ CD44+ and CD117- expression within tumor tissue compared to the control and CDDP groups. In the inner ear, the expression of cochlear cell proteins calretinin, math-1 and myosin2A were identified to be highest in MSC group. 15-decibel loss at 12, 16, 20 and 32 kHz frequencies with CDDP was resolved with MSC administration. Conclusion: MSC prevented hearing loss caused by CDDP without disrupting the antitumor effect of CDDP. Systemic MSC may be assessed for clinical use to reduce the side effects of CDDP.

Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals

Blood ◽  
2003 ◽  
Vol 102 (10) ◽  
pp. 3837-3844 ◽  
Author(s):  
Farida Djouad ◽  
Pascale Plence ◽  
Claire Bony ◽  
Philippe Tropel ◽  
Florence Apparailly ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Side Effects ◽  
Tumor Growth ◽  
Tumor Model ◽  
Bone Morphogenetic Protein 2 ◽  
Melanoma Tumor ◽  
Immunocompetent Mice

Abstract Mesenchymal stem cells (MSCs) are largely studied for their potential clinical use. Recently, they have gained further interest after demonstration of an immunosuppressive role. In this study, we investigated whether in vivo injection of MSCs could display side effects related to systemic immunosuppression favoring tumor growth. We first showed in vitro that the murine C3H10T1/2 (C3) MSC line and primary MSCs exhibit immunosuppressive properties in mixed lymphocyte reaction. We demonstrated that this effect is mediated by soluble factors, secreted only on “activation” of MSCs in the presence of splenocytes. Moreover, the immunosuppression is mediated by CD8+ regulatory cells responsible for the inhibition of allogeneic lymphocyte proliferation. We then demonstrated that the C3 MSCs expressing the human bone morphogenetic protein 2 (hBMP-2) differentiation factor were not rejected when implanted in various allogeneic immunocompetent mice and were still able to differentiate into bone. Importantly, using a murine melanoma tumor model, we showed that the subcutaneous injection of B16 melanoma cells led to tumor growth in allogeneic recipients only when MSCs were coinjected. Although the potential side effects of immunosuppression induced by MSCs have to be considered in further clinical studies, the usefulness of MSCs for various therapeutic applications still remains of great interest. (Blood. 2003;102:3837-3844)

scholarly journals EVALUATION OF THE EFFECT OF MESENCHYMAL STEM CELLS ON CHEMOTHERAPY RESPONSE FOR NEUROBLASTOMA TREATMENT IN AN EXPERIMENTAL ANIMAL MODEL

2020 ◽  
Author(s):  
Safiye Aktas ◽  
Yuksel Olgun ◽  
Hande Evin ◽  
Ayse Pinar Ercetin ◽  
Tekincan Cagri Aktas ◽  
...  
Keyword(s):  
Stem Cells ◽  
Flow Cytometry ◽  
Mesenchymal Stem Cells ◽  
Side Effects ◽  
Tumor Tissue ◽  
Statistical Significance ◽  
Annexin V ◽  
High Dose ◽  
Chemotherapy Response ◽  
Physiological Serum

ABSTRACTHigh-dose cisplatin (CDDP) causes dose-limiting side effects in neuroblastoma (NB) treatment. Mesenchymal stem cells (MSC) are a current research area in cellular treatments due to multipotential characteristics. The aim of this study is to assess the interaction of MSC with CDDP in an athymic nude mouse NB model. Athymic male nude mice (n=28) were injected subcutaneously with C1300 NB cell line. After tumor growth to 1 cm diameter in 7-10 days, mice were randomly assigned to one of 4 experimental groups of control, CDDP treatment, MSC treatment and CDDP+MSC treatment with 7 mice in each group. Animals had basal auditory tests performed and had physiological serum or CDDP (20 mg/kg) injected into the peritoneum and were intravenously injected with 1×105 MSC once. Seven days later, hearing tests were performed again and the animals were sacrificed. Tumor tissue was assessed in terms of necrosis, apoptosis and viability. Apoptosis was evaluated with annexin V+PI flow cytometry analysis and TUNEL. Additionally, the MSC rate within the tumor was assessed with flow cytometry for triple CD34+ CD44+ and CD117-expression. Additionally, liver, kidney, brain and cochlear tissue were analyzed with light microscopy in terms of systemic side effect profile. Expression of the cochlear cell proteins of calretinin, math-1 and myosin2A were immunohistochemically assessed in ear sections. Statistical analysis used the nonparametric Kruskal Wallis and Mann Whitney U tests with p<0.05 significance. Tumor tissues were found to have statistically significantly higher levels of necrosis in the CDDP group and CDDP+MSC group compared to the control and MSC groups (p=0.001, p=0.006). The CDDP+MSC group had lower tumor necrosis rates than the CDDP group but this was not observed to have statistical significance (p=0.05). MSC did not change the tumor dimensions in the CDDP group (p=0.557). The groups administered MSC had higher triple CD34+ CD44+ and CD117- expression within tumor tissue compared to the control and CDDP groups. In the inner ear, the expression of cochlear cell proteins calretinin, math-1 and myosin2A were identified to be highest in the groups administered MSC. Auditory tests observed that the 15-decibel loss at 12, 16, 20 and 32 kHz frequencies in both ears with CDDP was resolved with MSC administration. With this study, IV administration of MSC treatment was observed to prevent the hearing loss caused by CDDP without disrupting the antitumor effect of CDDP. Systemic MSC may be assessed for clinical use to reduce the side effects of CDDP.

