scholarly journals Geranylgeraniol prevents zoledronic acid-mediated reduction of viable mesenchymal stem cells via induction of Rho-dependent YAP activation

2021 ◽  
Vol 8 (6) ◽  
pp. 202066
Author(s):  
Weerachai Singhatanadgit ◽  
Weerawan Hankamolsiri ◽  
Wanida Janvikul
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Zoledronic Acid ◽  
Cell Viability ◽  
Mevalonate Pathway ◽  
Intermediate Compound ◽  
Osteonecrosis Of The Jaw ◽  
Rhoa Activity ◽  
Positive Effects ◽  
Mediated Reduction

Long-term use of zoledronic acid (ZA) increases the risk of medication-related osteonecrosis of the jaw (MRONJ). This may be attributed to ZA-mediated reduction of viable mesenchymal stem cells (MSCs). ZA inhibits protein geranylgeranylation, thus suppressing cell viability and proliferation. Geranylgeraniol (GGOH), which is a naturally found intermediate compound in the mevalonate pathway, has positive effects against ZA. However, precise mechanisms by which GGOH may help preserve stem cell viability against ZA are not fully understood. The objective of this study was to investigate the cytoprotective mechanisms of GGOH against ZA. The results showed that while ZA dramatically decreased the number of viable MSCs, GGOH prevented this negative effect. GGOH-rescued ZA-exposed MSCs formed mineralization comparable to that produced by normal MSCs. Mechanistically, GGOH preserved the number of viable MSCs by its reversal of ZA-mediated Ki67 + MSC number reduction, cell cycle arrest and apoptosis. Moreover, GGOH prevented ZA-suppressed RhoA activity and YAP activation. The results also established the involvement of Rho-dependent YAP and YAP-mediated CDK6 in the cytoprotective ability of GGOH against ZA. In conclusion, GGOH preserves a pool of viable MSCs with osteogenic potency against ZA by rescuing the activity of Rho-dependent YAP activation, suggesting GGOH as a promising agent and YAP as a potential therapeutic target for MRONJ.

High Glucose Affects the Cytotoxic Potential of Rapamycin, Metformin and Hydrogen Peroxide in Cultured Human Mesenchymal Stem Cells

2019 ◽  
Vol 19 (9) ◽  
pp. 688-698 ◽  
Author(s):  
Azam Roohi ◽  
Mahin Nikougoftar ◽  
Hamed Montazeri ◽  
Shadisadat Navabi ◽  
Fazel Shokri ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Hydrogen Peroxide ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Cell Viability ◽  
High Glucose ◽  
Cell Cycle Distribution ◽  
Efficient Treatment ◽  
Chronic Hyperglycemia ◽  
Placental Mesenchymal Stem Cells

Background: Oxidative stress and chronic hyperglycemia are two major side effects of type 2 diabetes affecting all cell types including mesenchymal stem cells (MSCs). As a cell therapy choice, understanding the behavior of MSCs will provide crucial information for efficient treatment. Methods: Placental mesenchymal stem cells were treated with various concentrations of glucose, metformin, rapamycin, and hydrogen peroxide to monitor their viability and cell cycle distribution. Cellular viability was examined via the MTT assay. Cell cycle distribution was studied by propidium iodide staining and apoptosis was determined using Annexin Vpropidium iodide staining and flow cytometry. Involvement of potential signaling pathways was evaluated by Western blotting for activation of Akt, P70S6K, and AMPK. Results: The results indicated that high glucose augmented cell viability and reduced metformin toxic potential. However, the hydrogen peroxide and rapamycin toxicities were exacerbated. Conclusion: Our findings suggest that high glucose concentration has a major effect on placental mesenchymal stem cell viability in the presence of rapamycin, metformin and hydrogen peroxide in culture.

scholarly journals Efficacy of topical and systemic transplantation of mesenchymal stem cells in a rat model of diabetic ischemic wounds

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jianxin Yan ◽  
Jiaji Liang ◽  
Yingxuan Cao ◽  
Mariya M. El Akkawi ◽  
Xuan Liao ◽  
...  
Keyword(s):  
Stem Cells ◽  
Wound Healing ◽  
Mesenchymal Stem Cells ◽  
Chronic Wounds ◽  
Blood Perfusion ◽  
Systemic Administration ◽  
Critical Parameters ◽  
Administration Routes ◽  
Positive Effects ◽  
Systemic Treatments