scholarly journals Autologous Adipose-Derived Mesenchymal Stem Cells Combined with Shockwave Therapy Synergistically Ameliorates the Osteoarthritic Pathological Factors in Knee Joint

2021 ◽  
Vol 14 (4) ◽  
pp. 318
Author(s):  
Jai-Hong Cheng ◽  
Ke-Tien Yen ◽  
Wen-Yi Chou ◽  
Shun-Wun Jhan ◽  
Shan-Ling Hsu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Knee Joint ◽  
Synergistic Effects ◽  
Type Ii Collagen ◽  
High Dose ◽  
Trabecular Thickness ◽  
Treatment Groups ◽  
Shockwave Therapy ◽  
Morphogenetic Protein

Adipose-derived mesenchymal stem cells (ADSCs) and shockwave (SW) therapy have been shown to exert a chondroprotective effect for osteoarthritis (OA). The results of this study demonstrated that autologous ADSCs had dose-dependent and synergistic effects with SW therapy (0.25 mJ/mm2 with 800 impulses) in OA rat knee joint. Autologous, high-dose 2 × 106 ADSCs (ADSC2 group) combined with SW therapy significantly increased the bone volume, trabecular thickness, and trabecular number among in the treatment groups. ADSC2 combined with SW therapy significantly reduced the synovitis score and OARSI score in comparison with other treatments. In the analysis of inflammation-induced extracellular matrix factors of the articular cartilage in OA, the results displayed that ADSC2 combined with SW therapy had a greater than other treatments in terms of reducing tumor necrosis factor-inducible gene (TSG)-6 and proteoglycan (PRG)-4, in addition to increasing tissue inhibitor matrix metalloproteinase (TIMP)-1 and type II collagen. Furthermore, ADSC2 combined with SW therapy significantly reduced the expression of inflammation-induced bone morphogenetic protein (BMP)-2 and BMP-6. Therefore, the results demonstrated that ADSC2 combined with SW therapy had a synergistic effect to ameliorate osteoarthritic pathological factors in OA joints.

Mesenchymal Stem Cells and their Exosomes: Promising Therapeutics for Chronic Pain

2019 ◽  
Vol 14 (8) ◽  
pp. 644-653 ◽  
Author(s):  
Jinxuan Ren ◽  
Na Liu ◽  
Na Sun ◽  
Kehan Zhang ◽  
Lina Yu
Keyword(s):  
Stem Cells ◽  
Chronic Pain ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Side Effects ◽  
Human Life ◽  
Analgesic Effects ◽  
Pain Models ◽  
Inflammatory Drugs ◽  
Anxiety Depression

Chronic pain is a common condition that seriously affects the quality of human life with variable etiology and complicated symptoms; people who suffer from chronic pain may experience anxiety, depression, insomnia, and other harmful emotions. Currently, chronic pain treatments are nonsteroidal anti-inflammatory drugs and opioids; these drugs are demonstrated to be insufficient and cause severe side effects. Therefore, research into new therapeutic strategies for chronic pain is a top priority. In recent years, stem cell transplantation has been demonstrated to be a potent alternative for the treatment of chronic pain. Mesenchymal stem cells (MSCs), a type of pluripotent stem cell, exhibit multi-directional differentiation, promotion of stem cell implantation, and immune regulation; they have also been shown to exert analgesic effects in several chronic pain models. Exosomes produced by MSCs have been demonstrated to relieve painful symptoms with fewer side effects. In this review, we summarize the therapeutic use of MSCs in various chronic pain studies. We also discuss ways to enhance the treatment effect of MSCs. We predict in the future, cell-free therapies for chronic pain will develop from exosomes secreted by MSCs.

scholarly journals Bone marrow mesenchymal stem cells promote remyelination in spinal cord by driving oligodendrocyte progenitor cell differentiation via TNFα/RelB-Hes1 pathway: a rat model study of 2,5-hexanedione-induced neurotoxicity

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Shuangyue Li ◽  
Huai Guan ◽  
Yan Zhang ◽  
Sheng Li ◽  
Kaixin Li ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Statistical Significance ◽  
High Dose ◽  
Sprague Dawley ◽  
Oligodendrocyte Progenitor ◽  
Hes1 Expression ◽  
Marrow Mesenchymal Stem Cells

Abstract Background N-hexane, with its metabolite 2,5-hexanedine (HD), is an industrial hazardous material. Chronic hexane exposure causes segmental demyelination in the peripheral nerves, and high-dose intoxication may also affect central nervous system. Demyelinating conditions are difficult to treat and stem cell therapy using bone marrow mesenchymal stem cells (BMSCs) is a promising novel strategy. Our previous study found that BMSCs promoted motor function recovery in rats modeling hexane neurotoxicity. This work aimed to explore the underlying mechanisms and focused on the changes in spinal cord. Methods Sprague Dawley rats were intoxicated with HD (400 mg/kg/day, i.p, for 5 weeks). A bolus of BMSCs (5 × 107 cells/kg) was injected via tail vein. Demyelination and remyelination of the spinal cord before and after BMSC treatment were examined microscopically. Cultured oligodendrocyte progenitor cells (OPCs) were incubated with HD ± BMSC-derived conditional medium (BMSC-CM). OPC differentiation was studied by immunostaining and morphometric analysis. The expressional changes of Hes1, a transcription factor negatively regulating OPC-differentiation, were studied. The upstream Notch1 and TNFα/RelB pathways were studied, and some key signaling molecules were measured. The correlation between neurotrophin NGF and TNFα was also investigated. Statistical significance was evaluated using one-way ANOVA and performed using SPSS 13.0. Results  The demyelinating damage by HD and remyelination by BMSCs were evidenced by electron microscopy, LFB staining and NG2/MBP immunohistochemistry. In vitro cultured OPCs showed more differentiation after incubation with BMSC-CM. Hes1 expression was found to be significantly increased by HD and decreased by BMSC or BMSC-CM. The change of Hes1 was found, however, independent of Notch1 activation, but dependent on TNFα/RelB signaling. HD was found to increase TNFα, RelB and Hes1 expression, and BMSCs were found to have the opposite effect. Addition of recombinant TNFα to OPCs or RelB overexpression similarly caused upregulation of Hes1 expression. The secretion of NGF by BMSC and activation of NGF receptor was found important for suppression of TNFα production in OPCs. Conclusions  Our findings demonstrated that BMSCs promote remyelination in the spinal cord of HD-exposed rats via TNFα/RelB-Hes1 pathway, providing novel insights for evaluating and further exploring the therapeutical effect of BMSCs on demyelinating neurodegenerative disease.

scholarly journals Melatonin Inhibits the Ferroptotic Pathway in Rat Bone Marrow Mesenchymal Stem Cells by Activating the PI3K-AKT-mTOR Signaling Axis to Attenuate Steroid-induced Osteoporosis

2021 ◽  
Author(s):  
meng li ◽  
ning yang ◽  
li hao ◽  
wei zhou ◽  
lei li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Signaling ◽  
High Dose ◽  
Treatment Pathways ◽  
Marrow Mesenchymal Stem Cells