Abstract Background Mesenchymal stem cells (MSCs) exert positive effects in chronic wounds. However, critical parameters, such as the most effective administration routes, remain unclear. Accordingly, the purpose of this study was to compare the effects of topical and systemic transplantation MSCs on diabetic ischemic wound healing and explored the underlying mechanisms. Method A diabetic ischemic wound model was created on the dorsal foot of type 2 diabetes mellitus (T2DM) rat. Bone marrow-derived mesenchymal stem cells (BM-MSCs) were administered via two routes: topical injection and intravenous (IV) infusion. Wound healing outcomes and blood glucose level were assessed dynamically. Meanwhile, blood flow recovery was evaluated in ischemic gastrocnemius muscles. The homing and transdifferentiation of mKate2-labeled BM-MSCs were assessed by fluorescence imaging and immunohistochemistry (IHC) analysis. Result Both topical and systemic treatments had a positive effect on the diabetic ischemic wound showing a significant reduction in wound area at day 14. Histological results showed an increase in the length of epithelial edges, collagen content, microvessel density in the wound bed, and a higher expression of vascular endothelial growth factor (VEGF). Meanwhile, systemic administration can ameliorate hyperglycemia and improve the blood perfusion of the ischemic hindlimb. BM-MSCs administered systemically were found distributed in wounded tissue and transdifferentiated into endothelial cells. Furthermore, BM-MSCs stimulated angiogenesis at wound sites by downregulating phosphatase and tensin homolog (PTEN) and activation of AKT signaling pathway. Conclusions The results demonstrated that both transplantation delivery method (topical and systemic) of BM-MSCs accelerated wound healing remarkably under pathological conditions. Nevertheless, systemic administration has the potential to ameliorate hyperglycemia and repair the damaged tissue.

scholarly journals Melatonin-Pretreated Mesenchymal Stem Cells Improved Cognition in a Diabetic Murine Model

2021 ◽  
Vol 12 ◽  
Author(s):  
Shaimaa Nasr Amin ◽  
Nivin Sharawy ◽  
Nashwa El Tablawy ◽  
Dalia Azmy Elberry ◽  
Mira Farouk Youssef ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Stem Cells ◽  
Animal Model ◽  
Mesenchymal Stem Cells ◽  
Synaptic Plasticity ◽  
Object Recognition ◽  
Ex Vivo ◽  
Type I ◽  
Positive Effects ◽  
Tnf Α

Diabetes mellitus (DM) is a multisystem endocrine disorder affecting the brain. Mesenchymal stem cells (MSCs) pretreated with Melatonin have been shown to increase the potency of MSCs. This work aimed to compare Melatonin, stem cells, and stem cells pretreated with Melatonin on the cognitive functions and markers of synaptic plasticity in an animal model of type I diabetes mellitus (TIDM). Thirty-six rats represented the animal model; six rats for isolation of MSCs and 30 rats were divided into five groups: control, TIDM, TIDM + Melatonin, TIDM + Stem cells, and TIDM + Stem ex vivo Melatonin. Functional assessment was performed with Y-maze, forced swimming test and novel object recognition. Histological and biochemical evaluation of hippocampal Neuroligin 1, Sortilin, Brain-Derived Neurotrophic Factor (BDNF), inducible nitric oxide synthase (iNOS), toll-like receptor 2 (TLR2), Tumor necrosis factor-alpha (TNF-α), and Growth Associated Protein 43 (GAP43). The TIDM group showed a significant decrease of hippocampal Neuroligin, Sortilin, and BDNF and a significant increase in iNOS, TNF-α, TLR2, and GAP43. Melatonin or stem cells groups showed improvement compared to the diabetic group but not compared to the control group. TIDM + Stem ex vivo Melatonin group showed a significant improvement, and some values were restored to normal. Ex vivo melatonin-treated stem cells had improved spatial working and object recognition memory and depression, with positive effects on glucose homeostasis, inflammatory markers levels and synaptic plasticity markers expression.

scholarly journals Quantitative assessment of the impact of cryopreservation on human bone marrow-derived mesenchymal stem cells: up to 24 h post-thaw and beyond

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Soukaina Bahsoun ◽  
Karen Coopman ◽  
Elizabeth C. Akam
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Cell Viability ◽  
Cell Lines ◽  
Metabolic Activity ◽  
Proliferation Rate ◽  
Human Bone ◽  
Human Bone Marrow ◽  
Apoptosis Level

Abstract Background The effects of cryopreservation on human bone marrow-derived mesenchymal stem cells (hBM-MSCs) are still ill-defined. In this study, a quantitative approach was adopted to measure several post-thaw cell attributes in order to provide an accurate reflection of the freezing and thawing impact. Methods Fresh and cryopreserved passage-matched cells from three different donors were discretely analysed and compared for their viability, apoptosis level, phenotypic marker expression, metabolic activity, adhesion potential, proliferation rate, colony-forming unit ability (CFUF) and differentiation potentials. Results The results of this study show that cryopreservation reduces cell viability, increases apoptosis level and impairs hBM-MSC metabolic activity and adhesion potential in the first 4 h after thawing. At 24 h post-thaw, cell viability recovered, and apoptosis level dropped but metabolic activity and adhesion potential remained lower than fresh cells. This suggests that a 24-h period is not enough for a full recovery. Beyond 24 h post-thaw, the observed effects are variable for the three cell lines. While no difference is observed in the pre- and post-cryopreservation proliferation rate, cryopreservation reduced the CFUF ability of two of the cell lines and variably affected the adipogenic and osteogenic differentiation potentials of the three cell lines. Conclusion The data collected in this study clearly show that fresh and cryopreserved hBM-MSCs are different, and these differences will inevitably introduce variabilities to the product and process development and subsequently imply financial losses. In order to avoid product divergence pre- and post-cryopreservation, effective strategies to mitigate freezing effects must be developed and implemented.