Abstract ObjectivesSteroid-induced osteoporosis (SIOP) is a secondary osteoporosis, which is a systemic bone disease characterized by low bone mass, bone microstructure damage, increased bone fragility, and easy fracture. However, the specific mechanism remains unclear. Glucocorticoid-induced death of osteoblasts and bone marrow mesenchymal stem cells (BMSCs) is an important factor in SIOP. Ferroptosis is an iron-dependent programmed cell death that differs from apoptosis, cell necrosis, and autophagy, which can be induced by many factors. Herein, we aimed to explore whether glucocorticoids (GCs) cause ferroptosis in BMSCs and determine possible treatment pathways and mechanisms of action. Melatonin (MT), a hormone secreted by the pineal gland, displays strong antioxidant abilities to scavenge free radicals and alleviates ferroptosis in many tissues and organs. MethodsIn this study, we used high-dose dexamethasone (DEX) to observe whether glucocorticoids induced ferroptosis in BMSCs. We then assessed whether MT can inhibit the ferroptotic pathway, thereby providing early protection against GC-induced SIOP, and investigated the signaling pathways involved.ResultsIn vitro experiments showed that MT intervention significantly improved GC-induced ferroptosis in BMSCs and significantly improved SIOP in vivo. Pathway analysis showed that MT improves ferroptosis by activating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) axis. MT upregulates expression of PI3K, which is an important regulator of ferroptosis resistance. PI3K activators mimic the anti-ferroptosis effect of MT, but after blocking the PI3K pathway, the effect of MT is weakened. Obviously, MT can protect against SIOP induced by GC. Notably, even after GC-induced ferroptosis begins, MT can confer protection against SIOP. ConclusionOur research confirms that GC-induced ferroptosis is closely related to SIOP. Melatonin can inhibit ferroptosis by activating the PI3K-AKT-mTOR signaling pathway, thereby reducing the occurrence of steroid-induced osteoporosis. Therefore, MT may provide a novel strategy for preventing and treating SIOP.

scholarly journals Phase I Trial of Intra-arterial Administration of Autologous Bone Marrow-Derived Mesenchymal Stem Cells in Patients with Multiple System Atrophy

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Seok Jong Chung ◽  
Tae Yong Lee ◽  
Yang Hyun Lee ◽  
KyoungWon Baik ◽  
Jin Ho Jung ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Multiple System Atrophy ◽  
Phase I ◽  
Dose Group ◽  
Low Dose ◽  
Autologous Bone Marrow ◽  
High Dose ◽  
Autologous Bone

Background. This study is aimed at investigating the safety and tolerability of the intra-arterial administration of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) in patients with multiple system atrophy- (MSA-) cerebellar type (MSA-C). Methods. This was a single-center, open-label phase I clinical trial in patients with MSA-C. A three-stage dose escalation scheme (low-dose, 3.0 × 10 5 cells/kg; medium-dose, 6.0 × 10 5 cells/kg; high-dose, 9.0 × 10 5 cells/kg) was applied to determine the maximum tolerated dose of intra-arterial administration of BM-MSCs based on the no-observed-adverse-effect level derived from the toxicity study. The occurrence of adverse events was evaluated 1 day before and 1, 14, and 28 days after BM-MSC therapy. Additionally, we assessed changes in the Unified MSA Rating Scale (UMSARS) score 3 months after BM-MSC treatment. Results. One serious adverse drug reaction (ADR) of leptomeningeal enhancement following the intra-arterial BM-MSC administration occurred in one patient in the low-dose group. The safety review of the Internal Monitoring Committee interpreted this as radiological evidence of the blood-brain barrier permeability for MSCs. No other ADRs were observed in the medium- or high-dose groups. In particular, no ischemic lesions on diffusion-weighted images were observed in any of the study participants. Additionally, the medium- and high-dose groups tended to show a slower increase in UMSARS scores than the low-dose group during the 3-month follow-up. Conclusion. The present study confirmed that a single intra-arterial administration of autologous BM-MSCs is a safe and promising neuroprotective strategy in patients with MSA-C.

scholarly journals Effect of Silicon, Titanium, and Zirconium Ion Implantation on NiTi Biocompatibility

2012 ◽  
Vol 2012 ◽  
pp. 1-16 ◽  
Author(s):  
L. L. Meisner ◽  
A. I. Lotkov ◽  
V. A. Matveeva ◽  
L. V. Artemieva ◽  
S. N. Meisner ◽  
...  
Keyword(s):  
Stem Cells ◽  
Flow Cytometry ◽  
Mesenchymal Stem Cells ◽  
Ion Implantation ◽  
Cell Counting ◽  
High Dose ◽  
Surface Layers ◽  
Test Flow ◽  
Ion Implanted

The objective of the work was to study the effect of high-dose ion implantation (HDII) of NiTi surface layers with Si Ti, or Zr, on the NiTi biocompatibility. The biocompatibility was judged from the intensity and peculiarities of proliferation of mesenchymal stem cells (MSCs) on the NiTi specimen surfaces treated by special mechanical, electrochemical, and HDII methods and differing in chemical composition, morphology, and roughness. It is shown that the ion-implanted NiTi specimens are nontoxic to rat MSCs. When cultivated with the test materials or on their surfaces, the MSCs retain the viability, adhesion, morphology, and capability for proliferationin vitro, as evidenced by cell counting in a Goryaev chamber, MTT test, flow cytometry, and light and fluorescence microscopy. The unimplanted NiTi specimens fail to stimulate MSC proliferation, and this allows the assumption of bioinertness of their surface layers. Conversely, the ion-implanted NiTi specimens reveal properties favorable for MSC proliferation on their surface.

scholarly journals Mesenchymal Stem Cells As Guideposts for Nanoparticle-Mediated Targeted Drug Delivery in Ovarian Cancer

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 965
Author(s):  
Buddhadev Layek ◽  
Mihir Shetty ◽  
Susheel Kumar Nethi ◽  
Drishti Sehgal ◽  
Timothy K. Starr ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Drug Delivery ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Solid Tumors ◽  
Efficient Delivery ◽  
Tumor Tissues ◽  
Specific Accumulation ◽  
Targeting Strategy ◽  
High Binding Affinity

Nanocarriers have been extensively utilized for the systemic targeting of various solid tumors and their metastases. However, current drug delivery systems, in general, suffer from a lack of selectivity for tumor cells. Here, we develop a novel two-step targeting strategy that relies on the selective accumulation of targetable synthetic receptors (i.e., azide moieties) in tumor tissues, followed by delivery of drug-loaded nanoparticles having a high binding affinity for these receptors. Mesenchymal stem cells (MSCs) were used as vehicles for the tumor-specific accumulation of azide moieties, while dibenzyl cyclooctyne (DBCO) was used as the targeting ligand. Biodistribution and antitumor efficacy studies were performed in both orthotopic metastatic and patient-derived xenograft (PDX) tumor models of ovarian cancer. Our studies show that nanoparticles are retained in tumors at a significantly higher concentration in mice that received azide-labeled MSCs (MSC-Az). Furthermore, we observed significantly reduced tumor growth (p < 0.05) and improved survival in mice receiving MSC-Az along with paclitaxel-loaded DBCO-functionalized nanoparticles compared to controls. These studies demonstrate the feasibility of a two-step targeting strategy for efficient delivery of concentrated chemotherapy for treating solid tumors.

scholarly journals Long-Term Quantitative Biodistribution and Side Effects of Human Mesenchymal Stem Cells (hMSCs) Engraftment in NOD/SCID Mice following Irradiation

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Sabine François ◽  
Benoit Usunier ◽  
Luc Douay ◽  
Marc Benderitter ◽  
Alain Chapel
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Side Effects ◽  
Total Body Irradiation ◽  
Human Mesenchymal Stem Cells ◽  
Scid Mice ◽  
Human Mscs ◽  
Long Term Treatment ◽  
Total Body

There is little information on the fate of infused mesenchymal stem cells (MSCs) and long-term side effects after irradiation exposure. We addressed these questions using human MSCs (hMSCs) intravenously infused to nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice submitted to total body irradiation (TBI) or local irradiation (abdominal or leg irradiation). The animals were sacrificed 3 to 120 days after irradiation and the quantitative and spatial distribution of hMSCs were studied by polymerase chain reaction (PCR). Following their infusion into nonirradiated animals, hMSCs homed to various tissues. Engraftment depended on the dose of irradiation and the area exposed. Total body irradiation induced an increased hMSC engraftment level compared to nonirradiated mice, while local irradiations increased hMSC engraftment locally in the area of irradiation. Long-term engraftment of systemically administered hMSCs in NOD/SCID mice increased significantly in response to tissue injuries produced by local or total body irradiation until 2 weeks then slowly decreased depending on organs and the configuration of irradiation. In all cases, no tissue abnormality or abnormal hMSCs proliferation was observed at 120 days after irradiation. This work supports the safe and efficient use of MSCs by injection as an alternative approach in the short- and long-term treatment of severe complications after radiotherapy for patients refractory to conventional treatments.

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