Comparison of Effects of Curcumin and Nano-curcumin on the Survival of Human-Derived Mesenchymal Stem Cells: An Experimental Study

2020 ◽  
Vol 11 (2) ◽  
pp. 148-155
Author(s):  
Pinjari Hameeda ◽  
Sandeep Katti ◽  
Rajkishore Jammalamadugu ◽  
Kishore Bhatt ◽  
Malleswara Rao Peram ◽  
...  
Keyword(s):  
Stem Cells ◽  
Experimental Study ◽  
Mesenchymal Stem Cells ◽  
Survival Rate ◽  
Cell Viability ◽  
Cell Survival ◽  
Dependent Manner ◽  
Cell Survival Rate ◽  
Post Hoc ◽  
Dose Dependent

Aim: To evaluate and compare the effect of curcumin (CUR) and Nano-curcumin (N-CUR) on human-derived mesenchymal stem cells (MSCs) in a dose-dependent manner. Materials and Methods: An experimental study performed with putative MSCs from a total of five systemically healthy subjects with chronic periodontitis. These putative MSCs were isolated by cell culture and were further characterized and identified by colony-forming unit assay and immunocytochemical analysis using cell surface markers CD105, CD146, CD45 and CD73. The identified MSCs were treated with different doses of CUR and N-CUR, and compared with α-minimum essential medium (α -MEM) for its cell viability by performing MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay for 48 and 72 hr. The statistically analysis was performed using one-way analysis of variance (ANOVA) followed by Tukey’s post hoc test and Bonferroni’s post hoc test. Results: Compared to the α-MEM group, both CUR and N-CUR treated cells have shown significantly ( P = .029) higher survival rate at lower concentration (0.1 and 0.5 µM/L), at 48 hr incubation. However, there was no statistically significant difference between the CUR and N-CUR groups on cell survival rate at both 48 and 72 hr incubation. When compared between the concentrations of the same group, significantly higher cell viability ( P = .001) was observed at lower concentrations (0.1, 0.5 µM/L) in both test groups after incubation for 48 and 72 hr. Conclusion: Both CUR and N-CUR have a dose-dependent effect on human derived MSCs survival when incubated for 48 hr, whereas N-CUR shows increased cell survival rate even at 72 hr of incubation. Although, the cautious use of CUR and N-CUR at higher concentrations is recommended.

scholarly journals Exosomes from Human Umbilical Cord Mesenchymal Stem Cells Reduce Damage from Oxidative Stress and the Epithelial-Mesenchymal Transition in Renal Epithelial Cells Exposed to Oxalate and Calcium Oxalate Monohydrate

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Dian Li ◽  
Dan Zhang ◽  
Bo Tang ◽  
Yue Zhou ◽  
Wenhao Guo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Calcium Oxalate ◽  
Cell Viability ◽  
Umbilical Cord ◽  
Calcium Oxalate Monohydrate ◽  
Human Umbilical Cord ◽  
Epithelial Markers ◽  
Mesenchymal Transformation

Objective. To investigate whether exosomes from human umbilical cord mesenchymal stem cells (hUC-MSCs) can protect against the toxic effects of oxalate and calcium oxalate monohydrate (COM) crystals in human proximal tubular epithelial (HK-2) cells. Methods. Exosomes were isolated from hUC-MSCs, purified by ultracentrifugation, and verified by examination of cell morphology using transmission electron microscopy and the presence of specific biomarkers. HK-2 cells received 1 of 4 treatments: control (cells alone), hUC-MSC exosomes, oxalate+COM, or oxalate+COM and hUC-MSC exosomes. Cell viability was determined using the MTT assay. Oxidative stress was determined by measuring LDH activity and the levels of H2O2, malondialdehyde (MDA), and reactive oxygen species (ROS). Expressions of N-cadherin, TGF-β, and ZO-1 were determined by immunofluorescence. Expressions of epithelial markers, mesenchymal markers, and related signaling pathway proteins were determined by western blotting. Results. After 48 h, cells in the oxalate+COM group lost their adhesion, appeared long, spindle-shaped, and scattered, and the number of cells had significantly decreased. The oxalate+COM treatment also upregulated TGF-β and mesenchymal markers, downregulated epithelial markers, increased the levels of LDH, H2O2, MDA, and ROS, decreased cell viability, and increased cell migration. The isolated exosomes had double-layer membranes, had hollow, circular, or elliptical shapes, had diameters mostly between 30 and 100 nm, and expressed CD9, CD63, and Alix. Treatment of HK-2 cells with hUC-MSC exosomes reversed or partly reversed all the effects of oxalate+COM. Conclusions. Exosomes from hUC-MSCs alleviate the oxidative injury and the epithelial-mesenchymal transformation of HK-2 cells that is induced by oxalate+COM.

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